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Purpose Prior to the 2020 release of a joint consensus guideline on monitoring of vancomycin therapy for serious methicillin-resistant Staphylococcus aureus (MRSA) infections, clinicians had escalated vancomycin doses for 2 decades while targeting trough concentrations of 15 to 20 µg/mL, leading to an increased frequency of nephrotoxicity. For MRSA infections, the 2020 guideline recommends adjusting doses to achieve a 24-hour area under the concentration-time curve (AUC) of 400 to 600 µg · h/mL; however, monitoring of trough concentrations has been entrenched for 3 decades. Calculating dose regimens based on AUC will require obtaining an increased number of vancomycin serum concentrations and, possibly, advanced software. The aim of this investigation was to determine the relationship between AUC and trough concentration and the influence of dosing regimen on goal achievement. Methods The relationship between trough concentration and AUC was explored through derivation of an equation based on a 1-compartment model and simulations. Results 24-hour AUC is related to dosing interval divided by half-life in a nonlinear fashion. The target trough concentration can be individualized to achieve a desired AUC range, and limiting use of large doses (>15-20 mg/kg) can protect against excessive 24-hour AUC with trough-only monitoring. Conclusion After initially determining pharmacokinetic parameters, subsequent monitoring of AUC can be accomplished using trough concentrations only. Trough concentration may be used as a surrogate for AUC, although the acceptable target trough concentration will vary depending on dosing interval and elimination rate constant. This work included development of an AUC-trough equation to establish a patient-specific target for steady-state trough concentration.

Objectives To investigate the population pharmacokinetics of posaconazole gastroresistant tablets in children with cystic fibrosis (CF) and perform simulations to recommend optimal doses. Patients and methods Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from pharmacy records. Relevant clinical data were collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A stepwise covariate model-building exercise evaluated the influence of interacting medicines and liver function. Results One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7–17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77%–83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 h for two doses then 300 mg once daily (OD) in children aged 6–11 years; and 86%–88% with a dose of 400 mg every 12 h for two doses then 400 mg OD in adolescents aged 12–17 years. This dose scheme also yielded a 90% probability of achieving an AUC of 30 mg·h/L. AUC and trough concentration were highly correlated (r2 = 0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30 mg·h/L in 90% of patients. Conclusions A starting dose of 300 mg OD in those aged 6–11 years and 400 mg OD in those aged 12–17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg·h/L.

BackgroundThe role of favipiravir as a treatment for COVID-19 is unclear, with discrepant activity against SARS-CoV-2in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. In Vero-E6 cells, high concentrations are needed to inhibit SARS-CoV-2 replication. The purpose of this analysis was to use available data to simulate intracellular pharmacokinetics of favipiravir ribofuranosyl-5⍰-triphosphate (FAVI-RTP) to better understand the putative applicability as a COVID-19 intervention.MethodsPreviously publishedin vitrodata for the intracellular production and elimination of FAVI- RTP in MDCK cells incubated with parent favipiravir was fitted with a mathematical model to describe the time course of intracellular FAVI-RTP concentrations as a function of incubation concentration of parent favipiravir. Parameter estimates from this model fitting were then combined with a previously published population PK model for the plasma exposure of parent favipiravir in Chinese patients with severe influenza (the modelled free plasma concentration of favipiravir substituting forin vitroincubation concentration) to predict the human intracellular FAVI-RTP pharmacokinetics.ResultsIn vitroFAVI-RTP data was adequately described as a function ofin vitroincubation media concentrations of parent favipiravir with an empirical model, noting that the model simplifies and consolidates various processes and is used under various assumptions and within certain limits. Parameter estimates from the fittings toin vitrodata predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP when driven by a predicted free plasma concentration profile.ConclusionThis modelling approach has several important limitations that are discussed in the main text of the manuscript. However, the simulations indicate that despite rapid clearance of the parent drug from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. Population average intracellular FAVI-RTP concentrations are estimated to maintain the Km for the SARS-CoV-2 polymerase for 3 days following 800 mg BID dosing and 9 days following 1200 mg BID dosing after a 1600 mg BID loading dose on day 1. Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.

Background Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSAs). Methods A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dnDSAs during the follow-up period and 420 did not. Results We found no significant relationship between TAC trough level during the follow-up period and dnDSA incidence. Patients who developed dnDSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P Conclusions There was no clear relationship between TAC trough level and dnDSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4–6 ng/mL during the immunosuppression maintenance period.

ObjectivesNephrotoxicity represents a major complication of vancomycin administration, leading to high rates of morbidity and treatment failure. The aim of this meta-analysis was to evaluate the association between trough levels and risk of renal impairment, by defining an exposure–toxicity relationship and assessing its accuracy in predicting the development of acute kidney injury (AKI).MethodsMedline, Scopus, CENTRAL, Clinicaltrials.gov and Google Scholar databases were systematically searched from inception. Studies examining the effects of trough levels on nephrotoxicity risk in adult patients were deemed eligible.ResultsThe meta-analysis was based on 60 studies, including 13 304 patients. The development of AKI was significantly linked to both higher initial [standardized mean difference (SMD): 0.82; 95% CI: 0.65–0.98] and maximum (SMD: 1.06; 95% CI: 0.82–1.29) trough levels. Dose–response analysis indicated a curvilinear relationship between trough levels and nephrotoxicity risk (χ2 = 127.1; P value ConclusionsThe present findings suggest that the development of vancomycin-induced AKI is significantly associated with higher initial and maximum trough levels. An exposure–response relationship was defined, indicating that increasing trough levels correlate with a significant rise of nephrotoxicity risk. Future studies should verify the effectiveness of individualized pharmacokinetic tools that would enable the attainment of trough level targets and minimize the risk of renal toxicity.

BACKGROUND: Bevacizumab treatment is subject to large interpatient variability in efficacy, which may partly be explained by differences in complex bevacizumab pharmacokinetic characteristics that influence bevacizumab exposure. Exposure–response relationships have been identified for other monoclonal antibodies. We aimed to identify possible exposure–survival relationships in bevacizumab‐treated patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: Patients with mCRC who started first‐line bevacizumab‐based chemotherapy between July 2012 and July 2014, and from whom serial blood samples and survival were prospectively collected, were included. Follow‐up was carried out until July 2018. Total bevacizumab trough concentrations were measured from cycle 2 to cycle 30 of treatment. The receiver operating characteristic (ROC) curve analysis and Cox analysis were used to identify the relationship between concentrations and overall survival (OS). In addition, OS was compared between different trough concentration groups. RESULTS: One hundred fifty‐seven blood samples from 46 patients were evaluable for analyses. ROC analysis showed a clear separation in survival based on trough levels (area under the curve = 0.739, p = .009). Cox regression also showed a strong positive correlation between trough levels and survival (p = .0004). Three distinct groups of exposure were identified: low (median trough concentration [C(tm)] ≤41.9 mg/L); medium (C(tm) 43–87.2 mg/L) with median OS of 12.8 and 36 months, respectively (p = .0003); and high (C(tm) ≥7.9 mg/L), where the majority of patients were still alive 60 months after the initiation of treatment. CONCLUSION: This study shows that survival was proportional to the magnitude of exposure in patients with mCRC. Further clinical research should focus on clarifying these exposure–outcome relationships in order to optimize dosing. IMPLICATIONS FOR PRACTICE: Bevacizumab‐based chemotherapy is standard first‐line treatment in metastatic colorectal cancer. Moreover, bevacizumab presents complicated pharmacokinetics, and in many cases, clinical outcomes can be highly variable, with some patients responding remarkably well and others not. This study's results show that patients who experienced longer overall survival also had significantly higher exposure to bevacizumab. Therefore, bevacizumab trough concentrations could be used both as a predictive biomarker and as a tool for treatment monitoring and optimization. Finally, the development of validated, rapid, and sensitive assays for bevacizumab concentration measurements in combination with these results may lead to a therapeutic drug monitoring–guided approach in bevacizumab treatment with better clinical outcomes.

Background Therapeutic drug monitoring (TDM) is recommended to guide voriconazole therapy. Objectives To determine compliance of hospital-based voriconazole dosing and TDM with the Australian national guidelines and evaluate the predictive performance of a one-compartment population pharmacokinetic voriconazole model available in a commercial dose-prediction software package. Methods A retrospective audit of voriconazole therapy at an Australian public hospital (1 January to 31 December 2016) was undertaken. Data collected included patient demographics, dosing history and plasma concentrations. Concordance of dosing and TDM with Australian guidelines was assessed. Observed concentrations were compared with those predicted by dose-prediction software. Measures of bias (mean prediction error) and precision (mean squared prediction error) were calculated. Results Adherence to dosing guidelines for 110 courses of therapy (41% for prophylaxis and 59% for invasive fungal infections) was poor, unless oral formulation guidelines recommended a 200 mg dose, the most commonly prescribed dose (56% of prescriptions). Plasma voriconazole concentrations were obtained for 82% (90/110) of courses [median of 3 (range: 1–27) obtained per course]. A minority (27%) of plasma concentrations were trough concentrations [median concentration: 1.5 mg/L (range: 5.0 mg/L)]. Of trough concentrations, 57% (58/101) were therapeutic, 37% (37/101) were subtherapeutic and 6% (6/101) were supratherapeutic. The dose-prediction software performed well, with acceptable bias and precision of 0.09 mg/L (95% CI −0.08 to 0.27) and 1.32 (mg/L)2 (95% CI 0.96–1.67), respectively. Conclusions Voriconazole dosing was suboptimal based on published guidelines and TDM results. Dose-prediction software could enhance TDM-guided therapy.

Background The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. Methods We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. Results We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4–8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35–65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9–18.8), piperacillin was 78.6 mg/L (49.5–127.3), tazobactam was 9.5 mg/L (6.3–14.2), and vancomycin was 14.3 mg/L (11.6–21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. Conclusions In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Objectives The dosing regimen of daptomycin for critically ill patients undergoing continuous renal replacement therapy (CRRT) remains controversial. The goal of this study was to provide guidance for optimal daptomycin therapy in CRRT patients with Staphylococcus aureus infections. Methods Individual concentration data of 32 CRRT subjects pooled from previously published studies were used to construct the population pharmacokinetic model for daptomycin. Model-based simulations were performed to evaluate the efficacy and risk of toxicity for daptomycin doses of 4, 6 and 8 mg/kg, q24h or q48h, under CRRT doses of 25, 30 and 35 mL/h/kg. Efficacy was assessed by the bacteriostatic and bactericidal AUC/MIC targets and drug exposure-based efficacy references. Toxicity was estimated by safety exposure references and the trough concentration threshold. Results A two-compartment model adequately described the pharmacokinetics of daptomycin. Efficacy analysis demonstrated that q48h dosing is associated with an extremely low probability of bactericidal target attainment on every second day after dosing and q24h dosing is preferred for a high probability of bactericidal target attainment. Toxicity evaluation showed that 8 mg/kg q24h has a high probability for reaching the toxicity-related concentration threshold, while 6 mg/kg q24h gives a satisfactory risk–benefit balance. The studied CRRT doses had a limited impact on efficacy and a CRRT dose of 30–35 mL/h/kg may lower the risk of toxicity. Conclusions The model predicted that the combination of 6 mg/kg q24h daptomycin dose and CRRT dose of 30–35 mL/h/kg would achieve the best balance of efficacy and safety.

Objectives Cefepime-induced neurotoxicity (CIN) has been demonstrated to be associated with cefepime plasma concentrations; however, the toxicity threshold remains unclear. The primary objective of this study was to identify the cefepime plasma trough concentration at which neurotoxicity occurs. Secondary objectives were to determine the incidence of CIN at a large tertiary institution and to identify patient factors associated with the development of CIN. Methods A retrospective review of all adult patients administered cefepime between October 2017 and May 2018 in a tertiary hospital was conducted to determine total incidence of CIN. A receiver operating characteristic (ROC) curve was constructed to review the sensitivity and specificity of using various cefepime trough plasma concentrations to predict the development of neurotoxicity. Cefepime plasma concentrations were measured using ultra-HPLC. A regression was conducted to identify patient factors associated with CIN. Results In total, 206 patients were administered 259 courses of cefepime, with an overall CIN incidence of 6% (16/259 courses). A total of 64 courses had a cefepime trough concentration measured (24.7%). A cefepime trough concentration of 36 mg/L provided the best differentiation between patients who experienced neurotoxicity and those who did not. No other patient covariates were identified to be significantly associated with neurotoxicity occurring. Conclusions A cefepime trough plasma concentration ≥36 mg/L appears to be the most sensitive and specific cut-off to predict CIN occurring. No patient factors were associated with the development of CIN when accounting for cefepime trough plasma concentrations.

Background The benefit of pharmacokinetics (PK) -guided dosing is that both prophylactic and “on demand” dosing will be based on actual FVIII trough and peak levels instead of current FVIII estimates based on body weight and in-vivo recovery based dosing. Knowledge will increase with regards the relationship between FVIII level and bleeding in individual patients. The dose and frequency of factor VIII for patients on prophylaxis should only be reduced if clinically justified and impact should be monitored with regard to bleeding events, bleeding pattern and joint status. Objective To assess the trough and peak level of factor VIII in patients with hemophilia A on low dose prophylaxis and its impact on the clinical and radiological joint status. Patients and Methods A cross sectional study was performed in Ain-Shams University, Pediatrics Hospital, Hemophilia Clinic. It included 25 children and adolescents with hemophilia A on prophylactic factor VIII during the period from September 2018 to August 2019. Factor VIII used was recombinant 3rd generation with a dose of 45 IU/Kg/week rounded to the nearest 500IU. Trough level of factor VIII was done before prophylactic dose and peak level was done one hour postinfusion through chromogenic assay using STAGO-Immuno-Def VIII reagent. Clinical joint score and Functional Independence Score of Hemophilia (FISH) were done. Radiological joint scores were done using conventional x-ray, ultrasound and MRI. Cut-off level of trough levels was studied at 1% and 1%-5% of factor VIII. Results Patients were classified into 3 groups,4 patients (21.1%) had trough level 5%. No significant difference between trough level of factor VIII and clinical joint scores and FISH scores of patients. Median score of the worst joint of patients with trough level >5% was 5 in comparison to 8 and 7 in patients with trough level 1%-5% and 5% was 9.50 ± 2.12 in comparison to 12.92 ± 5.41 and 11.00 ± 3.56 for patients with troughs 1%-5% and Conclusion Low trough levels alone did not warrant intensification of the prophylaxis regimen; rather, the dose and dosing frequency should be adjusted based on individual’s bleeding pattern and many other factors as shown in our study the insignificant relation between trough levels of factor VIII and clinical and radiological outcomes.. More frequent factor VIII monitoring and incorporation into population based PK are warranted.

Background Flatfoot subjects presents an increase plantar foot area related to a plantar pressure feedback impairment. The Lyapunov Exponent is considered a nonlinear parameter used to characterize a signal chaotic behavior measuring the information rate loss from time series, i.e., for the Center of Pressure data. This exponent is used to quantify and measure the capability and resistance of subjects to several perturbations. The study purpose was to investigate the postural stability differences among foot posture condition through the Lyapunov Exponent analysis. Methods The sample of the observation descriptive study consisted of 31 participants (23.26 yo ± 4.43 SD) comprising a total of 62 feet, where 15 integrated into the experimental group with bilateral flatfoot condition and the remaining 16 in the control group with the bilateral neutral foot condition. Subjects were screened, before posture analysis, using the Navicular Drop Test and Resting Calcaneal Stance Position test, to characterize each group. All participants were subjected to a bipedal weight-bearing stance posture stability analysis a force platform, both in eyes-open and closed condition. The Lyapunov Exponent was calculated using the Matlab-R2020b (MathWorks Inc., USA) software. Results Regarding the Center of Pressure outcomes, only the Lyapunov Exponent value upon the Antero-Posterior component regarding groups in the eyes closed condition (diff = 3.09°, p = .016) presented a significant result. Conclusion Flatfoot subjects present a significant difference compared to neutral foot participants, in bipedal weight-bearing stance, in the eyes closed condition regarding the Lyapunov Exponent. This relates to increase variability and decrease stability regarding the Antero-Posterior component.

Background Certolizumab pegol (CZP) has been successfully used for the treatment of Crohn disease (CD); however, real-world data regarding the utility of CZP trough levels (CTLs) are lacking. We aimed to correlate CTL with CD outcomes and to determine frequency of CZP antibodies. Methods Retrospective evaluation of all CD patients on maintenance CZP with CTL obtained between 2016 and 2019. Outcomes included: median CTL, presence of anti-CZP antibodies, biochemical response (BR), clinical response (CR), radiologic response (RR), radiologic healing (RH), and mucosal healing (MH). Results Seventy-seven CD patients were included. Median CTL was 18.9 µg/mL (interquartile range, 7.6–35.4). Twenty-three patients (27.3%) had positive antibody levels, with lower median CTL compared to patients with no antibodies (0.0 vs 29.8; P < 0.0001). Median CTL levels were higher in patients with vs without CR (30.4 vs 10.3 µg/mL; P = 0.0015) and RR (29.6 vs 5.8 µg/mL; P = 0.006). CZP dosing at least every 2 weeks was associated with higher odds of achieving MH (odds ratio, 3.2; 95% confidence interval, 1.03–9.97). CTL resulted in change in clinical management in 62.7% of cases and presence of CMZ antibodies was associated with an odds ratio of 5.83 (95% confidence interval, 1.57–21.73) of change in management. Receiver operating characteristic curve and quartile analysis suggested that CTL >19 µg/mL is associated with increased rates of CR and RR. Conclusions Higher CTL was significantly associated with CR and RR. The rate of CZP antibodies was 27.3%. Our data suggest maintenance CTL of ≥19 µg/mL should be achieved in order to optimize outcomes in clinical practice.

Background and Aims Due to unavailability of the generic tacrolimus, commonly used in renal transplant patients in Tunisia, all renal transplant switched to the Brand. No previous studies have assessed the pharmacokinetic differences of this generic tacrolimus compared to the brand. The aim of the present study was to evaluate the effect of this switch on the tacrolimus dose (D) and on the dose-adjusted tacrolimus trough blood concentrations (C0/D) in Tunisian renal transplant recipients. Method For the 255 renal transplant monitored in biochemestry department of Sahloul University hospital, 808tacrolimus trough concentration (C0) were collected from october 2018 to February 2020 and were divided to 406 C0 determination before switch and 402 after switch. The dose and the post-transplantation period was recorded for each C0. Results The generic tacrolimus doses used were significantly higher compared to the brand: 0,12 mg/kg [0,02-0,6] vs 0,11 mg/kg [0,02-0,22] p Conclusion Approval of a generic is dependent on bioequivalence testing in healthy adult volunteers after a single dose, however studies on renal graft recipient populations after chronic use are needed to assed bioequivalence in this special population.

Background and Aims PLA2R is an autoantigen present in glomerular podocytes of Membranous Nephropathy (MN) patients. Several drugs have been tried which included nonspecific anti-proteinuric agents; corticosteroids, alone or with alkylating agents; cyclosporine; intravenous Ig; mycophenolate mofetil; and rituximab. There is no standard therapy for patients with frequent relapsing or steroid-dependent MN. We propose the efficacy of low dose Tacrolimus (TAC) plus prednisolone and associated changes in anti-PLA2R in adult IMN. Method Total 101 membranous nephropathy patients were treated with combination of prednisolone 1mg/kg alt-day) and Tac 0.1mg/kg/day (trough 6-10 ng/ml first 6M and 4-6 ng/ml for next 3M) then both taper by 1/3 every month up to 12M. Out of 101 patients; 15 diabetic; 7 lupus; 1HBV and 1 ankylosing spondylitis patients were excluded. Finally; 77 Patients were followed and evaluated for the anti-PLA2R level at baseline; 3M; 6M; 12M and end of follow-up (17-61 ; median 38 months). CR; PR; relapse; and side-effects were recorded.Of the 77 patients; at 3M 60(77.92%; CR-37; PR-23); at 6M 61(79.22%; CR-53; PR-8); at 12M 53(68.86%; CR-47; PR-6) achieved remission. Eight (10.38%) relapsed and 16(20.77%) showed no response at 12M. At end of follow-up; out of 54 responsive patients 37(68.51%; CR-36; PR-1) remained in remission and 17(31.48%) patients relapsed. Results Out of 77 patients; 51 (66.3%) were anti-PLA2R positive. Remission rate was significantly low in PLA2R+ve than PLA2R-ve (36/51 vs 24/26; p=0.03) at 3M; (36/51 vs 25/26; p=0.009) at 6M and (31/51 vs 22/26; p=0.03) at 12M. PLA2R level was decreased by 60.38% and 77.56% at 3M and 6M respectively (1A & 1B). There were significant correlations between PLA2R level and 24h proteinuria at baseline; 3M and at 6M (1C). During therapy 4 patients develop cutaneous tenia; 1 osteonecrosis of the femur head; 1 corpus tunnel syndrome; 4 onset diabetes; 3 tremor; and 14 patients experienced GI symptoms. The eGFR was decreased significantly (p=0.003) by 26.5% at the end of therapy and was normalized after stopping Tac; and 5 non-responsive patients had doubling of serum creatinine and progressively deteriorated eGFR. To note; 4 females had pregnancy and successful delivery in our cohort of patients. Conclusion PLA2R+ve patients showed poor response compare to PLA2R-ve patients. Remission with Tacrolimus and prednisolone therapy is comparable to historical Ponticelli (Pred plus CYP) regimen. Successful pregnency was ovserved on Tac based regimen.

Objective Lifelong low-protein, high-carbohydrate diets extend lifespan in rodent. Consistently in human, the administration of oral carbohydrate drinks the day before surgery might improve clinical outcome. However, the fundamental questions of what represents a macronutritionally balanced diet, and how this impact surgical stress remain unanswered. Methods Here, we induced dietary protein dilution by giving mice ad libitum access to 50% sucrose water, without any food restriction. Mice were randomized into four regimens: regular diet (17,6 % protein, Ctrl), and a low protein diet (5.6% protein, LP), with or without high sucrose water (50% sucrose) for 7 days. At the end of the preconditioning, calorimetric data, fasting blood glucose, IGF1, glucose tolerance, and finally resistance to renal failure following a bilateral renal ischemia-reperfusion was evaluated. Results We demonstrate that access to carbohydrate drinks promotes dietary protein restriction despite a total caloric intake that was twice higher. This short-term self-restriction in daily protein, independent of caloric intake, improved insulin sensitivity, reduced serum triglyceride, and enhanced mitochondrial respiration as well as energy expenditure. Importantly, a 7-day pre-conditioning protein dilution regimen promotes recovery following kidney ischemia and reperfusion (IRI), a model of surgical stress. This protection from kidney IRI inversely correlated with pre-operative protein intake, but not carbohydrate or fat. The benefit of a low protein, high-carbohydrate regimen was independent of the protein sensing pathway eIF2α/ATF4, NRF2 and hydrogen sulfide, but instead required Insulin-like growth factor 1 (IGF1) downregulation. Conclusion These results support further clinical studies of a low protein diet combined with carbohydrate drinks prior to surgery.

Background and Aims Hemodialysis (HD) patients (Pts) with nonvalvular atrial fibrillation (AF) on anti-vitamin-K oral anticoagulation (VK-OAC) are at high risk for cardio-vascular events, major bleeding and rapid vascular/valvular calcification. Thus, current VK-OAC is debated since prospective studies are missing, but all direct oral anticoagulation drugs (DOACs) are not labeled for ESRD. We studied the clinical feasibility of long-term DOAC treatment in HD-pts using individual dosing by regular anticoagulant drug-effect monitoring. Method We analysed 9 HD-patients with AF (median age 77 yrs; range=R: 59-86; 7 Male) on DOAC therapy for at least 6 months (n=1 rivaroxaban=Riva, n=8 apixaban=Apix) initiated by cardiologist with patients informed consent with lower dose as in CKD-4 under regular (weekly) anti-Xa drug-effect monitoring (prior HD) using available routine laboratory test validated for low-molecular heparin: Target trough range (12-24h after drug) was 0.1-1.0 U/ml (=prophylactic to therapeutic anti-Xa levels; test range 1.6 U/ml). Bleeding caused drug stop/reduction until anti-Xa control. Results Median study time was 14 months (R: 6-24). We analysed 310 anti-Xa levels on Apix and 83 levels on Riva. After dose adjustment finally 2 Apix-Pts (22%) received full CKD-4 dose (35 mg/week=wk) and 7 patients (78%) had median dose of 10 mg/wk (10-27 mg; 6x Apix) or 40 mg/wk Riva, i.e. 29% and 38% of usual CKD-4 dose. Two Pts with higher dose had clinical reasons: short-bowl-syndrome (less resorption) or high grade (3-4) left atrial sludge (therapeutic goal). Overall, median anti-Xa level was 0.47 U/ml (R: 1.6) and 80% were in center-accepted targets: 0.1-1.2 U/ml. Lower dose Pts had higher in-target-rate (83%) than the 2 high dose Pts (70%) by more exceeding the upper limit. During our study we saw no cerebral/systemic thrombo-embolic event or major bleeding, but 2 pts had epistaxis (need out-patient intervention), 1x persistent macrohematuria (need catheterization) and 3 pts. had multiple subcutaneous hematoma, none needed event-related transfusion. We saw two non-cardiovascular deaths (22%; 2/9): 1x pneumonic sepsis, 1x advanced cancer. Conclusion We provide new clinical feasibility data on long-term DOACs therapy in HD-patients. Since DOACs are not labelled for ESRD we recommend strict indication plus regular anti-Xa drug-effect monitoring for adequate individual dosing. Our data support initial doses as for CKD-4 but applied only on HD-free days (4x/wk; =57% of usual) and adjustment in steady-state (1-2 wks): final individual doses were increased up to 100% in some patients, but mostly were reduced to 30-40% of usual CKD-4 doses. Overall, this individual dosing approach for DOACs provided adequate anti-Xa levels to prevent thrombo-embolic as well as major bleeding events. This initial data need to be confirmed in larger studies to improve evidence-based management of HD-patients with nonvalvular AF.

Background Posaconazole is a recommended option for antifungal prophylaxis in paediatric patients >12 years of age. However, little is known about plasma exposures and safety following administration of the delayed-release tablets (DRTs) in children and adolescents. Methods In a retrospective observational study, we analysed steady-state trough concentrations of posaconazole in all paediatric patients who had received the DRT formulation between May 2015 and December 2018 for antifungal prophylaxis. Dosing was guided by a published population pharmacokinetic model with weight-based dosing. Drug concentrations in plasma were measured by a validated tandem MS method. Liver function and drug discontinuations due to adverse effects were also assessed. Results A total of 34 patients (21 male, 13 female; median age 12 years, range 5–17 years; median body weight 43.5 kg, range 16–84 kg) undergoing treatment for haemato-oncological disorders (n=23) or immunosuppression for polyarthritis (n=1) or post-allogeneic HSCT (n=11) received posaconazole DRTs for a median of 70 days (range 9–391 days). The median first steady-state trough plasma concentration following model-derived dosing was 1607 ng/mL (range 501–8485 ng/mL) with trough concentrations being above the dosing target of ≥700 ng/mL in 32/34 patients (94%). Considering all (first and subsequent) trough concentrations, target attainment was 90% (63/70 samples). Posaconazole was well tolerated without adverse event-related discontinuations or breakthrough infections. Conclusions Administration of posaconazole DRTs to paediatric patients guided by a population pharmacokinetic-derived dosing algorithm resulted in predictable and potentially effective exposures and was well tolerated over prolonged time periods.

Background and Aims Histological healing may be the ultimate therapeutic goal in ulcerative colitis [UC]. We investigated, for the first time, the association between vedolizumab trough levels and histological healing in UC. Methods This is a single-centre retrospective cohort study including all consecutive UC patients on vedolizumab maintenance therapy who had a histological evaluation blindly to clinical data and underwent therapeutic drug monitoring, between June 2014 and March 2018. Per-event analysis was performed. Histological healing was defined as a Nancy histological index ≤1. Results Thirty-five histological samples were analysed. Median [interquartile range] vedolizumab trough levels were higher in the group with histological healing (31.5 [25–49.1] μg/mL) compared with the group without histological healing (15 [9–26.6] μg/mL, p = 0.02). The higher vedolizumab trough level quartiles tended to be associated with greater rates of histological healing [p = 0.10]. A cut-off vedolizumab trough level of 25 μg/mL predicted histological healing with an accuracy of 74% and an area under the receiver operating curve of 0.62 [95% confidence interval 0.58–0.92, p = 0.004]. Bivariate analysis identified a vedolizumab trough level ≥25 µg/mL [p = 0.006], a partial Mayo score ≤1 [p = 0.008], C-reactive protein level Conclusions Histological healing was associated with higher vedolizumab trough levels during maintenance therapy in UC. A vedolizumab trough level threshold of 25 μg/mL proved most optimal to predict histological healing according to the Nancy histological index. Confirmation of these data in larger, independent cohorts is needed.

BackgroundLower blepharoplasty has been used for rejuvenating lower eyelids, and diverse modifications have been used to treat conjunct deformities at the tear trough/lid-cheek junction. Strategies for recontouring prominent tear trough/lid-cheek junctions, including orbital fat manipulation, have been reported with good results in the literature. Micro-autologous fat transplantation (MAFT) is a previously unevaluated, potentially advantageous approach to blending the prominent tear trough/lid-cheek junction.ObjectivesWe determined the long-term results after 3-step transcutaneous lower blepharoplasty with MAFT for patients with aging eyelids and prominent tear trough/lid-cheek junctions.MethodsWe evaluated 205 patients with aging lower eyelids who underwent transcutaneous lower blepharoplasty with MAFT between October 2010 and September 2016. The 3-step procedure involved a subciliary elliptical skin excision, resection of 3 orbital fat compartments, and MAFT for the tear trough/lid-cheek junction employing a MAFT-GUN under intravenous anesthesia.ResultsThe mean patient age was 52 years (range, 34-78 years). The mean operating time was 61 minutes. The mean fat volumes delivered to the tear trough/lid-cheek junctions were 2.80 mL and 2.76 mL for the left and right sides, respectively. The average weights of the 3 resected orbital fat compartments were 0.58 g for the left side and 0.56 g for the right side. Patients showed significant improvement and maintenance at an average follow-up of 60.2 months (range, 18-90 months).ConclusionsThree-step transcutaneous lower blepharoplasty with MAFT is an effective, reliable, and promising method with high patient satisfaction and minimal risk of complications. Long-term results demonstrated its utility for aging lower eyelid treatment.Level of Evidence: 4

Background Vancomycin is a first-line antibiotic used for the treatment of severe gram-positive bacterial infections. Clinical guidelines recommend that the vancomycin trough concentration be 10-15 mg/L for regular infections and 15-20 mg/L for severe infections. We investigated whether increasing the vancomycin concentration would result in better clinical outcomes with sustainable adverse effects (AEs) in the Chinese population. Methods A prospective, open, multicenter clinical observational study was performed in patients with gram-positive bacterial infections from 13 teaching hospitals. Patients received vancomycin therapeutic drug monitoring. Clinical, microbiological, and laboratory data were collected. Results In total, 510 patients were enrolled, and 470 were evaluable, of whom 370 were adults and 100 were children; 35.53% had methicillin-resistant Staphylococcus aureus infections (vancomycin 50% minimum inhibitory concentration [MIC50] = 1, 90% minimum inhibitory concentration [MIC90] = 1), and 23.19% had Enterococcus species infections (vancomycin MIC50 = 1, MIC90 = 2). The average trough concentration was 10.54 ± 8.08 mg/L in adults and 6.74 ± 8.93 mg/L in children. The infection was eradicated in 86.22% of adults and 96% of children. Thirty-six vancomycin-related nephrotoxicity cases were reported in the enrolled population. No severe AEs or deaths were related to vancomycin therapy. Logistic regression analysis showed that trough concentration had no relationship with clinical outcomes (adults P = .75, children P = .68) but was correlated with adult nephrotoxicity (P < .0001). Vancomycin trough concentration had an applicable cut point at 13 mg/L. Conclusions Our study shows that vancomycin trough concentration has no statistical correlation with clinical outcomes, and is an indicator of nephrotoxicity in the observed population. We found no evidence that increasing vancomycin trough concentration to 15-20 mg/L can benefit Chinese patients with complicated infections. Clinical Trials Registration ChiCTR-OPC-16007920.

Introduction The glycopeptide teicoplanin is commonly utilized to facilitate outpatient parenteral antimicrobial therapy (OPAT). Licensed for once daily maintenance dosing, teicoplanin’s long half-life allows for less frequent dosing (e.g. thrice weekly) following successful loading. This service evaluation reviews the safety and effectiveness of a novel thrice weekly teicoplanin dosing regimen. Methods A retrospective, observational study was conducted at Chelsea and Westminster Hospital (March 2018 to July 2020), evaluating trough serum teicoplanin concentrations for patients receiving >5 days of teicoplanin in the OPAT setting. Teicoplanin dosing and administration (once daily versus thrice weekly), clinical outcomes and therapeutic levels were analysed for all patients. The project was registered with clinical governance locally. Results A total of 82 patients treated with teicoplanin in the OPAT service were included; 53/82 receiving thrice weekly and 29/82 receiving once daily dosing. Mean teicoplanin trough levels were similar in both groups (26.2 mg/L and 25.8 mg/L in once daily and thrice weekly groups, P = 0.8895). High clinical success rates were recorded in both groups (25/29 [86.2%] versus 50/53 [94.3%]). No correlation with clinical outcomes and initial teicoplanin serum levels was identified. Normal renal function (>90 mL/min) was associated with lower teicoplanin serum concentrations (mean [±SD] 21.4 mg/L [±10.1] versus 29.7 mg/L [±14], P = 0.0178) in the thrice weekly dosed group but not with the once daily dosed group (mean [±SD] 28.2 mg/L [±9.4] versus 23.7 mg/L [±9.9], P = 0.2201). Conclusions This study supports thrice weekly teicoplanin as a convenient and effective OPAT for administration in the OPAT setting. Therapeutic drug monitoring is advised to adjust for intra-patient variability.

Background There is considerable individual variation in the low-density lipoprotein cholesterol (LDL-C) reduction at all classes and doses of statins. Knowledge of the determinants of individual variation LDL-C response upon statin treatment may pave the way for personalized and optimized statin treatment. Purpose We aimed to determine clinical and drug related predictors of variability of LDL-C response to atorvastatin 40 mg in patients with coronary heart disease. Methods This is an explorative study among 70 patients enrolled in the MUscle Side-Effects of atorvastatin in coronary patients (MUSE) randomized double blinded cross-over trial. Absolute and relative changes in LDL-C after 7 weeks treatment with atorvastatin 40 mg/day and 7 weeks treatment with placebo, were calculated for each patient. Linear regression analyses were applied to investigate the association between clinical (10 variables) and drug related (atorvastatin and/or metabolites, 18 variables) predictors and changes in LDL-C. Results Adherence to allocated treatment was high as confirmed by atorvastatin levels in blood and a mean proportion of days covered of 99% (range 91–100%). Mean reduction in LDL-C on atorvastatin treatment (LDL-C atorvastatin – LDL-C placebo) was 2.1 (SD 0.7, range 0.3 to 3.4) mmol/L. Mean percentage reduction in LDL-C was 51.1 (SD 11.2, range 29 to 60)%, and 37 patients (52.9%) had Conclusions There is considerable inter-individual variation in the LDL-C response upon treatment with atorvastatin despite confirmed high statin adherence. This is the first study reporting that genetic polymorphisms involved in the metabolism of statins and atorvastatin metabolites predict lower LDL-C response. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Association of Health, Grant/Award

Background Although patients taking direct oral anticoagulants (DOACs) do not require routine coagulation monitoring, the distribution of anti-factor Xa activity (AXA) values, prothrombin time (PT), PT-international normalized ratio (INR) and activated partial thromboplastin time (APTT) in patients on apixaban, edoxaban and rivaroxaban therapy is still not clear. Purpose The aim is to set the standard values of AXA values, PT, PT-INR and APTT in patients using DOACs. Methods We measured AXA, using chromogenic assay with the HemosIL Liquid Heparin kit, PT, PT-INR and APTT at trough and peak times in 224 patients with non-valvular atrial fibrillation and venous thromboembolism, of whom 90 received apixaban, 100 received edoxaban and 34 received rivaroxaban. The peak time was defined as 3 hours after the intake of apixaban or rivaroxaban, and 2 hours after the intake of edoxaban. The trough time was defined as that immediately before the intake. The AXA values, PT, PT-INR and APTT were measured at least 72 hours after the start of treatment. The dosage of DOACs is defined according to the prescribing information in Japan. Results (The order of results below is apixaban, edoxaban and rivaroxaban, respectively.) The average AXA values were 2.29, 0.23 and 0.39 (IU/mL) at trough time, and 3.04, 1.01 and 1.70 (IU/mL) at peak time. The average PT values were 17.9, 12.9 and 13.1 (s) at trough time, and 19.7, 15.5 and 17.5 (s) at peak time. The average PT-INR values were 1.49, 1.07 and 1.08 at trough time, and 1.65, 1.29 and 1.45 at peak time. The average APPT values were 34.5, 31.3 and 32.0 (s) at trough time, and 39.5, 35.9 and 39.8 (s) at peak time. Conclusion Our findings reveal the standard values of AXA, PT, PT-INR and APTT in patients using apixaban, edoxaban and rivaroxaban in each dosage. The DOACs should be changed if the measured value is out of those standard values in 90% confidence interval. Funding Acknowledgement Type of funding source: None

Background Recent studies suggest pediatric Crohn’s Disease (CD) patients have higher infliximab clearance (IFX CL) for body weight and lower serum IFX when dosing by weight. Our aim was to determine if IFX CL calculated based on therapeutic drug monitoring (TDM) data predicts long term outcome. Methods Retrospective study of CD patients seen at the Stollery Children’s hospital from Jan 2013-Jul 2019. Anthropometric, lab, IFX TDM & disease data were collected for those having >2 serum IFX levels. IFX CL was calculated using non linear mixed effects modelling. The data was fit to a 2-compartment model with linear elimination. Outcomes were defined at 4, 9 & 15 months. Remission is defined as wPCDAI Results 85 subjects were included, with a median follow up of 670 days (IQR: 304,1105). See table 1 for baseline characteristics. Regression analysis showed early IFX CL was the only significant early predictor of remission for every timepoint. Baseline IFX CL and end of induction IFX CL, measured in L/h, were associated with 15-month remission with an OR of 0.606 (95%CI: 0.394,0.931; p=0.022) and 0.373 (95%CI: 0.207,0.669; p=0.001) respectively. Similar results obtained at 4 & 9 months. ROC analysis of remission was done using only early IFX CL. A baseline IFX CL of 5.83 L/h predicted 15-month remission with a sensitivity & specificity of 0.649 & 0.667 (AUC=0.701). End of induction IFX CL of 6.06 L/h predicted 15-month remission with a sensitivity & specificity of 0.676 & 0.611 (AUC=0.709). Similar results obtained at 4 & 9 months. Conclusion In all timepoints, early IFX CL was a strong predictor of later remission compared to dose intensity, frequency, IFX levels and wPCDAI & CRP at end of induction. This suggests early IFX CL is a marker of early biological response to IFX. Early dose optimization is required in those with high IFX CL to ensure optimal response with adequate drug exposure. This will facilitate early change in treatment for those with inadequate response.

Background SB5 is approved as a biosimilar to the adalimumab (ADA) originator. Bio- and efficacy equivalence, as well as comparable safety and immunogenicity have been demonstrated in Phase I and III randomised clinical trials. In this study we want to describe the trough levels and effectiveness of switch to a biosimilar in a real-life Inflammatory Bowel Disease (IBD) population. Methods In 2 Belgian IBD centres, patients in clinical remission or stable response and treated with ADA originator were offered to enter a phase IV, interventional trial of switch to biosimilar SB5. Assessments were done at baseline, at 8 weeks, 6 and 12 months post-switch. Therapy type and dosing regimen remained unchanged the first 8 weeks; after week 8, dose adjustments could be made based on trough level and/or at the discretion of the treating physician. Trough serum ADA concentrations were measured by enzyme-linked immunosorbent assay (ELISA). The primary outcome measurement was the description of ADA trough level over time after the switch. The secondary outcome measurements were secondary loss of response (SLOR) (defined at physician’s discretion), disease activity scores and biochemical assessments (faecal calprotectin (fCal), leukocyte count (LC) and C-reactive protein (CRP)). Results In the study, 110 patients were enrolled from whom 84 had Crohn’s disease and 26 had ulcerative colitis. By 12 months, SB5 was stopped in 5 patients because of high ADA antidrug antibodies at both baseline and at week 8. Nine patients presented with SLOR of whom 3 discontinued treatment with SB5, the remaining 6 patients received treatment optimisation. Table 1 displays the core results concerning the ADA trough levels over time. Table 2a and 2b display disease activity scores and biochemical parameters at the different time points. Conclusion In this pragmatic, interventional phase IV trial, ADA trough levels remain within the therapeutic range after switch from originator to SB5. The proportion of patients in our study with SLOR is in line with what is described in literature. In patients persisting on SB5, no change in disease activity over time is observed, based on both disease activity scores and biochemical parameters.

Background Ustekinumab (UST) has been shown to effectively induce and maintain remission in inflammatory bowel disease (IBD). Only a few studies thus far have focused on UST pharmacokinetics suggesting that both, trough levels after i.v. induction as well as trough levels during stable maintenance might be associated with clinical and endoscopic response to UST. Data from real-world cohorts in this setting are scarce. Therefore, the aim of our study was to assess whether clinical response to UST was associated with a specific pharmacokinetic pattern. Methods All IBD patients treated with UST in one tertiary IBD centre between January 2017 and August 2020 were retrospectively retrieved from the database. Disease activity was assessed by Harvey-Bradshaw index (HBI) and partial Mayo score in Crohn’s disease (CD) and ulcerative colitis (UC) pts; respectively. Clinical response was defined as a decrease of HBI of ≥2 points or partial Mayo score ≥3 points. Patients not responding to therapy by week 16, or loosing original response received dose escalation from 90mg s.c. every 8 weeks to 90mg every 4 weeks. UST through levels were assessed by commercially available ELISA kit (IDKmonitor®) at week 8 after i.v. induction and/or during maintenance therapy after a minimum period of 16 weeks of treatment. Results In total, 61 IBD patients were included (mean age 38 years, range 22–70; 38 women; 54 CD/6 UC/1 IBD-U). All patients were antiTNF experienced, minority (11; 18%) had also been treated with vedolizumab prior UST. Thirty-nine pts (64%) were responders, out of these 15 pts (38%) required dose escalation at some point of the treatment due to secondary loss of response. UST through levels at week 8 were significantly higher than the maintenance levels (mean 5.6±SEM 0.7µg/mL vs. 2.2±0.3µg/mL; p Conclusion In this limited size real-world cohort of IBD patients, we found no difference in pharmacokinetics between reponders and non-reponders to ustekinumab.

Background The correlation between vedolizumab trough levels and inflammatory bowel diseases (IBD) remission rates has not yet been fully defined. We aimed to evaluate the association between vedolizumab serum trough levels and disease clinical and extra-intestinal manifestations (EIMs) and biomarker activity in IBD patients. Methods Forty-six patients (31 ulcerative colitis, 15 Crohn’s disease) who started vedolizumab therapy were retrospectively followed. Clinical and laboratory data were collected before treatment, during induction and maintenance until week 52 from initiation. Documentation of EIMs included peripheral and axial arthropathy, cutaneous and ocular manifestations and perianal disease. Clinical remission was defined as a Harvey-Bradshaw Index (HBI) Results Higher week-2 trough serum vedolizumab levels were associated with week 14 clinical remission compared to patients with an active disease (30.55±2.22 µg/ml vs 22.28±3.57µg/ml, p=0.05) and with weeks-14 and -30 biomarker normalization (33.77±2.98 µg/ml vs 23.6±3.19 µg/ml, p=0.05 and 30.33±1.95 µg/ml vs 19.66±6.83 µg/ml, p=0.05, respectively). Week-6 vedolizumab levels were associated with week-30 clinical remission (30.52±3.48 µg/ml vs 15.35±4.94 µg/ml, p=0.03) and biomarker normalization (28.44±2.36 µg/ml vs 15.76±4.87µg/ml, p=0.02), and week 14 vedolizumab levels were associated week 30 biomarker normalization (14.81±1.64 µg/ml vs 6.23±2.25 µg/ml, p=0.03). Throughout the follow-up period, 24% of patients presented with EIMs (n=11). No association was found between vedolizumab levels and endoscopic outcomes or EIMs activity. Conclusion Trough serum vedolizumab levels at induction is associated with remission induction and maintenance but not with EIMs improvement. Assessment of early vedolizumab trough levels may be considered for prediction of response to therapy.

Background and Aims Little is known regarding the safe fixed dose of mycophenolic acid (MPA) for preventing biopsy-proven acute rejection (BPAR) in kidney transplant recipients (KTRs). We investigated the correlation of MPA trough concentration (MPA C0) and dose with renal transplant outcomes and adverse events. Method This study included 79 consecutive KTRs who received MPA with tacrolimus (TAC) and corticosteroids. The MPA C0 of all the enrolled KTRs was measured, which was determined monthly by using particle-enhanced turbidimetric inhibition immunoassay for 12 months, and clinical data were collected at each time point. The clinical endpoints included BPAR, any cytopenia, and BK or cytomegalovirus infections. Results No differences in MPA C0 and dose were observed between KTRs with or without BPAR or viral infections under statistically comparable TAC concentrations. MPA C0 was significantly higher in patients with leukopenia (P = 0.021) and anemia (P = 0.002) compared with those without cytopenia. The MPA dose was significantly higher in patients with thrombocytopenia (P = 0.002) compared with those without thrombocytopenia. MPA C0 ≥ 3.5 µg/mL was an independent risk factor for leukopenia (adjusted odds ratio [AOR] 3.80, 95% confidence interval [CI] 1.24–11.64, P = 0.019) and anemia (AOR 5.90, 95% CI 1.27–27.51, P = 0.024). An MPA dose greater than the mean value of 1188.8 mg/day was an independent risk factor for thrombocytopenia (AOR 3.83, 95% CI 1.15–12.78, P = 0.029). However, an MPA dose less than the mean value of 1137.3 mg/day did not increase the risk of BPAR. Conclusion Either a higher MPA C0 or dose was associated with an increased risk of cytopenia, but neither a lower MPA C0 nor dose was associated with BPAR within the first year of transplantation. Hence, a reduced MPA dose with TAC and corticosteroids might be safe in terms of reducing hematologic abnormalities without causing rejection.

Background and Aims Tacrolimus is an integral part of the immunosuppressive regimen after solid organ transplantation. Due to its narrow therapeutic window, it requires frequent serum trough level (C0) monitoring and dose adjustment. Both over-and under treatment may have harmful effects regarding overall mortality and graft survival due to increased risk of cardiovascular diseases, malignancies, new onset diabetes and rejection. C0 and total daily dose ratio (CD) has recently been suggested as a potential predictor of worse graft outcome in the early period after transplantation, however, long term prospective studies are lacking. We hypothesized the association between lower CD ratio and increased risk of death with functioning graft (DWFG), graft loss (GL) and overall death (D) in our prospective cohort study. Method Our study included 386 prevalent kidney transplant recipients (205(53%) males, median and IQR age of 47.5 (13.2) years, eGFR 53.5 (22.5) ml/min/1.73m2, time since last transplant 51 (26-79) months) out of a total of 993 enrolled between 2006-2007. Sociodemographic, past medical history, clinical and laboratory data were collected and CD was recorded at baseline and 1 year after the enrollment. The associations between CD and CD2 ratios and above mentioned outcomes were examined using survival models.. Results The median and IQR of CD was 2.1(1.4-3.2) at baseline and 2.0 (1.3-3.0) 1 year later (CD2). There was 46 (11.9%) DWFG, 79 (20.5%) GL and 68 (17.6%) D, respectively. After adjustment for important confounders (age, gender, eGFR, Charlson score, dialysis duration, donor age, rejection), neither CD (DWGL: HR 0.56(0.30-1.03) p=0.06; GL: HR 0.82(0.50-1.36) p=0.46; D: HR 0.79(0.48-1.32) p=0.38) nor CD2 (DWGL: HR 1.12(0.54-2.31) p=0.74; GL: HR 0.76(0.61-1.97) p=0.78; D: HR 1.19(0.64-2.20) p=0.59) found to be predictors of the outcomes. Conclusion CD ratio was not associated with increased risk of death with functioning graft, graft loss or overall death in our prevalent kidney transplant recipients.

Background Optimal valganciclovir dosing for cytomegalovirus (CMV) prophylaxis in solid-organ transplant (SOT) patients on continuous veno-venous hemodialysis (CVVHD) is not known. Ganciclovir trough concentrations ≥0.60 μg/mL have been suggested for CMV prophylaxis. This study was conducted to determine if valganciclovir 450 mg enterally every 24 hours achieves ganciclovir trough concentrations ≥0.60 μg/mL in patients on CVVHD. Methods This single-center, prospective, open-label, pharmacokinetic study included adult SOT patients admitted to an intensive care unit from March 2018 to June 2019 on CVVHD. All patients were receiving valganciclovir 450 mg enterally every 24 hours for CMV prophylaxis prior to enrollment. Each patient had a peak and trough sample drawn at steady state. Results Ten SOT patients were included in the study (6 liver, 1 simultaneous liver-kidney, 2 bilateral lung, 1 heart). The mean ± SD age was 51.8 ± 14.0 years, and average body mass index was 27 ± 6.9 kg/m2. Ganciclovir trough concentrations ranged from 0.31 to 3.16 μg/mL, and 80% of participants have trough concentrations ≥0.60 μg/mL. No patients had documented neutropenia while on valganciclovir and CVVHD; 60% of patients had significant thrombocytopenia. Conclusions Valganciclovir 450 mg enterally every 24 hours achieved ganciclovir trough concentrations ≥0.60 μg/mL in most patients on CVVHD, similar to those reported with intravenous ganciclovir for prophylaxis in this population. Based on these data, valganciclovir may require dosing every 24 hours to achieve concentrations equivalent to ganciclovir. Neutropenia did not occur in the study period. Thrombocytopenia was common and likely multifactorial.

Background and Aims We aimed to evaluate the relationship of serum adalimumab trough levels (ATL) with disease activity of inflammatory bowel disease (IBD) patients in a large, well-characterized referral center-based cohort. Methods We compared serum ATL between those with clinical, biochemical, or endoscopic/radiologic disease activity and those without. Results A total of 236 patients with IBD were included. Higher cutoff levels were associated with endoscopic and/or radiologic responses (cutoff value: 5.3 mcg/mL, P = 0.003) compared with improvement in C-reactive protein (cutoff value: 4.3 mcg/mL, P = 0.031). Conclusions Higher cutoff ATL was associated with endoscopic and/or radiologic response.

Aim The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of a second anti-TNF according to the pharmacokinetics of the first anti-TNF in patients with inflammatory bowel disease (IBD). Methods In patients in loss of response (LOR) to a first optimized anti-TNF and switched to a second anti-TNF, pharmacokinetics of anti-TNF were measured at the switch time, 30 weeks later, at the time of LOR, or at the end of the study (102 weeks). Results At the switch time, patients (n = 59) belonged to 4 groups according to the pharmacokinetics of the first anti-TNF: group 1 (n = 18), therapeutic trough levels; group 2 (n = 13) undetectable trough levels with antibodies against anti-TNF; group 3 (n = 13) without antibodies against anti-TNF; and group 4 (n = 15) subtherapeutic trough levels. After switching, the failure rates at week 30 and during the follow-up were as follows, respectively: in group 1 with therapeutic levels, 50% and 78%, despite therapeutic levels of the second anti-TNF in 83% of cases; in group 2 with undetectable levels and antibodies, 15% and 69% with undetectable levels of the second anti-TNF and antibodies in 85% of cases; in group 3 with undetectable levels without antibodies, 0% and 31% with therapeutic levels in 77% of cases; in group 4 with subtherapeutic levels, 13% and 33% with therapeutic levels in 73% of cases. Clinical remission rates were significantly lower (P ≤ 0.05) in groups 1 and 2 with therapeutic or undetectable levels with antibodies than in the 2 other groups. Conclusion In the case of LOR with therapeutic levels of the first anti-TNF or undetectable levels with antibodies, the switch to a second anti-TNF results in pharmacokinetic profile similar to the first one and again in LOR in most of the patients.

BackgroundMonitoring of mycophenolic acid (MPA) levels may be useful for effective mycophenolate mofetil (MMF) dosing. However, whether commonly obtained trough levels are an acceptable method of surveillance remains debatable. We hypothesized that trough levels of MPA would be a poor predictor of area under the curve (AUC) for MPA.MethodsA total of 51 patients with lupus nephritis who were on MMF 1500 mg twice a day and had a 4-h AUC done were included in this study. MPA levels were measured prior to (C0) and at 1 (C1), 2 (C2) and 4 (C4) h, followed by 1500 mg of MMF. The MPA AUC values were calculated using the linear trapezoidal rule. Regression analysis was used to examine the relationship between the MPA trough and AUC. Differences in the MPA trough and AUC between different clinical and demographic categories were compared using t-tests.ResultsWhen grouped by tertiles there was significant overlap in MPA, AUC 0-4 and MPA trough in all tertiles. Although there was a statistically significant correlation between MPA trough levels and AUC, this association was weak and accounted for only 30% of the variability in MPA trough levels. This relationship might be even more unreliable in men than women. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with increased MPA trough levels and AUC at 0-4 h (AUC0–4).ConclusionTrough levels of MPA do not show a strong correlation with AUC. In clinical situations where MPA levels are essential to guide therapy, an AUC0–4 would be a better indicator of the adequacy of treatment.

Background Dolutegravir, an HIV integrase strand-transfer inhibitor, and simeprevir, an HCV NS3/4A PI, have the potential to interact as dolutegravir is a P-glycoprotein, uridine glucuronosyl transferase 1A1 and cytochrome P4503A substrate and simeprevir has been shown to mildly inhibit these. Objectives To compare dolutegravir and simeprevir pharmacokinetics (PK) when given separately versus in combination. Methods Healthy volunteers received: (i) 150 mg of simeprevir once daily for 7 days; (ii) 50 mg of dolutegravir once daily for 7 days; and (iii) 150 mg of simeprevir once daily plus 50 mg of dolutegravir once daily for 7 days, with randomization to treatment sequence. Twenty-four hour intensive PK sampling was performed on day 7 of each sequence following observed dosing and a standardized meal. PK parameters were determined using non-compartmental methods and compared using paired t-tests. Bioequivalence for area under the curve (AUCtau) and maximum concentration (Cmax) were also assessed. NCT02404805. Results Twenty-four subjects completed all three sequences. Dolutegravir trough was increased 24% (P = 0.0003) with simeprevir. Dolutegravir AUCtau was increased 15% (P = 0.002), but was deemed bioequivalent as the 90% CI for the geometric mean ratio was 107%-123%. Dolutegravir Cmax was bioequivalent. Simeprevir PK was unaffected by dolutegravir. There were no discontinuations due to adverse events and all adverse events were mild to moderate in severity. Conclusions Dolutegravir trough was increased slightly with simeprevir, but AUCtau was bioequivalent. Despite the increase in trough, dolutegravir concentrations were well within the range with established safety data. Suggesting that simeprevir and dolutegravir can be safely co-administered.

Limited data exist on intravenous (IV) posaconazole dosing and the risk for hepatotoxicity it confers to children. In this study, we evaluated dosing and resulting trough levels in 10 pediatric patients on IV posaconazole. A therapeutic level in these patients was achieved 95% of the time. We found a median minimum effective dose of 6.55 mg/kg of body weight. No correlation was found between the duration or posaconazole trough level and an increased alanine transaminase level.

Background New vancomycin (VAN) guidelines have been published, with recommendations that dosing in patients (pts) with methicillin-resistant S. aureus (MRSA) infections be guided by VAN area under the concentration-time curve from 0 to 24 h to MIC ratio (AUC24). The guidelines emphasize daily AUC24 values should be between 400-600 mg*h/L to maximize efficacy and minimize likelihood of acute kidney injury (AKI). Our physicians and clinical pharmacists currently use trough levels to manage outpatient VAN dosing with a general target of 15-20 mg/L. The current pharmacokinetic (PK) model provides an option for dosing using trough or calculated AUC24. Methods We identified pts receiving VAN for S. aureus infections (default MIC of 1 mg/mL) from 2018-2020. We conducted a PK evaluation of pts with ≥1 trough level and compared it to model predicted AUC24. Data collected included pt characteristics, VAN regimen, trough concentrations, PK evaluation, and AKI, defined as a 50% decrease in CrCL from baseline. A Bayesian PK model was used to calculate predicted dosing based upon trough concentrations (DoseMeRx®, Moorestown, NJ). Results 100 pts (mean age: 61±15 yrs, 62% male) from 6 OICs were included, with 82% treated for MRSA and 18% for methicillin-sensitive S. aureus infection. Mean initial dose of VAN in the OIC was 2.6±1 g/d in divided doses, most frequently every 12 hrs (68%). Median duration of outpatient therapy was 28 days [IQR, 16-36]. 69% received VAN in the hospital prior to the OIC. 100 pts had 239 trough levels with a corresponding PK analysis. Mean trough levels were 17.1±6.4 mg/L. Mean corresponding AUC24 was 498±98 mg*h/L. The relationship between trough and AUC24 is shown in Fig 1. 25 evaluations indicated an AUC24 < 400, with 8 (32%) resulting in a dose increase. 13 evaluations indicated AUC24 > 600, with 6 (46%) resulting in a subsequent dose decrease. 4 pts developed reversible AKI, all with AUC24 > 540. Use of AUC24 for dosing provided opportunities to adjust dosing in 38/239 evaluations (16%). Figure 1. Relationship between Trough and AUC24 (n=239) Conclusion This PK evaluation showed a correlation between trough levels and AUC24 with opportunities for VAN dose adjustment using AUC24, and to identify pts at risk for developing AKI. Dosing with AUC24 is particularly useful in the outpatient setting in which true trough evaluations can be difficult to obtain. Disclosures Brian S. Metzger, MD, MPH, Allergan (Speaker’s Bureau)Cumberland (Speaker’s Bureau)Melinta (Speaker’s Bureau) Richard L. Hengel, MD, Merck & Co. (Other Financial or Material Support, Grant Steering Committee Member) Kimberly A. Couch, PharmD, MA, FIDSA, FASHP, Allergan (Speaker’s Bureau) Lucinda J. Van Anglen, PharmD, Merck & Co. (Grant/Research Support)

Introduction The slow oscillation (0.5-1Hz, SO) is the most studied sleep waveform and reflects sleep homeostasis and is crucial for memory consolidation. It is not clear how SO causally affects brain networks. We used the effective connectivity technique to investigate causal information flow across the electrode manifold during the SO. Methods Night sleep EEG signals of 59 adult participants were recorded and visually scored into five sleep stages. We used three EEG channels for each region including frontal, central, parietal, and occipital. SOs were detected automatically and signals from one second before to one second after the SO’s troughs were used for estimating effective connectivity in SO and non-SO windows. Windowing technique and generalized partial directed coherence were employed to estimate causal information flow (CIF) between selected brain regions. The Linear mixed-effect (LME) method was used to model the peaks of the CIF based on different predictors including SO channel, source and sink of CIF, and distance between each of SO channel, source and sink regions. Results The results of CIF estimation showed two peaks of CIF about 250ms before and after the SO’s trough, but no difference between CIF in SO’s trough and non-SO windows. We found no effect of source and sink regions, and their distance on CIF (p-value > 0.05). However, distance between SO channel to source and sink region (p-value < 0.05) significantly predicted CIF. The coefficients of the LME model showed a direct effect of distance between SO channel to sink region and opposite effect of distance between SO channel to source region on CIF peaks. Conclusion The results showed there were significant changes of brain regions causal communication during SOs and these changes were affected by the distance of SO channel to sink and source region of CIF. Channels that are closer to the SO send more information and regions farther from the SO channel receive more information. Based on the results, we hypothesize that the SO brain networks are optimized to facilitate communication between regions that are far apart. Support (if any)

Background Ustekinumab, anti-IL12/23 antibody have contributed to the good prognosis in patients with Crohn’s disease (CD). However, good biomarkers for the prediction of treatment- effects of ustekinumab (UST) are not clear. We elucidated whether trough concentration of UST could predict the clinical remission and seronegative inflammation in CD patients in clinical practice. Methods This was a single-centre prospective observational study approved by the institutional review board of our hospital. Forty CD patients treated by administration of intravenous UST 6 mg/kg and subcutaneous UST 90mg every 8 weeks were enrolled in this study. CDAI, serum CRP and plasma UST trough concentration were evaluated at every visit. All data were examined in total patients, patients with UST induction at remission state after pretreatment (Induction at remission group) and patients with UST induction at active state after pretreatment (Induction at non-remission group). Endpoints were time course changes of clinical remission rate, CDAI, CRP and UST trough concentration until week 40. Results In total, 40 participants were included in the final analysis. The mean age and disease duration of the participants were 41.3 and 11.7 years. Of the participants, 65% (26/40) were male, 25% (10/40) used thiopurine, and 30% (12/40) used steroids. TNF-failure of the patients were 65.0% (26/40). Remission rate of total patients significantly increased at week 8 (30, 60, 68, 78, 78, and 73% at every 8 weeks from baseline). Both CDAI and CRP significantly decreased from baseline at week 8. Remission rate of Induction at remission group (n=12) did not significantly decrease from baseline (100, 92, 92, 92, 92, and 83% at every 8 weeks from baseline). Remission rate of Induction at non-remission group (n=28) significantly increased until week 24 from baseline (0, 46, 57, 71, 71, and 68% at every 8 weeks from baseline). Trough concentrations of total patients at week 8, 16, 24 were 3.54, 1.57 and 1.43 μg/mL, respectively. Trough at each week was not significantly different between Induction at remission and at non-remission groups. Immunomodulator use did not affect trough concentration. Cut-off values of prediction for remission at week 8, 16, and 24 were 2.80, 1.28* and 1.12* μg/mL, respectively. Cut-off values of prediction for normal CRP at week 8, 16, and 24 were 3.27, 1.24* and 1.24* mg/mL, respectively (*: Each factor significantly could be detected). Conclusion UST trough concentration at subcutaneous injection could predict clinical remission and normal CRP. Pretreatment did not affect UST trough concentration.

Background Infliximab (IFX) is a monoclonal antibody that targets cytokine tumor necrosis factor; it is used for the treatment of patients with active inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). IFX induces and maintains remission and mucosal healing in patients with IBD. Measurement of trough levels (TL) of IFX is important to assess if the drug is within its therapeutic concentrationand to explain lack/loss of response. Standard laboratory tests to assess IFX trough levels (enzyme linked immunosorbent assays, ELISA) present some downsides, related to the long turnaround (about 3 hours), and the need of specialized equipment and laboratory personnel. For this reason, point-of care testing (POCT) was developed to provide results within a few minutes from blood collection, leading to a decision-making approach. Aim To determine the degree of analytical correlation between a recently developed POCT (ProciseDx) IFX assay which analyze capillary whole blood and the comparative ELISA from serum. Methods From October 2020 to January 2021, patients (aged≥18 years) taking IFX were recruited at Gastroenterology Unit, Padua University Hospital. In each patient, IFX levels from capillary whole blood collected by finger stick were performed using the ProciseDx IFX assay with reportable range between 1.7-77.2 µg/mL; at the same time, a serum sample from venous blood was collected to carry out Grifols’ Promonitor ELISA test (range 0.035–14.4 µg/mL). A Deming regression test was used to identify the correlation between the two methods. Results Eighty-seven patients were enrolled (63% males; mean age of 44±16), with 52% of them having CD, 45% UC and 3% an undetermined-Inflammatory Bowel Disease. The assessment with ProciseDx POCT was feasible in each patient and only in three cases blood collection from finger prick was repeated. Moreover, from blood collection to results we needed about 3±0.5 minutes, while serum ELISA analysis required the collection of at least 40 samples (around three weeks at our centre) and 3 hours to be performed. 39 patients (59% males; mean age of 44±16) had TL as assessed by ProciseDx IFX assay lower than 1.7 or greater than 14.4 µg/mL, in accordance with ELISA assessment. Among the remaining 48 patients (67% males with mean age of 45±17), The correlation between the two tests was high (the total results showed an R squared of 0.691 (95% CI 0.717-0.902). Conclusion The ProciseDx POCT has good accuracy but was more rapid and easy to be performed in providing the results of Therapeutic Drug Monitoring in outpatients taking IFX. This could lead to a more effective optimization of the biological drug, thus avoiding treatment failure.

Background Anti-tumor necrosis factor alpha (anti-TNFα) therapy is commonly used to treat refractory pediatric inflammatory bowel disease (IBD). Prolonged use of anti-TNFα therapy has been linked to a number of adverse events. We aimed to assess the relationship between serum trough concentrations (TC) of anti-TNFα and adverse events rate among patients with pediatric IBD. Methods The medical records of 135 pediatric patients with IBD who were treated with anti-TNFα agents from 2015 to 2020 and had sequential monitoring of TC were reviewed retrospectively for the presence of adverse events (infusion reactions, infections, acute cutaneous reactions, psoriatiform rashes, elevated transaminases and others). The association between demographic or disease related variables and adverse events were analyzed using multivariate analysis. Results Out of 135 patients, [59 (43.7%) female, mean age at diagnosis 12.9 (±3)years, 111 (82.2%) Crohn’s disease] who had 1645 measurements of TC [1037(63%) infliximab, range 0-46 µgr/ml] during a median follow-up period of 1.7 years (1.1-2.7), we recorded 120 adverse events in 42 patients (31%). When analyzing TC as continuous measure or as a categorical measure (> or Conclusion Based on our cohort, higher TCs were not associated with higher rate of anti-TNF related adverse events whereas younger age at diagnosis increased the risk for such events. The study protocol was approved by the local Internal Review Board at the Rabin/Schneider Medical Center (RMC0320-10).

Objectives To evaluate the ability of body-weight-driven renal function assessment (RFA) formulae to predict on-target elimination rate ranges for gentamicin in patients with varying degrees of renal function. Methods A 6 year retrospective pharmacokinetic study was conducted at a university teaching hospital. Results A total of 85 patients met the inclusion criteria and 127 pharmacokinetic files were analysed from patients on medical-surgical wards (53%) and medical-surgical ICUs (13%) receiving intravenous gentamicin for treatment, as well as those for patients receiving it for surgical prophylaxis (34%). Each RFA formula was examined against standard dosing tables for gentamicin. A table of acceptable elimination rates was generated using a traditional peak of 8 mg/L and trough between 0.5 and 2 mg/L associated with each of the dosing interval extensions. The ability of each RFA formula to select on-target elimination rates was evaluated. The RFA formula assuming a normalized body weight of 72 kg and a modified creatinine reagent adjustment factor of 90% provided the most accurate on-target elimination rate selection. This method was superior to dosing interval selection based on the Modification in Diet Renal Disease (MDRD) formula, Sanford's guide method, as well as the Cockcroft-Gault formulae using total body weight, ideal body weight or lean body weight ( P < 0.0001). Conclusions Based on the use of gentamicin as a surrogate guide for renally adjusted drugs, these results support dosing interval selection based on a normalized body weight method and a formula reagent adjustment factor of 90% within the Cockcroft-Gault formula.

Background Anti-TNF α antibodies have contributed to the good prognosis in patients with inflammatory bowel diseases (IBDs). Adherence of these drugs affects the treatment effects in patients with IBDs. Recently, the use of an adalimumab (ADA) autoinjector (AI) was approved in Japan. However, the effects of the use of this AI in patients with IBDs are not clear. We elucidated whether the use of an AI for ADA administration improves the adherence to and acceptability of ADA therapy compared with the use of syringe (SYR) type. Methods This was a single-centre prospective observational study approved by the institutional review board of our hospital. Twenty-six quiescent IBD patients, including ulcerative colitis and Crohn’s disease, treated by administration of ADA 40 mg using SYR every other week for >6 months or naive to ADA were enrolled in this study. The patients administered treatment using SYR were switched to an AI. The AI-naive and AI-switched patients were administered ADA treatment using AI for 6 months. The levels of adherence and acceptability, including pain and satisfaction levels, were measured using the visual analogue scale before and after treatment with ADA administered using AI. Serum ADA trough levels were also examined. Results Of the 26 enrolled patients, 1 with selection error, 1 with a rejection of approval and 2 with recurrence were excluded. In total, 24 participants were included in the final analysis. The mean (SD) age of the participants was 12.6 (8.4) years. Of the participants, 54.5% (12/22) were male, 68.2% (15/22) had ulcerative colitis, 27.3% (6/22) used thiopurine and 77.35 (17/22) were administered treatment using SYR. The adherence rate improved after switching to AI. The adherence rate of patients who received maintenance ADA was not significantly different from that of the ADA-naive patients (SYR type: 89.1 ± 12.7 mm, AI-switch: 94.0 ± 8.6 mm, AI-naive: 87.0 ± 21.6 mm, not significant [NS]). According to the acceptability of ADA AI, the pain intensity significantly decreased after switching. It was also significantly lower in the AI-naive group than in the SYR group (SYR: 55.0 ± 24.8 mm, AI-switch*: 87.3 ± 15.4 mm, AI-naive*: 92.2 ± 10.1 mm, *p < 0.01 compared with SYR). The level of satisfaction significantly increased after switching (SYR: 62.6 ± 27.9 mm, AI-switch*: 85.9 ± 12.5 mm, AI-naive: 81.2 ± 20.9 mm; *p < 0.01, compared with SYR). The ADA trough level was not significantly different after switching (SYR: 11.0 ± 9.1 mg/ml, AI-switch: 9.9 ± 5.5 mg/ml, NS). Conclusion ADA administration using AI resulted in significantly improved acceptability without changes in serum ADA trough levels.

Background Although higher infliximab (IFX) trough levels (TL) have been associated with better outcomes, the ideal predictive sampling time and cut-points to achieve endoscopic remission remain unclear in children with inflammatory bowel disease (IBD). Therefore, we evaluated the pharmacokinetics of IFX during induction to predict long-term outcome of IFX. Methods All children with Crohn’s disease (CD) or ulcerative colitis (UC) starting IFX therapy (5 mg/kg at weeks 0–2–6–12) for active luminal disease from May 2017 till May 2019 were followed prospectively. IFX levels were measured by Ridascreen IFX Monitoring ELISA (TL at weeks 2–6–12, peak at weeks 0–2–6 and intermediate at weeks 1–4). IFX levels and cumulative drug exposure (area under the curve (AUC) till week 12) were correlated with the outcome at month 6. Clinical remission was defined as PUCAI/PCDAI Results A total of 252 serum induction levels were included from 32 patients (20 CD and 12 UC; 38% male; median age at start of IFX 13.8 years [11.3–14.9]; 84% on concomitant thiopurines). Clinical remission was achieved in 24 (75%) patients and 18 (56%) were in endoscopic remission (all in deep remission) at month 6. Endoscopic remission at month 6 was associated with significantly higher median IFX TL at week 4 (38.8 µg/ml [24.3–46.0] vs. 23.5 µg/ml [10.5–36.6], p = 0.017), at week 6 (19.9 µg/ml [10.1–26.3] vs. 11.1 µg/ml [3.7–19.9], p = 0.031), at week 12 (9.6 µg/ml [5.5–11.9] vs. 3.5 µg/ml [2.7–7.2], p = 0.004; fig1.) and higher AUC week 0–12 (4574.7 µg*day/ml [3783.0–5160.8] vs. 3722.9 µg*day/ml [3102.2–3991.9], p = 0.008). Median IFX TL at week 12 were significantly higher in children with clinical remission (8.6 µg/ml [5.1–12.0] vs. 4.3 µg/ml [3.1–5.9], p = 0.033), but not for biological remission (6.7 µg/ml [4.0–12.0] vs. 4.3 µg/ml [1.2–7.2], p = 0.250; Figure 2) at month 6. ROC analysis identified an IFX TL at week 12 ≥ 5.0 µg/ml and an AUC weeks 0–12 ≥ 4056.0 µg*day/ml as minimal target to achieve endoscopic remission at mo. 6 (AUROC: 0.796 [95% CI: 0.62–0.97] and AUROC: 0.778 [95% CI: 0.61–0.94], respectively; Figure 3.). Height, haemoglobin and PCDAI score at start of IFX therapy, significantly correlated with week 12 IFX TL. Conclusion Adequate IFX exposure during induction in paediatric IBD patients is associated with significantly better clinical, endoscopic and deep remission rates at month 6. Model-informed precision dosing can assist physicians to achieve optimal exposure during induction more precisely (and rapidly) what is essential for an optimal outcome.

Background Anti-TNF α agents, including infliximab (IFX) and adalimumab (ADA), are arguably the most effective medical therapies for fistulising perianal Crohn’s disease (CD). Increased rates of perianal fistula healing have been reported with increased IFX trough levels. Our study aimed to determine the correlation between perianal fistula healing and closure with IFX and ADA trough levels in fistulising perianal CD patients on maintenance therapy. Methods In this multi-centre retrospective cross-sectional study, we identified CD patients with perianal fistulae on maintenance IFX or ADA who had an IFX or ADA trough level within 3 months of clinical assessment. Data collected included demographics, serum IFX and ADA trough levels (mg/l) and concomitant medical and surgical therapy. The primary outcome was fistula healing, defined as a cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing as well as closure of all external fistula openings. Receiver operating characteristic (ROC) curve analysis was performed to identify the IFX and ADA concentration cut-off points with combined maximal sensitivity and specificity that corresponded to fistula healing. Results A total of 123 patients (IFX = 72; ADA = 51) were included. Fifty-four (75.0%) patients on maintenance IFX achieved fistula healing and 22 (30.6%) achieved fistula closure. Patients who achieved fistula healing had significantly higher median IFX trough levels compared with patients who did not [6.2 (interquartile range 3.1 - 9.6) vs. 3.0 (0.3 - 6.2), (p = 0.007)]. The median IFX trough levels for patients with and without fistula closure were not significantly different [6.4 (2.9 - 9.8) vs. 4.9 (2.5 - 8.9), (p = 0.277)]. Forty (78.4%) patients on maintenance ADA achieved fistula healing and eighteen (35.3%) fistula closure. Patients who achieved fistula healing had a significantly higher median ADA level compared with those who did not [8.7 (6.6 - 12.0) vs. 5.4 (2.5 - 8.3), p = 0.007]. The median ADA trough levels for patients with fistula closure and without fistula closure were not significantly different [9.6 (6.7 – 12.0) vs. 7.7 (4.4–9.8), p = 0.098]. An IFX cut off point of 6.10mg/l was associated with healing (sensitivity 52%; specificity 78%; area under the curve (AUC) 0.72). An ADA cut off point of 7.05mg/l was associated with healing (sensitivity 70%; specificity 73%; AUC 0.77). Conclusion Higher IFX and ADA trough levels are associated with fistula healing. No association between IFX and ADA trough levels and fistula closure was seen, although larger numbers may be required. To the best our knowledge, this is the first study to demonstrate a significant association with both higher IFX and ADA levels with fistula healing in perianal CD.

Background Pharmacokinetics of vedolizumab have been associated with therapy outcome, although real-life data has been contradictory. Thus, we set to examine whether vedolizumab levels before therapy intensification may be associated with clinical, inflammatory and endoscopic outcomes further on. Methods In this retrospective cohort study, vedolizumab drug levels were determined in vedolizumab-treated patients with insufficient therapy response from six medical centers in Israel and Europe, before they underwent dose-intensification. The success of dose-increase gauged by clinical scores, inflammatory (C-reactive protein values, calprotectin) indices and endoscopic data was assessed vis-à-vis pre-escalation drug levels. Results Overall, 161 IBD patients (74, 46% Crohn’s disease) were included, of whom 32 patients underwent intensification at end-of-induction (week 10) and 129 during maintenance period (weeks 14–44, median week 30). In total, 34%, 60% and 30% of the 161 patients reached clinical, inflammatory and endoscopic remission by 6 months after intensification, respectively. Among 129 patients intensified during maintenance period, pre-intensification trough levels were not lower among those reaching clinical and inflammatory remission after dose-escalation (median vedolizumab levels 34.4 vs. 24.4 μg/ml, 30.7 vs. 30.5 μg/ml, p = 0.09, 0.25 respectively). Patients who reached mucosal healing also had higher, rather than lower, vedolizumab levels before intensification (median vedolizumab levels 31.3 vs. 17 μg/ml, p = 0.04 for patients with and without mucosal healing, respectively). Similarly, among 32 patients intensified at week 6 by an extra-dose at week 10, those with higher, while not lower, levels before escalation had higher rates of post-escalation clinical remission (median levels 101 vs. 61.5 μg/ml, p = 0.05). A similar trend was observed in terms of mucosal healing (88.5 vs. 43 μg/ml, p = 0.09) and inflammatory remission (median levels 100 vs. 55 μg/ml p = 0.15). Conclusion Lower vedolizumab trough levels before interval shortening were not predictive of success of the intervention. These results argue against a pharmacokinetic basis for insufficient response to vedolizumab and question the need for dose-escalation. A higher pre-escalation drug-level was associated with better later outcomes, possibly indicating a lower inflammatory burden, and may serve to predict patients with low likelihood to respond to therapy continuation.

Background The previous usual adalimumab (ADA) intensification regimen was 40 mg every week (ew)). Recently the original laboratory commercialised the 80 mg injection pen, with pharmacokinetic studies indicating an alternative intensification dose of 80 mg every other week (eow) similar to 40 mg ew, even though interchangeability has not been assessed in clinical practice. In the biosimilars era, this pen was sold to many Hospitals at the same price as the 40mg pen. For this fact and for patient comfort, we proposed our stable-intensificated-ADA IDB patients on a 40 mg ew regimen, to change the dose to 80 mg eow (clinical practice). Methods In this setting, we designed an observational study to monitor clinical, analytical and pharmacokinetic outcomes through this posologic change, for patients who signed the Informed Consent. Clinical (Harvey–Bradshaw index (HBI), partial Mayo score), analytic parameters and ADA trough levels were prospectively obtained at baseline, 4 and 8 months after posologic change. We describe the evolution of this cohort and calculate savings. Results 12 from 18 patients initially evaluated for new dose regimen were finally changed. All of them agreed to participate in the study. Eighty-three per cent were CD patients, 58% males, median age 51 years old (intecuartil range (IQR) 42–55). Median age at IBD diagnosis was 34 years (IQR 24–44). In 9 patients ADA was the first-line biologic. Median IBD duration before starting ADA was 6 years (IQR 5–8). Median time from ADA initiation to intensification was 31 months (IQR 14–55). The median time of ADA intensification was 37 months (IQR 30–66). Seventy per cent of patients were on immunosuppressors (IS) at the start of the study. Table 1 shows the results of clinical, analytical variables and ADA trough levels at baseline, 4 and 8 months. No differences were found. At 4 months, all patients maintained ADA 80 mg eow. Two patients referred mild worsening, (HBI from 3–4 to 5–6) without significant changes in CRP, calprotectin or ADA levels. They recovered after restoring the previous regimen (ADA 40mg ew). At 8 months, ADA was stopped in one patient in remission with undetectable ADA levels and positive ATI. Total savings in the first 8 months were 59022 €. Conclusion in IBD patients with stable response to ADA intensification regimen of 40 mg ew, changing to 80mg eow seems to maintain response and similar trough levels, although some patients may perceive mild symptoms. Economic savings are 50% per patient.

Background Ustekinumab (UTK) is a human immunoglobulin (Ig) G1 kappa monoclonal antibody approved in 2017 for the treatment of Crohn’s Disease (CD). Up until now, there has not been enough evidence of the relationship between ustekinumab trough levels (UTL) and the clinical evolution and biological markers of the disease. Our study aimed to investigate the relationship between UTL and different biomarkers in a real-world setting. Methods We performed a retrospective observational study including patients up to 18 years with CD receiving subcutaneous maintenance regimen of 90 mg UTK every 8 weeks and available UTL. Biochemical response and remission were evaluated with faecal calprotectin (FC) and C-Reactive Protein (CRP) levels. The biochemical response was defined as a decrease of 50% or more of FC and/or CRP baseline levels, and biochemical remission as FC level Results Forty-two patients were included (27 men and 15 female), with an average age of 47.7 years. The average FC levels were 1358,5μg/ml at the beginning of the treatment. In the maintenance period, we observed a biochemical response in 69% of patients, whose UTL were significantly higher than in non-responders (2.25 µg/ml [IQR: 3.08] vs. 0..65 µg/ml [IQR: 1.95]. respectively; p = 0.037). Likewise. 38% of patients achieved biochemical remission (responders 2.125 µg/ml [IQR: 2.25] vs. non-responders 1.5 µg/ml [IQR: 3.26]; p = 0.476). The AUC for predicting biochemical response by means of UTL was 0.703 [CI 95%: 0.529–0.877] (p = 0.037), with sensitivity of 51%, specificity of 76% and a cut-off of 2.20 μg/ml. Conclusion There is limited data on the association between UTL and patient outcome. Our study demonstrates the association between improvement of different biomarkers and higher levels of UTL, with a significant statistic result for biochemical response and non-significant statistic result for biochemical remission, maybe due to a small sample, but with a positive trend. Further studies are necessary in order to conclude that UTL is significant in the management and evolution of the disease and to determinate the optimal cut-off.