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Vancomycin is a glycopeptide antibiotic that has been used primarily in the treatment of methicillin-resistantStaphylococcus aureusinfections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended.Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinician’s experience and expertise.In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. The target trough concentration was attained at comparable rates with the model- and expert-recommended dosing regimens, suggesting that the ML model successfully incorporated the experts’ knowledge. The predictive model developed here will contribute to improved decision making for initial vancomycin dosing and early attainment of therapeutic windows.

Introduction Because of its lower risk of renal toxicity than vancomycin, teicoplanin is the preferred treatment for methicillin-resistant Staphylococcus aureus infection in patients undergoing continuous venovenous haemodiafiltration (CVVHDF) in whom renal function is expected to recover. The dosing regimen for achieving a trough concentration (Cmin) of ≥20 μg/mL remains unclear in patients on CVVHDF using the low flow rate adopted in Japan. Methods The study was conducted in patients undergoing CVVHDF with a flow rate of Results Overall, 60 patients were eligible for study inclusion. The proportion of patients achieving the Cmin target was significantly higher for the enhanced regimen than for the high-dose regimen (52.9% versus 8.3%, p = 0.003). In multivariate analysis, the enhanced regimen (odds ratio [OR] = 39.93, 95% confidence interval [CI] = 5.03–317.17) and hypoalbuminaemia (OR = 0.04, 95% CI = 0.01–0.44) were independent predictors of the achievement of Cmin ≥ 20 μg/mL. Conclusions An enhanced teicoplanin regimen was proposed to treat complicated or invasive infections by methicillin-resistant Staphylococcus aureus in patients receiving CVVHDF even with a low flow rate.

Purpose: We aimed to evaluate the blood concentration of levetiracetam (LEV), as a second-line drug, in patients with status epilepticus (SE) in an emergency clinical setting. Methods: We prospectively evaluated 20 consecutive patients with SE admitted to our department between July 2017 and July 2019. LEV (2500 mg) was administered via bolus infusion after diazepam infusion, followed by 500 mg every 12 h for 48 h and then 500 mg orally. The primary outcomes were LEV blood concentration 15 min, 12 h, 48 h, and 96 h after administration and the proportion of patients showing trough LEV concentration within the therapeutic range. The secondary outcomes were the discontinuation of apparent convulsive seizure, epileptic wave on electroencephalogram, tracheal intubation, adverse events related to blood parameters, and abnormal findings in vital signs examination. Results: Median blood LEV (2500 mg) concentration at 15 min after administration was 81.6 μg/mL. The median trough concentration after 12, 48, and 96 h was 28.8, 10.5, and 9.1 μg/mL, respectively. Moreover, 95% of patients had trough concentration above the lower limit of the therapeutic blood concentration (>12 μg/mL) after 12 h. Regarding secondary outcomes, endotracheal intubation, seizure suppression, and abnormal electroencephalogram findings were observed in approximately 40%, 90%–95%, and 41% of patients, respectively. No abnormal findings were noted in blood tests and vital sign examination, although the AST/ALT levels increased in 10% of the patients. Conclusion: After bolus administration of 2500 mg, the blood LEV concentration reached the therapeutic window in patients with early-stage SE.

Objectives This systematic review and meta-analysis was designed to determine the optimal trough concentration of voriconazole for children with invasive fungal infections (IFIs). Methods We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and Japana Centra Revuo Medicina) for clinical studies describing the voriconazole trough concentration. We used stepwise cut-off values of 1.0–2.0 mg/L for efficacy and 3.0–6.0 mg/L for safety. The efficacy outcomes were treatment success and all-cause mortality, and the safety outcomes were hepatotoxicity, neurotoxicity and all-cause adverse events. Results Nine studies involving 211 patients were included in the analysis. The probability of treatment success against IFIs was significantly increased at cut-off values of ≥1.0 mg/L (odds ratio [OR] = 2.65, 95% confidence interval [CI] = 1.20–5.87). Our analysis did not find any relationship between the trough concentration and survival. Concerning safety, the occurrence of any outcomes did not significantly differ according to the voriconazole trough concentrations at any cut-off value. However, in a subgroup analysis of Asian study locations, a significantly higher risk of hepatotoxicity was demonstrated at voriconazole trough cut-off values ≥ 3.0 mg/L (OR = 8.40, 95% CI = 1.36–51.92). Although a significant correlation between the voriconazole concentration and hepatotoxicity was evident in regression curve analysis, (y = 0.1198e0.2298x), no correlation was demonstrated for neurotoxicity (y = 0.3913e−0.008x). Conclusion Our findings suggest that the optimal trough concentration for increasing clinical success and minimizing hepatotoxicity during voriconazole therapy in children with IFIs, particularly for Asian populations, is 1.0–3.0 mg/L.

Background The optimal loading dose of teicoplanin in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) has never been determined by therapeutic drug monitoring. This study investigated the appropriateness of proposed loading dose regimens of teicoplanin when administered to patients receiving VA-ECMO by using a previously proposed loading dosage and measuring the teicoplanin trough concentration (Ctrough). Methods Patients who initiated teicoplanin therapy while receiving VA-ECMO were enrolled. Every included patient received four loading doses of teicoplanin at a dose of 12 mg/kg. The first three doses were administered 12 h apart, and the fourth dose was administered 24 h after the third dose. Blood samples were collected before administering the maintenance dose (i.e., the fifth dose), and the teicoplanin Ctrough was measured. Serum teicoplanin levels were determined using an Agilent 1290 ultra-high performance liquid chromatography system. Results The teicoplanin Ctrough was successfully tested in 11 patients. Their median age was 68.2 years, and 81.8% of them were men. The median of each loading dose was 11.6 (range, 10.7–12.8) mg/kg. The median teicoplanin Ctrough was 22.01 (range, 14.85–44.84) mg/L. All patients had a Ctrough of more than 10 mg/L, whereas 90.9% (10/11) of the patients achieved a Ctrough of more than 15 mg/L. Conclusion The loading dosage consisting of four doses of teicoplanin administered within the first 72 h at a dose of 12 mg/kg/dose could achieve an adequate therapeutic Ctrough of teicoplanin in patients receiving VA-ECMO.

Objective This study was designed to investigate the characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia. Methods Fifty-seven cancer patients complicated with severe pneumonia were included in this research. Vancomycin serum trough concentrations were measured using the fluorescence polarization immunoassay (FPIA) method. The Bayesian estimator was used to calculate the pharmacokinetic parameters. Results The average initial therapeutic dose of vancomycin was 15.18 ± 3.29 mg/kg (q12 h). Our study shows that vancomycin initial trough concentrations measured in cancer patients are significantly reduced (6.54 ± 3.11 mg/L; p 1.44 mg/L), Delayed group (Cys-C≤1.44 mg/L) had much lower trough concentrations. Meanwhile, CL and CLcr were significantly increased in Delayed group (Cys-C≤1.44 mg/L). Although the clinical outcomes were similar between two groups, the duration of vasoactive agent in Early group was considerably shorter compared with Delayed group (χ2 = 4.213; p Conclusions The serum trough concentration of vancomycin was significantly reduced in cancer patients complicated with severe pneumonia. Higher dosage regimen is needed to ensure clinical effectiveness. The Cys-C level measured prior to administration of vancomycin is suggested to be the most suitable parameter to predict whether vancomycin trough concentration is up to standard dosage. Especially for patients with baseline Cys-c less than 1.44 mg/L, it is more likely to need higher dosage algorithm.

Although the superiority of vancomycin dosing based on area under the concentration-time curve (AUC0-24) over that based on trough concentration has been reported, a dosing strategy to achieve the target AUC0-24 has yet to be developed. The objective of this study was to develop a convenient useable nomogram for vancomycin dosing to obtain the target AUC0-24 (400 μg h/mL). The nomogram was pharmacokinetically developed in a retrospective manner. The number of enrolled patients and concentrations was 166 and 309 for development of the nomogram, 99 and 181 for evaluation of the nomogram, respectively. The nomogram was developed as doses per personal body weight corresponding to each range of estimated glomerular filtration rate (eGFR), which was identified to be the covariate for vancomycin clearance by non-linear mixed effect modeling. The nomogram described the surrogate trough concentration for the target AUC0-24 was calculatedly different for each eGFR range (9.3–15.0 μg/mL). The rate of attainment of therapeutic range using surrogate trough concentration to obtain the target AUC0-24 was 63.8% in the evaluation period. We have developed and evaluated the first convenient useable nomogram of vancomycin dosing to obtain the target AUC0-24.

Background Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every 3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab 400 mg dose every 6 weeks (Q6W) with the Q3W regimens. Methods The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses. Concentration-time profiles were simulated using the established population pharmacokinetic model of pembrolizumab based on 2993 subjects from five clinical trials across tumour types. Efficacy was bridged by evaluating projections of average concentration over the dosing interval (Cavg) and trough concentration (Cmin) at steady state (ss). Safety was bridged by ensuring that concentrations were below those at 10 mg/kg dose every 2 weeks (Q2W), the maximum clinical dose. Results The 400 mg Q6W dose had similar predicted exposure (Cavg,ss, geometric mean ∼1% higher) as the 200 mg Q3W dose. Fewer than 1% of subjects had transiently lower Cmin,ss than that observed for 200 mg and 2 mg/kg Q3W. Despite these reductions, similar target saturation is expected. The predicted peak concentrations (Cmax,ss) for 400 mg Q6W were substantially (∼65%) lower than the 10 mg/kg Q2W dose. Conclusions Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg Q3W doses across tumour types. Clinical trial registration numbers NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.

Background: Vancomycin is a common drug used in children with severe infection. In adults, at least 15 mg/L of the optimal vancomycin trough concentration (Ctrough) is needed to generate the target 24-h area under the concentration-time curve (AUC24) to the minimum inhibitory concentration (MIC) of 400 for a pathogen with the MIC ≤1 mg/L. Objectives: To determine vancomycin PK in children with severe infection and to explore the correlation between vancomycin Ctrough and AUC24 in children, as well as to propose the appropriate vancomycin dosages using Monte Carlo simulation. Materials and methods: Children aged 2–18 years who were admitted to Chiang Mai University Hospital and received intravenous vancomycin for severe infection were included in the study. Serum samples for vancomycin PK were obtained before and serially after the administration of the first dose according to the protocol. Pharmacokinetic analyses were performed using Phoenix WinNonlin® 7.0 and NLME™7.0. Results: Fourteen children with 64% males and age range from 2 to 13 years were included in this study. Non-compartmental analysis revealed the median volume of distribution, clearance, and elimination half-life of 0.58 L/kg, 2.82 mL/kg/min and 2.33 h, respectively. Vancomycin serum concentrations were best described by a two-compartmental model with first-order elimination.The observed Ctrough at 6 h correlated well with the AUC24. The median vancomycin Ctrough at steady state that correlated with the AUC24 ≥ 400 and

Background/purpose: Dabigatran is effective in preventing ischemic stroke and systemic embolism in patients with atrial fibrillation. Although the therapeutic window for dabigatran is wide, its pharmacokinetic properties can differ between specific populations. This study aimed to establish a real-life plasma dabigatran concentration database and investigate potential factors affecting this concentration in Asians. Methods: Patients under dabigatran therapy were recruited. Plasma dabigatran concentration was determined in trough and peak blood samples by using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Factors affecting the dabigatran concentration were investigated. Results: A total of 46 patients (33 male, 71.7%) were prospectively enrolled. Most of them were receiving a low dose regimen (110 mg twice daily, n = 38, 82.6%). The trough and peak concentrations were significantly correlated (p 3 points, and HAS-BLED score ≥3 points. Multiple linear regression analysis identified body weight and serum creatinine as key factors predicting trough concentration (p = 0.003 and 0.005, respectively). Importantly, drug adherence was the only independent factor associated with low trough concentration, defined as the lowest 20th percentile in our study cohort (n = 10, hazard ratio = 9.07; 95% CI, 1.12 to 73.22; p = 0.004). Conclusion: Dabigatran monitoring may be considered for patients at risk of overexposure, especially those with low body weight and renal insufficiency, and also for detecting those with extremely low drug concentration. Keywords: Adherence, Atrial fibrillation, Dabigatran, Drug concentration, Ischemic stroke, Pharmacokinetics

A rapid and specific reversed-phase high-performance liquid chromatographic (RP-HPLC) assay with UV detection has been developed and validated for the simultaneous determination of imipenem and meropenem in human plasma. The extraction process was performed through protein precipitation method using acetonitrile and dichloromethane, and the recoveries of quality controls (QCs) were > 91.5%. Isocratic elution followed by gradient elution of acetonitrile and water was employed over a C18 analytical column for separation. The detection was performed at 298 nm. This method was accurate and reproducible (coefficient of variation, CV < 8%), allowing quantification of carbapenem at the plasma-level ranges from 0.1 to 100 μg/ml without interference of any of the 30 frequently prescribed drugs. Stabilities of imipenem and meropenem were determined with or without stabilizer solutions at -80°C, -20°C, +4 °C and room temperature 20°C. These two drugs showed higher stability at the low temperatures. Addition of 3-(N-morpholino) propanesulfonic acid (MOPS) might also increase their stability. The results of therapeutic drug monitoring (TDM) in neonates and adults showed high inter- and intra- individual variabilities in the trough concentrations of imipenem and meropenem, thus confirming the importance and necessity of TDM. For neonatal patients, imipenem 20 mg/kg, q12h (40mg/kg/day) failed to produce significant therapeutic effects, and either the dose or the frequency was adjusted to achieve 60mg/kg/day or above to maintain the trough concentration required for the curative effect. The low operational cost and good separation efficiency would help implement this assay for the routine therapeutic drug monitoring of imipenem and meropenem in hospitals.

Recently, several studies on pharmacokinetics parameters of daptomycin reported that plasma trough concentration was linked to efficacy and adverse effects, suggesting the usefulness of therapeutic drug monitoring. Although some methods for determining total daptomycin concentration using liquid chromatography coupled to tandem mass spectrometry were established previously, no sensitive quantification method for free drug concentration was established. In this study, we aimed to develop a quantitative method of measuring both total and free daptomycin concentrations using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), by which both trough and maximum concentrations can be measured. Plasma samples were prepared by solid phase extraction. Free fractions were obtained by ultrafiltration. The assay fulfilled the requirements of US Food and Drug Administration and the European Medicines Agency for assay validation. The methods for total and free drug showed good fit over wide ranges of 0.5–200 and 0.04–40 μg/mL, with lower limits of quantitation of 0.5 and 0.04 μg/mL, respectively. Recovery rate of free daptomycin from ultrafiltration was approximately 100%. Extraction recovery rates of total and free drug measurements ranged from 57.1 to 67.4% and 54.6 to 62.3%, while matrix effect varied between 111.9 and 118.7% and 104.0 and 127.1%, respectively. The maximum and trough concentrations of total and free daptomycin in plasma from two patients in intensive care unit were successfully determined, demonstrating the feasibility of clinical application of the novel methods for determining plasma total and free daptomycin concentrations. In conclusion, we succeeded to develop a sensitive and selective method using UPLC-MS/MS for quantitative measurement of total and free daptomycin concentrations in plasma.

Cefepime is a first-line antibiotic for the treatment of febrile neutropenia (FN) in haematological cancer patients. Therapeutic drug monitoring (TDM) of cefepime is frequently advocated. However, it remains unclear what range of concentrations should be targeted for maximal efficacy and minimal toxicity. Therefore, we examined the relationship between cefepime exposure and clinical efficacy or neurotoxicity in FN patients. This prospective, observational, single-centre study included all adult hospitalised patients presenting with FN at the haematology ward and treated with cefepime from August 2019 until October 2020. Primary outcomes were incidence of breakthrough infection and neurotoxicity and their relationship with free cefepime serum trough concentrations. A total of 76 patients were included, contributing 96 cefepime treatment courses. The median (interquartile range) estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) and free cefepime trough concentration were 101 (85-112) mL/min/1.73m2 and 8.6 (4.9-16.2) mg/L, respectively. Interpatient and intrapatient variability in cefepime trough concentrations was largely explained by renal function. No cefepime-related breakthrough infections occurred during cefepime treatment. Neurotoxicity, probably induced by cefepime administration, occurred during 6/96 (6.3%) treatment courses. Patients with neurotoxicity showed a significant trend for higher trough concentrations (median 15.4 mg/L vs. 8.6 mg/L; P 1 mg/L.

Background We evaluated the effects of using erythromycin (ERY) in liver transplant recipients to improve the early postoperative control of tacrolimus (TAC) concentration. Methods This study adopts a retrospective medical record analysis method from January 2015 to December 2017. Assessment items include TAC daily dose (D), TAC whole blood trough level (Co), rejection episodes, and adverse effects. The magnitude of ERY inhibition on TAC metabolism was decided by analyzing dose-corrected trough concentration (Co/D). Oral 250 mg ERY every day to every other day was prescribed when patients needed to swallow more than 10 capsules of TAC per day, TAC trough levels rose too slowly, and/or acute rejection occurred. TAC trough levels were obtained daily. ERY was stopped when the TAC trough level was above 10 ng/mL or rejection episode relieved. Results A total of 8 liver transplant recipients was collected. Oral ERY was administered at 6 to 13 days after transplantation. The duration of ERY regimen was 2 to 7 days. The average initial and maximum Co/D was 0.6 ± 0.0 and 1.8 ± 1.0. After ERY was deleted, Co/D was back to the value without ERY at about 2 to 20 days. The magnitude of interaction between tacrolimus and erythromycin is 1.4- to 4.6-fold. The highest dose of TAC was 10 to 12 mg/d. There were no drug-related complications during this period. Acute rejection relapsed in 1 patient after we stopped ERY. Conclusion Coadministration of ERY and TAC is a strategic choice for liver transplant recipients whose TAC blood concentration was difficult in approaching therapeutic levels.

Background The online percent coefficient of variation reporting system could monitor the variation of tacrolimus trough level (T0) and identify kidney transplant recipients (KTRs) with a higher percent coefficient of variation (%CV) instantly. Consequently, transplant doctors and pharmacists could take actions to improve drug variability. The purpose of this study was to determine the efficacy of the system for higher intrapatient variability of T0 in KTRs. Methods The T0 data were collected with KTRs routinely followed up at an outpatient clinic between June 2016 and November 2016. The %CV was calculated with T0 data within 6 months before and after the index date. The last outpatient clinic visit date was before December 1, 2016. The KTRs with %CV of T0 greater than 22% were enrolled. Results The study consisted of 183 KTRs (96 male, 87 female), the median age was 50 years (interquartile range [IQR], 41.0–57.0), and the median years post-kidney transplantation was 7 years (IQR, 3.0–12.4). The median T0 and creatinine level at baseline were 6.09 ng/mL (IQR, 4.80–7.52) and 1.33 mg/dL (IQR, 1.03–1.72), respectively. After the intervention, the median %CV of T0 was significantly lower than before, 32% (IQR, 26%–42%) vs 22% (IQR, 15%–33%), P Conclusions The results of this study indicate that continuously aggressive intervention with an online %CV reporting system effectively improves intrapatient variability of T0 in KTRs.

Introduction Dabrafenib and trametinib bitherapy provides significant benefits in BRAFV600 mut metastatic melanoma patients; however, adverse events (AE) occur, leading to dose reduction in 33% of patients. We aimed to investigate a relation between plasma dabrafenib and trametinib concentrations and occurrence of AE. Methods Plasma samples from metastatic BRAFV600 mut melanoma patients treated with dabrafenib ± trametinib were prospectively collected at trough concentration before any dose reduction. Dabrafenib and trametinib were measured by UPLC-MS/MS. Plasma threshold of concentration associated with dose reduction for AE was studied by ROC-curve analysis. Results Twenty-seven patients (13M/14F) were included. Dabrafenib trough plasma concentrations displayed high interindividual variability, ranging from 15.4 to 279.6 ng/ml, mean ± SD 58.7 ± 61.1 ng/ml. Trough trametinib plasma concentrations ranged from 4.1 to 23.8 ng/ml, mean ± SD 11.9 ± 4.1 ng/ml. Mean trough dabrafenib plasma concentration was higher in patients with AE requiring dose reduction (30%) than in other patients: 118.6 ng/ml and 33.5 ng/ml respectively ( P A dabrafenib trough plasma threshold of 48 ng/ml can predict the occurrence of adverse events requiring dose reduction.

A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open‐label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low‐dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time‐normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy‐proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration, This post hoc exploratory analysis of the US92 study assesses efficacy and safety events with specific everolimus and tacrolimus trough concentrations, and supports maintaining an everolimus trough concentration of 3–8 ng/mL when combined with low‐dose tacrolimus to achieve favorable efficacy and safety outcomes in renal transplant patients.

Summary Objective To examine the variability and safety of serum trough concentrations of vancomycin in patients admitted to the intensive care unit (ICU) and to analyze the factors influencing the trough concentration. Methods Data were collected retrospectively from ICU patients receiving vancomycin treatment at a fixed dose of 2g/day due to unobtainable weight data, at Changzhou No. 2 People's Hospital, between 2012 and 2015. Vancomycin trough concentrations were compared between groups stratified by sex, age, and estimated glomerular filtration rate (eGFR). Results The vancomycin trough concentration varied significantly among ICU patients on a fixed dose of 2g/day. Only 16.9% of ICU patients met the concentration target of 15–20mg/l, while 25% of patients showed supratherapeutic concentrations. A higher proportion of female patients than male patients showed supratherapeutic concentrations (40.4% vs. 15.5%). The trough concentration was positively correlated with age ( y =0.279 x −2.085; R 2 =0.186) and negatively correlated with eGFR ( y =−0.2 x +33.776; R 2 =0.366). Vancomycin-related nephrotoxicity occurred at an incidence of 5.9%. Conclusions These results suggest that the fixed-dose regimen is not appropriate for ICU patients in view of the low incidence of target trough concentrations and the high incidence of supratherapeutic concentrations. The dose should be individualized based on weight, age, and renal function to improve outcomes and patient safety.

Background Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. Patients and methods This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI C min ) and 3-month PSA response. Results From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50–78]). In univariate analysis, ABI C min was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4–15.6) versus 8.0 ng/mL (CI 95% 5.8–11.6; P = 0.0015). In multivariate analysis, only ABI C min was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01–1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI C min was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI C min above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31–0.99], 12.2 [CI 95% 9.2–19.5] versus 7.4 [CI 95% 5.5–14.7] months otherwise, P = 0.044). Conclusions We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients.

An important element in antimicrobial stewardship programmes is early switch from intravenous (i.v.) to oral antimicrobial treatment, especially for highly bioavailable drugs. The antifungal agent voriconazole is available both in i.v. and oral formulations and bioavailability is estimated to be >90% in healthy volunteers, making this drug a suitable candidate for such a transition. Recently, two studies have shown that the bioavailability of voriconazole is substantially lower in patients. However, for both studies various factors that could influence the voriconazole serum concentration, such as inflammation, concomitant intake of food with oral voriconazole, and gastrointestinal complications, were not included in the evaluation. Therefore, in this study a retrospective chart review was performed in adult patients treated with both oral and i.v. voriconazole at the same dose and within a limited (≤5 days) time interval in order to evaluate the effect of switching the route of administration on voriconazole serum concentrations. A total of 13 patients were included. The mean voriconazole trough concentration was 2.28 mg/L [95% confidence interval (CI) 1.29-3.26 mg/L] for i.v. voriconazole administration and 2.04 mg/L (95% CI 0.78-3.30 mg/L) for oral administration. No significant difference was found in the mean oral and i.v. trough concentrations of voriconazole (P = 0.390). The mean bioavailability was 83.0% (95% CI 59.0-107.0%). These findings suggest that factors other than bioavailability may cause the observed difference in voriconazole trough concentrations between oral and i.v. administration in the earlier studies and stress the need for an antimicrobial stewardship team to guide voriconazole dosing.

Background The aim of this study was to assess the differences in pharmacokinetic (PK) profiles after the 1:1 ratio-based conversion from a twice-daily to a once-daily tacrolimus formulation (TD-TAC and OD-TAC, respectively) in pediatric recipients of kidney transplants. Methods TD-TAC was initially administered to 29 pediatric patients who underwent kidney transplantations between April 2010 and September 2015 and were then subsequently switched to OD-TAC. The switch dose ratio was 1:1, and the 24-hour complete PK parameter assessment was performed before and after the regimen was changed from TD-TAC to OD-TAC. Results The mean total daily dose at baseline was 5.5 ± 2.9 mg (0.18 ± 0.10 mg/kg body weight). Consecutive PK studies revealed no significant difference in the mean time to achieve maximum concentrations and the area under the concentration–time curve from 0 to 24 hours (AUC 0–24 ) of both drug formulations. However, the mean trough concentration (C min ) and the maximum concentration of OD-TAC were 22% and 6% lower and higher, respectively, than those of TD-TAC. Therefore, a better correlation was observed between the AUC 0–24 and C min of OD-TAC than between those of TD-TAC. Conclusions After the change from TD-TAC to OD-TAC, the AUC 0–24 values were equivalent despite a 22% reduction in C min . C min may therefore be an excellent predictor in the therapeutic drug monitoring of OD-TAC because of its superior correlation with AUC 0–24 .

Introduction Orally administered tacrolimus is widely used in hematopoietic cell transplant patients, but multiple clinical situations may arise rendering oral administration infeasible. The undesirable sequelae of intravenous administration, including toxicity, challenges with administration and cost call for innovative solutions to conserve existing supply and optimize safety and efficacy of medication delivery. We sought to demonstrate feasibility of sublingual tacrolimus use and estimate a sublingual-to-oral (SL:PO) conversion ratio in the hematopoietic cell transplant setting. Methods Ten adults undergoing allogeneic hematopoietic cell transplant received tacrolimus 0.04 mg/kg/dose twice daily. Initial doses were given via sublingual route and a steady state trough level was collected after 4 consecutive doses. Participants were then switched to oral tacrolimus, the dose adjusted for a goal trough 8-12ng/mL, and another steady state trough was drawn. Total daily dose was divided by trough concentration for each route to determine the dosing ratio of SL:PO. Results Median trough level following sublingual administration was 11.3 ng/mL. Three of these were within goal, 3 were low (4.7–6.4 ng/mL) and 4 were elevated (15.9–18.6 ng/mL). Median SL:PO ratio was 1.02. In 5 participants the SL:PO ratio was Conclusions Results demonstrate reliable absorption with sublingual tacrolimus use in patients undergoing hematopoietic cell transplant. Sublingual administration may allow for avoidance of the undesirable complications of IV tacrolimus, such as increased toxicities, required hospitalization for continuous infusion, risk of dose conversion and dilution errors and increased cost. Trial Registry name: Use of Sublingual Tacrolimus in Adult Blood and Marrow Transplant Patients, NCT04041219 https://clinicaltrials.gov/ct2/show/NCT04041219?term=NCT04041219&draw=2&rank=1

Background Because of the narrow therapeutic index of digoxin, most cardiologists in Egypt give digoxin holiday for atrial fibrillation and heart failure, it is not clear if the interrupted digoxin regimens are effective since serum digoxin concentrations might fall below the therapeutic range. Objective To evaluate and compare the digoxin serum concentration and patient’s quality of life in the continuous versus interrupted digoxin dosing regimens. Methods Patients were randomized to receive one of four regimens: regimen 1: 0.25 mg daily except Friday ( N = 17); regimen 2: 0.25 mg daily except Thursday and Friday ( N = 17); regimen 3: 0.125 mg daily ( N = 17); and regimen 4: a tailored dose was calculated based on renal function and given daily ( N = 23). After reaching steady state in the two holiday regimens, two plasma samples were collected (preholiday and post holiday trough concentrations); in the other two groups one trough plasma sample was collected. Quality of life questionnaire for atrial fibrillation (QLAF), was administered to all patients at baseline and then after at least one month of digoxin therapy. Results There was a statistically significant difference between the preholiday trough concentration and the trough steady state concentration across the four regimens ( p = 0.002). There was no significant difference in the QLAF questionnaire domains, total scores at baseline, or after the follow up between the four regimens. Conclusion Once daily tablet (0.25 mg) was suitable in maintaining digoxin serum concentration in the recommended therapeutic range, fluctuation in digoxin serum concentration did not affect quality of life for atrial fibrillation patients.

Background Afatinib (AFA), an irreversible ErbB family blocker, is used at the standard starting dose of 40mg for the treatment of patients with EGFR M+ NSCLC. It has been shown previously tolerability guided dose reduction effectively decreases incidence and severity of treatment related adverse events (AEs) during the treatment, and that treatment-related dose reduction was more likely in patients who had higher plasma concentrations of AFA before dose adaptation (Yang et al., Annals of Oncology 2016). After dose reduction, concentrations were similar to those obtained in patients who did not experience AEs, with comparable efficacy. We thus intended to determine a threshold concentration related with dose-reduction or AEs leading to dose-reduction (AELDR). Methods Patients (N = 390) with AFA treatment, analyzable trough plasma concentration (Cmin) determination at D22 and follow-up of at least 6 months were identified from LUX-Lung (LL3 & LL6) studies. Receiver operating characteristic (ROC) curve analysis (univariable regression model) was performed to assess a discrimination potential of AFA Cmin for AELDR. Results The most discriminating threshold of AFA Cmin associated with dose reduction or AELDR between D22 sampling and M6 is at 34 ng/ml. With this concentration threshold, there is a maximal AUC of 0.63 (95%CI: [0.58 – 0.69], a maximal Younden index of 0.267 (49% sensitivity, 78% specificity), with an odds ratio of 3.37 [2.10 – 5.40]) indicating that dose reduction or AELDR are more frequent in patients with concentration ≥34 ng/mL. The analysis also showed that concentration is more often elevated in female, older (>65y), eastern Asian and low-body weight patients. Conclusions Monitoring of AFA plasma levels might be useful for the management of AEs in patients with NSCLC, especially for patients having factors known to be associated with higher AFA plasma exposure or toxicities. These results support the approach of adapting treatment dose based on plasma concentrations of AFA both forAEs and efficacy. Clinical trial identification NCT01121393, NCT00949650. Legal entity responsible for the study M. Molimard. Funding Boehringer Ingelheim. Disclosure C. Frohn: Full / Part-time employment: Boehringer Ingelheim International GmbH. C. Maritaz: Full / Part-time employment: Boehringer Ingelheim France. All other authors have declared no conflicts of interest.

Prescribing appropriate Tacrolimus (Tac) dosing is still a challenge for clinicians due to the interindividual variability in dose requirement and the narrow therapeutic index. Our objective is to identify potential factors that affects Tac exposure in Tunisian Kidney patients and to develop and validate a Tac dose requirement algorithm including genetic and nongenetic variables. A cross-sectional study was performed. To assess the implication of each covariate on Tac exposure, we classified the patients according to quartiles of exposure index (trough Tac concentration/Dose: C0/D). The total population was divided into the building (75%) and validation (25%) groups. Multiple linear regression was applied to determine the algorithm of Tac dose including the patient's genetic and nongenetic variables. A total of 685 samples issued from 102 kidney transplant patients were included in the study. The post-transplant time (PT), ATG therapy, CYP3A4, and CYP3A5 polymorphisms were significantly associated with trough Tac C0/D. However, the age, sex, body weight, and induction by basiliximab did not show any effect on C0/D. Predicted Tac dose was calculated as follows: Tac Dose = − 2,725 - (10−3 * PT day) + (0,09*weight) + (1,40*ATG) + (2,09* CYP3A4*1B allele) + (0,88*gender) + (0,05*Age) + (1,10*CYP3A4*22 allele) + (2,30* target ranges). Our study designed the first algorithm that predicts the Tac dose requirement in Tunisian Kidney transplant patients including genetic and non-genetic factors. The application of such an algorithm should reduce the number of patients with Tac trough concentration outside the target range and could minimize the time to reach a therapeutic C0.

There are many anticoagulant test indexes available for direct oral anticoagulants (DOACs), but how to select the appropriate index and the index cutoff values are still controversial. This is the first study, to our knowledge, to assess the association of different coagulation indicators with clinical outcomes among DOACs using a meta-analysis of observational studies.A medical literature search was conducted using PubMed, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Library from inception to February 2020. Studies that reported relationships between coagulation indexes and clinical outcomes or the diagnostic value of coagulation assays were included in the analysis.A total of 17 articles (7 meta-analyses and 10 systematic reviews) from 8904 citations were included in the analysis. In the analysis of bleeding events with coagulation indexes for DOACs, for peak prothrombin time level (cutoff value of 19-25 s), the pooled results found a sensitivity of 0.61 (95% CI, 0.44-0.75) and a specificity of 0.71 (95% CI, 0.49-0.86). For rivaroxaban, the trough anti-factor Xa concentration (AXA-C) (cutoff value of 400-500 ng/mL) had a sensitivity of 0.53 (95% CI, 0.16-0.87) and a specificity of 0.87 (95% CI, 0.71-0.94), with a diagnostic odds ratio of 7 (95% CI, 2-32). For apixaban, trough AXA-C had a sensitivity of 0.85 (95% CI, 0.60-0.96) and a specificity of 0.83 (95% CI, 0.52-0.95). The AUC of the AXA-C peak was higher than that of the trough AXA-C for apixaban, with a higher sensitivity and specificity. Compared with trough concentration of anti-factor IIa for dabigatran, the peak concentration had a higher specificity (98%) at the cutoff value of 484 ng/mL. In the analysis of thromboembolic events with coagulation indexes for DOACs, peak and trough prothrombin time values were not typically correlated with subsequent symptomatic venous thromboembolism, without a sensitivity or specificity higher than 90%. Trough AXA-C had a sensitivity of 100% and but a low specificity (50%) for rivaroxaban-apixaban. Trough AXA-C had a sensitivity of 100% and a specificity of 32% with a cutoff value of 108 ng/mL for dabigatran.Peak prothrombin time (19-25 s) and AXA-C had a better predictive value on bleeding outcomes for rivaroxaban and apixaban, whereas peak concentration of anti-factor IIa activity can be an indicator for dabigatran. Coagulation indexes might not be a good indicator of thromboembolic events of DOACs. Because the limited studies focused on association of coagulation indicators and clinical outcomes, more studies are needed to verify this in the future.

Background: Various pharmacokinetic studies have demonstrated that proposed pharmacodynamic targets for linezolid cannot be achieved in some patients treated with a fixed 600 mg 12-hourly regimen therefore supporting the use of higher than standard doses in these cases. This study aimed to report the pharmacokinetics and preliminary efficacy and safety of 600 mg 8-hourly dosing of linezolid.Methods: Observational pharmacokinetic study carried out in patients treated with a higher than standard doses of linezolid, 600 mg 8-hourly, for a proven or suspected infection caused by gram-positive bacteria between February 2013 and July 2014. Linezolid plasma concentrations were analysed using a validated HPLC method. Efficacy, safety and clinical outcomes were assessed.Results: Seven patients were included in this data collection and all achieved clinical cure. However, 57.1% of patients manifested haematological toxicity that was associated with trough concentrations exceeding the pre-defined upper limit of 6.3 mg/L (p = 0.047). The other patient that also manifested haematological toxicity had a trough concentration of 6.2 mg/L. The three patients that did not develop toxicity all had trough concentrations

The CDK4/6 inhibitors palbociclib and ribociclib are kinase inhibitors used in association with hormonal therapy for the management of patients with metastatic breast cancer. Like most kinase inhibitors, therapeutic drug monitoring may be used for personalize their dosage. To this aim, we developed and validated a sensitive and specific HPLC-MS/MS method for palbociclib and ribociclib quantification in blood samples. We then quantified exposure to palbociclib (plasma trough concentration; Ctrough) in a real-life cohort of patients with locally invasive or metastatic breast cancer (n = 18) at day 15 of the first cycle of palbociclib treatment to characterize palbociclib concentration at steady state (Clinicaltrials.gov identifier NCT04025541, IdRCB n° 2018-A00064-51, 03/07/2018). The geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 88.58 ng/mL (± 26.4 [46.5 ng/mL - 133 ng/mL]) at day 15. Some covariates, such as drug-drug interactions, could explain the concentration variations observed in our Caucasian cohort. These first results in real-life settings obtained with our HPLC-MS/MS method give important information on palbociclib monitoring and pharmacokinetic variability.

OBJECTIVES: To evaluate the chemical, pasting and sensory properties of complementary food made from locally food blends. METHODS: One kilogram (1 kg) each of maize, crayfish and carrot were purchased from Ogbete main market Enugu, Nigeria. The maize, crayfish and carrot flours were blended and coded in the ratio of 100:0:0, 70:25:5, 70:20:10, 70:15:15, 70:10:20 and 70:5:25 respectively and used to produce porridges. The porridges were evaluated for chemical, pasting and sensory properties using standard methods. RESULTS: The moisture, crude protein, ash, crude fibre and fat content of the porridges increased significantly (P

Background & Aims Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). Methods We performed a nonblinded, randomized controlled trial of 78 children with CD (6–18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). Results The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). Conclusions In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.

Summary Objective To identify specific risk factors of vancomycin-induced nephrotoxicity in China, as the relationship between vancomycin therapy (dosing and trough concentration monitoring) and nephrotoxicity has been the subject of critical debate. Methods The cases of 90 critically ill patients who received vancomycin therapy in Xijing Hospital in the northwest of China between March 2014 and January 2015 were reviewed retrospectively. Vancomycin dosing, blood serum trough concentration, and other independent risk factors associated with nephrotoxicity were evaluated in a multivariable model. Results Among the 90 critically ill patients, 59 were males; mean age was 46.3 years. The indications for vancomycin use were methicillin-resistant Staphylococcus aureus -associated pneumonia, central nervous system infection, and bacteremia. Clinical pharmacists prescribed weight-based dosing, ranging from 20 to 45mg/kg/day. Fourteen (15.6%) patients developed nephrotoxicity, with serum creatinine elevated significantly from a mean (standard deviation) of 90.0 (18.8) μmol/l to 133.8 (63.2) μmol/l ( p = 0.015). It was found that those with a vancomycin dosage >38mg/kg/day (50.0% vs. 11.3%, p = 0.004) and a vancomycin serum trough concentration >20mg/l (57.1% vs. 12.0%, p = 0.01) were more likely to develop nephrotoxicity. Conclusion The data from this study indicate that a vancomycin dosage >38mg/kg/day and a serum trough level >20mg/l are both independent factors associated with the development of nephrotoxicity, suggesting that renal function should be monitored closely during vancomycin treatment.

PurposeTherapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) in serum is frequently used in clinical settings however saliva could be an alternative to measure free concentration of drugs. In the present study, we observed the possible correlation of VPA concentration between serum and saliva in persons with epilepsy (PWE).MethodsA total of 59 paired serum and saliva samples were assayed from 65 consecutive PWE (51 males and 14 females; age range 9–65 years). Patients were subjected to either VPA monotherapy or its combination with other AEDs for at least three months. Steady state trough concentration of unbound VPA drug was quantified using HPLC. The correlation between serum and saliva free VPA concentration was evaluated.ResultsOut of 65 patients, 27 were on monotherapy of VPA and 38 were on VPA with other antiepileptic drugs. Saliva VPA concentration significantly correlated with serum free VPA concentration (p0.05) respectively.ConclusionsOur study reveals that serum and saliva VPA concentrations are significantly associated in PWE. These associations may facilitate monitoring and evaluation of VPA levels non-invasively for PWE.

Background Currently, there are no published data on pharmacokinetics (PK) of everolimus in combination with cyclosporine in Japanese renal transplant patients. We evaluated the PK of everolimus in Japanese de novo renal transplant patients who received everolimus in combination with cyclosporine. Methods In this phase 3, multicenter, randomized, open-label study, patients were randomized (1:1) to 1 of the 2 groups: everolimus 1.5 mg (targeted C0 of 3–8 ng/mL) plus reduced-dose cyclosporine or mycophenolate mofetil 2 g/d plus standard-dose cyclosporine. PK assessments for everolimus were performed on day 28 (month 1) in the PK subpopulation. Results A total of 11 patients (7 men), mean age 47.5 ± 11.21 years, were enrolled for PK analysis of everolimus. Starting at 1.5 mg (0.75 mg twice a day), the mean dose over a period of 28 days was 0.705 ± 0.1011 mg. Everolimus mean trough concentration was 4.307 ± 1.2459 ng/mL and mean peak concentration was 13.539 ± 3.5330 ng/mL, which peaked at 1 to 2 hours postdose. The average concentration was 7.558 ± 1.4723 ng/mL, area under the concentration-time curve was 90.70 ± 17.667 ng·h/mL, and peak-trough fluctuation was 122.6%. The PK parameters of everolimus were comparable to those in the earlier phase 3 studies (A2306 and A2307). The mean everolimus trough levels were within the target ranges at all time points ranging from 3.4 to 5.5 ng/mL (everolimus 0.75 mg twice a day, safety population). The majority of patients (>85% from day 7 onward) were maintained within the targeted everolimus trough blood levels (safety population). These data were similar to a non-Japanese study (A2309). Conclusions The pharmacokinetic characteristics of everolimus in Japanese de novo renal transplant patients did not differ from those previously observed in non-Japanese patients, hence the same dosage of everolimus may be acceptable in Japanese patients.

Introduction Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating swelling. APeX-1 was a Phase 2, double-blind, placebo-controlled study to evaluate the prevention of attacks with BCX7353, a once daily oral kallikrein inhibitor, in patients with HAE. Methods Patients with Type I or II HAE with a history of at least 0.5 HAE attacks/week were randomized to four different BCX7353 doses (62.5mg, 125mg, 250mg, 350mg once daily) or placebo for 4 weeks. Subjects completed diaries to record angioedema attack details. A trough sample for BCX7353 analysis was drawn on Day 15. Results There was a dose-dependent reduction in mean HAE attack rate relative to the mean historical attack rate through 125mg (0.66 attacks/week reduction at this dose); efficacy at doses ≥250mg was likely confounded by drug-related adverse events misattributed as attacks. Mean plasma trough BCX7353 levels also increased by dose level with 57% of subjects in the 125mg group achieving the target trough concentration (≥4xEC50 at 24h post-dose). Subjects were individually classified by achieving or not achieving the target trough. The odds for subjects achieving ≥50%, ≥70%, or ≥90% reduction in attacks if the target trough was met or exceeded were 5.6-, 12.9- and 26.4-times higher, respectively, than for subjects who did not meet or exceed target trough level. Conclusions Maintenance of BCX7353 plasma concentrations above the target trough concentration increased the odds of reducing HAE attacks. A BCX7353 dose >125mg and

Therapeutic drug monitoring (TDM) of voriconazole is important to optimize efficacy and to minimize toxicity and intolerance. In this study, we evaluated the effect of sustained high plasma trough concentration of voriconazole on the incidence of hepatotoxicity in hospitalized Japanese patients.Thirty-nine patients were divided into 3 groups according to trough concentrations in two consecutive TDMs:4 μg/ml in the first TDM (group A, n=25),4 μg/ml in the first and4 μg/ml in the second TDM (group B, n=8), and4 μg/ml in both first and second TDMs (group C, n=6).Incidences of hepatotoxicity in groups A, B and C were 16.0, 25.0 and 83.3%, and significant differences were observed between groups A and C and groups B and C. Multiple logistic regression analysis identified the classification into groups A, B and C as an independent variable of hepatotoxicity.These results suggest that sustained high trough concentration of voriconazole may increase the risk of hepatotoxicity, and decreasing trough concentration to4 μg/ml by dose adjustment after the initial TDM may reduce the incidence of hepatotoxicity in patients treated with voriconazole.

Background This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML). Patients and methods In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy. Results The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR. Conclusions The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.

We report a case in which the atazanavir (ATV) concentration in the plasma decreased after unilateral nephrectomy in a patient receiving tenofovir (TDF). The patient was a 39-year-old man diagnosed with human immunodeficiency virus type 1 infection and was being treated with TDF/emtricitabine, ATV, and ritonavir. Before nephrectomy, ATV and TDF plasma trough concentrations were 810 and 65 ng/ml, respectively. At this time, estimated glomerular filtration rate (eGFR) was 111 ml/min/1.73 m(2). Approximately 5 months after starting antiretroviral therapy (ART), the patient underwent nephrectomy. Plasma concentrations were remeasured 18 weeks after the operation, and the TDF concentration had increased to 109 ng/ml, whereas the ATV concentration decreased to 290 ng/ml. His eGFR decreased to 50 ml/min/1.73 m(2) at the time of the second measurement. The decreased ATV plasma concentration suggested that interactions between ATV and TDF were exacerbated by an increase in TDF plasma concentration caused by renal dysfunction. This case report suggests that it is important to monitor the ATV plasma concentration to ensure that it is no less than the target trough concentration when renal function decline is observed in patients receiving ART including ATV and TDF.

The purpose of this study was (i) to determine the optimal dosage of teicoplanin for each patient group stratified by renal function and weight based on a population pharmacokinetic model and observed distribution of patient characteristics and (ii) to develop new simplified dosing regimens designed to achieve 15-30 μg/mL. Patient data were collected retrospectively from routine therapeutic drug monitoring files of adult patients who were given the standard loading dose regimen of teicoplanin (400 mg twice on Day 1, followed by 400 mg once daily for 2 days) and whose trough concentration was measured just before administration on Day 4. Monte Carlo simulation was conducted to estimate the trough concentration at 72 h after the initial loading dose (C(min)(72 h)) and at steady state (C(ss)(min)). The percentage of observed C(min)(72 h) in patients who received the standard loading dose regimen outside the non-parametric 90% prediction interval (from 5th to 95th percentile) of the simulated C(min)(72 h) was10%. Simplified loading dose and maintenance dose regimens for each group stratified by renal function and weight were created to achieve C(min)(72 h) and C(ss)(min) of 15 μg/mL and 20-25 μg/mL, respectively. The percentage of C(min)(72 h) and C(ss)(min) in the range 15-30 μg/mL was 43-65% and 61-82% across each renal function and weight strata, respectively. These new simplified dosing regimens of teicoplanin could be helpful in individual adjustment of the loading and maintenance doses to achieve 15-30 μg/mL.

Selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus, including heterogeneously vancomycin-intermediate S. aureus (hVISA). Treatment of hVISA infections with vancomycin has been associated with treatment failure, therefore new treatments are required. The objective of this study was to evaluate the activity of telavancin, vancomycin and linezolid against hVISA clinical strains. Twenty-five hVISA isolates were evaluated for minimum inhibitory concentrations (MICs) by microdilution and for bactericidal activity by time-kill analysis [starting inoculum ca. 10(6)colony-forming units (CFU)/mL and ca. 10(8)CFU/mL] against telavancin, vancomycin and linezolid. MICs for 50% and 90% of the organisms (MIC(50) and MIC(90) values, respectively) were, respectively, 0.5mg/L and 1mg/L for telavancin and 2mg/L and 2mg/L for both vancomycin and linezolid. In time-kill studies, telavancin was bactericidal against all strains at plasma peak and trough concentrations and at low and high inocula. At low inoculum, the time to bactericidal activity (defined as 99.9% kill from initial inoculum) (T(99.9)) for telavancin was 5.6 ± 3.2 h at peak concentration and 12.3 ± 5.2 h at trough concentration. This was superior to vancomycin (P0.001), which had a T(99.9) of 18.8 ± 2.1 h at peak concentration and 19.1 ± 2.2 h at trough concentration. At high inoculum, telavancin had a T(99.9) of 16.3 ± 3.2 h at peak concentration and 21.4 ± 2.5 h at trough concentration, whilst vancomycin did not consistently achieve bactericidal activity. Linezolid was not bactericidal against any strain at either concentration or inoculum. In conclusion, the killing activity of telavancin against hVISA was found to be superior to vancomycin and linezolid.

The recent emergence of meticillin-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin has prompted clinicians to prescribe vancomycin therapy targeting high trough concentrations (15-20 mg/L). Relevant studies (n=12) analysing the occurrence of nephrotoxicity with high-dose therapy were reviewed. Most studies were retrospective and the temporal relationship between elevated trough levels and development of nephrotoxicity was unclear, precluding a definitive cause-effect analysis. Available data suggest an association between vancomycin trough level and risk of nephrotoxicity as a function of intensity and duration of therapy (>7 days), compounded by concomitant receipt of nephrotoxins, vasopressor therapy and underlying physiological impairment. In separate studies in which a high trough concentration was measured prior to the onset of nephrotoxicity, the frequency of occurrence was 21-28% in patients with concomitant risks compared with 7% in patients without risks. A similar comparison between risk and no-risk groups who attained a standard trough concentration (10-15 mg/L) indicates the rates of occurrence as 9-21% vs. 2%. Onset of nephrotoxicity ranged from 4 days to 8 days from the start of therapy. The degree of renal dysfunction was modest, with a reported decrease of 35-45% in creatinine clearance from baseline. Resolution occurred in >70% of patients by the time of discharge. Future studies should detail clearly the temporal relationship between drug exposure and onset of nephrotoxicity, confounding risk factors, extent of injury and time course of recovery, and should also determine the relative risk versus benefit of high-dose vancomycin versus alternative agents.

Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum trough concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective trough concentration (≥ 13 μg/mL). A logistic regression analysis was performed to test whether the area under the concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory concentration (MIC) for the isolates was

Background Conflicting evidence regarding the association of vancomycin serum concentrations with efficacy and toxicity has resulted in controversy regarding optimal target concentrations. Recent publications recommend attaining higher vancomycin trough concentrations of 15 to 20 mg/L for target infections, yet limited research is available assessing the correlation of vancomycin serum concentrations with toxicity. The aim of this study was to evaluate the association between vancomycin serum trough concentrations and nephrotoxicity. Methods A 2-phase retrospective analysis was completed. Phase 1 evaluated 2493 courses of vancomycin completed between January 2003 and December 2007. The analysis describes a 5-year trend in vancomycin prescribing practices and assesses the association of nephrotoxicity with baseline serum creatinine, vancomycin serum trough concentrations, and duration of vancomycin therapy. Phase 2 examined patients receiving vancomycin therapy during 2007 to evaluate specific risk factors for development of nephrotoxicity. Results The proportion of vancomycin serum trough concentrations ≥15 mg/L and ≥20 mg/L increased significantly over time. Statistical analysis identified vancomycin serum trough concentrations ≥14 mg/L, duration of vancomycin therapy ≥7 days, and baseline serum creatinine levels ≥1.7 mg/dL as independent predictors of nephrotoxicity. Phase 2 analysis again implicated mean vancomycin serum trough concentration as a significant predictor of nephrotoxicity. Nephrotoxicity resolved in 81% (17/21) of cases evaluated. Conclusions A higher vancomycin serum trough concentration and prolonged vancomycin therapy are associated with an increased risk of nephrotoxicity. The decision to target increased vancomycin trough concentrations should be based on an assessment of the severity of the infection and must consider the nephrotoxicity risk associated with increased vancomycin levels.

An initial loading dose of teicoplanin is required to reach the optimal trough concentration (or = 10 microg/mL) rapidly. To attain the optimal teicoplanin concentration efficiently, an individual loading dose regimen based on population pharmacokinetics, in which the target trough concentration was set to 15 microg/mL, was defined. Among 70 patients, 33 patients received the individual loading dose regimen, 33 patients received the conventional loading dose regimen (200mg or 400mg every 12h on Day 1 followed by 200mg once daily) and 4 patients received no loading dose. The proportion of patients showing an optimal plasma concentration was 88% in the individual loading dose regimen but only 33% in the conventional loading dose regimen. No patient without a loading dose showed the optimal concentration. Both total loading dose and plasma concentration were significantly (P0.001) higher in the individual loading dose group than in the conventional loading dose group. Notably, the trough concentration was almost constant in patients with individual loading doses ranging from 800 mg to 1800 mg. These findings suggest that individual adjustment of the initial loading dose of teicoplanin is potentially useful to attain the optimal concentration rapidly.

Objective To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life. Methods A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens. Results A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L. Conclusions To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment.

Voriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60-70% of Asian populations. Because the voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity, this study investigated the effect of CYP2C19 polymorphism on the relationship between voriconazole trough concentrations and liver function abnormalities in 29 Japanese patients with fungal infections (CYP2C19 wild-type, n =1 0; non-wild-type, n = 19). Hepatotoxicity, defined as liver enzyme abnormality according to the National Can- cer Institute criteria, was observed in 10 (34.5%) of 29 patients with a trough concentration ≥3.9 mg/L. Logistic regression analysis suggested that the therapeutic range for the voriconazole trough concen- tration should be 2-4 mg/L. Non-linear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild-type and 4.4-6.5 mg/kg/day for the non-wild-type in Japanese patients. These recommended initial dosages and subsequent dose adjust- ment for the target concentration range by therapeutic drug monitoring should avoid adverse events and thus enable continued effective voriconazole therapy for Japanese patients with mycoses.

Trastuzumab is a therapeutic monoclonal antibody against the Her2 oncoprotein, which is over-expressed in approximately 30% of breast cancers, and is now used routinely in the management of early and metastatic Her2+ disease. However, not all Her2+ breast cancer patients respond to trastuzumab and the pharmacodynamic and pharmacokinetic parameters behind this variation in response are unknown. Pharmacological investigations into variable response to trastuzumab have been hampered by the lack of a published feasible method to determine trastuzumab concentration in plasma. Here we describe the development and validation of a cell-based ELISA to measure trastuzurnab in human plasma. The assay specifically measures the interaction between trastuzumab and Her2 and has a dynamic range of between 10 and 120 mu g/ml. The mean intra-assay and inter-assay variability of the ELISA was 9%. Trastuzumab in plasma was stable for at least 10 weeks at -20 degrees C and 72 h at 4 degrees C, and was unaffected by 5 freeze/thaw cycles. Having validated the assay, the trough plasma trastuzurnab concentrations of 30 patients being treated for metastatic or early disease were measured. The median trough concentration was 62 (range 21 to 441) mu g/ml. This cell-based ELISA method has undergone appropriate validation and is suitable for quantification of trastuzumab in the plasma of patients treated with Herceptin. Refereed/Peer-reviewed

Objective: The goal of this investigation was to determine whether more aggressive vancomycin dosing is associated with greater risk for renal toxicity in patients with health care‐associated pneumonia (HCAP) attributed to methicilllin-resistant Staphylococcus aureus (MRSA). Methods: This was a retrospective, single-center, observational cohort study. The following information was obtained for all study patients from automated hospital, microbiology, and pharmacy databases: age, sex, weight, serial serum creatinine (SCr), ageand sex-adjusted creatinine clearance (CrCl) during receipt of vancomycin, vancomycin serum trough concentrations, duration of vancomycin therapy, and Acute Physiology and Chronic Health Evaluation II scores. Renal toxicity was defined as either a 0.5-mg/dL increase from baseline in SCr or a ≥50% increase in SCr based on serial SCr measurements. Data for patients who met the definition of renal toxicity were compared with data for those who did not. Results: Ninety-four patients (mean [SD] age, 59.0 [15.6] years; 59 [62.8%] men; 73 (77.7%) white; mean baseline CrCl, 70.3 [23.0] mL/min) were identified as having MRSA HCAP. Forty (42.6%) patients developed renal toxicity. Patients who developed renal toxicity were significantly more likely than patients who did not develop renal toxicity to have greater mean vancomycin serum trough concentrations (20.8 [9.9] µg/mL vs 14.3 [6.7] µg/mL, respectively; P < 0.001), vancomycin serum trough concentrations ≥15 µg/mL (67.5% vs 40.7%; P = 0.01), and a prolonged duration (≥14 days) of vancomycin treatment (45.0% vs 20.4%; P = 0.011). Logistic regression analysis identified a maximum vancomycin serum trough concentration of ≥15 µg/mL as being independently associated with renal toxicity (adjusted odds ratio = 2.82; 95% CI, 1.02‐7.74; P = 0.045). The overall mean change in CrCl for the study population was ‐13.5 (‐16.0) mL/min (range, 0.0 to ‐62.6 mL/min). Patients with maximum measured vancomycin serum trough concentrations ≥15 µg/mL (n = 49) had significantly greater absolute changes in CrCl compared with patients with maximum measured vancomycin serum trough concentrations