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BackgroundAlthough polymyxin B has been in use since the late 1950s, there have been limited studies done to unravel its pharmacokinetics (PK) and pharmacodynamics (PD) index.MethodsWe determined, in neutropenic infected mice, the PK, plasma protein binding and PK/PD index best correlating with efficacy for Escherichia coli and Klebsiella pneumoniae strains.ResultsThe pharmacokinetic profile showed non-linear PK; dose was significantly correlated with absorption rate and clearance. The inhibitory sigmoid dose–effect model for the fCmax/MIC index of E. coli fitted best, but was only modestly higher than the R2 of %fT>MIC and fAUC/MIC (R2 0.91–0.93). For K. pneumoniae the fAUC/MIC index had the best fit, which was slightly higher than the R2 of %fT>MIC and fCmax/MIC (R2 0.85–0.91). Static targets of polymyxin B fAUC/MIC were 27.5–102.6 (median 63.5) and 5.9–60.5 (median 11.6) in E. coli and in K. pneumoniae isolates, respectively. A 1 log kill effect was only reached in two E. coli isolates and one K. pneumoniae. The PTA with the standard dosing was low for isolates with MIC >0.25 mg/L.ConclusionsThis study confirms that fAUC/MIC can describe the exposure–response relationship for polymyxin B. The 1 log kill effect was achieved in the minority of the isolates whereas polymyxin B PK/PD targets cannot be attained for the majority of clinical isolates with the standard dosing regimen, indicating that polymyxin B may be not effective against serious infections as monotherapy.

PURPOSE: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.METHODS: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.RESULTS: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.CONCLUSIONS: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

Background:Intracellular tacrolimus concentration in peripheral blood mononuclear cells (PBMCs) (TAC [PBMC]) has been proposed to better represent its active concentration than its whole blood concentration. As tacrolimus acts on T lymphocytes and other white blood cells, including monocytes, we investigated the association of tacrolimus concentration in CD3 +T lymphocytes (TAC [CD3]) and CD14 +monocytes (TAC [CD14]) with acute rejection after kidney transplantation.Methods:From a total of 61 samples in this case-control study, 28 samples were obtained during biopsy-proven acute rejection (rejection group), and 33 samples were obtained in the absence of rejection (control group). PBMCs were collected from both cryopreserved (retrospectively) and freshly obtained (prospectively) samples. CD3 +T lymphocytes and CD14 +monocytes were isolated from PBMCs, and their intracellular tacrolimus concentrations were measured.Results:The correlation between tacrolimus whole-blood and intracellular concentrations was poor. TAC [CD3]was significantly lower than TAC [CD14](median 12.8 versus 81.6 pg/million cells; P < 0.001). No difference in TAC [PBMC](48.5 versus 44.4 pg/million cells; P = 0.82), TAC [CD3](13.4 versus 12.5 pg/million cells; P = 0.28), and TAC [CD14](90.0 versus 72.8 pg/million cells; P = 0.27) was found between the rejection and control groups. However, freshly isolated PBMCs showed significantly higher TAC [PBMC]than PBMCs from cryopreserved samples. Subgroup analysis of intracellular tacrolimus concentrations from freshly isolated cells did not show a difference between rejectors and nonrejectors.Conclusions:Differences in TAC [CD3]and TAC [CD14]between patients with and without rejection could not be demonstrated. However, further optimization of the cell isolation process is required because a difference in TAC [PBMC]between fresh and cryopreserved cells was observed. These results need to be confirmed in a study with a larger number of patients.

Aims: To describe the pharmacokinetics (PK) of cefotaxime as pre-emptive treatment in critically ill adult patients, including covariates and to determine the probability of target attainment (PTA) of different dosage regimens for Enterobacterales and Staphylococcus aureus.Methods: Five samples were drawn during 1 dosage interval in critically ill patients treated with cefotaxime 1 g q6h or q4h. PK parameters were estimated using NON-MEM (v7.4.2). The percentage of patients reaching 100% fT>MICECOFF was used to compare different dosage regimens for Enterobacterales and S. aureus.Results: This study included 92 patients (437 samples). The best structural model was a 2-compartment model with a combined error, interindividual variability on clearance, central volume and intercompartmental clearance. Correlations between interindividual variability were included. Clearance increased with higher estimated glomerular filtration rate (eGFR; creatinine clearance) and albumin concentration. For Enterobacterales, 1 g q8h reached 95% PTA and continuous infusion (CI) of 4 g 24 h(-1) 100% PTA at the highest eGFR and albumin concentration. For S. aureus the predefined target of 95% PTA was not reached with higher eGFR and/or albumin concentrations. CI of 6 g 24 h(-1) for S. aureus resulted in a minimum of 99% PTA.Conclusion: Cefotaxime PK in critically ill patients was best described by a 2-compartment model with eGFR and albumin concentration as covariates influencing clearance. For Enterobacterales 1 g q8h or CI of 4 g 24 h(-1) was adequate for all combinations of eGFR and albumin concentration. For S. aureus CI of 6 g 24 h(-1) would be preferred if eGFR and albumin concentration exceed 80 mL min(-1) and 40 g L-1 respectively.

Background and Objective: Intravenous immunoglobulin (IVIg) at a standard dosage is the treatment of choice for Guillain–Barré syndrome. The pharmacokinetics, however, is highly variable between patients, and a rapid clearance of IVIg is associated with poor recovery. We aimed to develop a model to predict the pharmacokinetics of a standard 5-day IVIg course (0.4 g/kg/day) in patients with Guillain–Barré syndrome. Methods: Non-linear mixed-effects modelling software (NONMEM®) was used to construct a pharmacokinetic model based on a model-building cohort of 177 patients with Guillain–Barré syndrome, with a total of 589 sequential serum samples tested for total immunoglobulin G (IgG) levels, and evaluated on an independent validation cohort that consisted of 177 patients with Guillain–Barré syndrome with 689 sequential serum samples. Results: The final two-compartment model accurately described the daily increment in serum IgG levels during a standard IVIg course; the initial rapid fall and then a gradual decline to steady-state levels thereafter. The covariates that increased IgG clearance were a more severe disease (as indicated by the Guillain–Barré syndrome disability score) and concomitant methylprednisolone treatment. When the current dosing regimen was simulated, the percentage of patients who reached a target ∆IgG > 7.3 g/L at 2 weeks decreased from 74% in mildly affected patients to only 33% in the most severely affected and mechanically ventilated patients (Guillain–Barré syndrome disability score of 5). Conclusions: This is the first population-pharmacokinetic model for standard IVIg treatment in Guillain–Barré syndrome. The model provides a new tool to predict the pharmacokinetics of alternative regimens of IVIg in Guillain–Barré syndrome to design future trials and personalise treatment.

Background and Objective: The tacrolimus concentration within peripheral blood mononuclear cells may correlate better with clinical outcomes after transplantation compared to concentrations measured in whole blood. However, intracellular tacrolimus measurements are not easily implemented in clinical practice. The prediction of intracellular concentrations based on whole-blood concentrations would be a solution for this. Therefore, the aim of this study was to describe the relationship between intracellular and whole-blood tacrolimus concentrations in a population pharmacokinetic (popPK) model. Methods: Pharmacokinetic analysis was performed using non-linear mixed effects modelling software (NONMEM). The final model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis. Results: A total of 590 tacrolimus concentrations from 184 kidney transplant recipients were included in the study. All tacrolimus concentrations were measured in the first three months after transplantation. The intracellular tacrolimus concentrations (n = 184) were best described with an effect compartment. The distribution into the effect compartment was described by the steady-state whole-blood to intracellular ratio (RWB:IC) and the intracellular distribution rate constant between the whole-blood and intracellular compartments. Lean body weight was negatively correlated [delta objective function value (ΔOFV) −8.395] and haematocrit was positively correlated (ΔOFV = − 6.752) with RWB:IC, and both lean body weight and haematocrit were included in the final model. Conclusion: We were able to accurately describe intracellular tacrolimus concentrations using whole-blood concentrations, lean body weight, and haematocrit values in a popPK model. This model may be used in the future to more accurately predict clinical outcomes after transplantation and to identify patients at risk for under- and overexposure.

Background: Pentobarbital pharmacokinetics (PK) remain elusive and the therapeutic windows narrow. Administration is frequent in critically ill children with refractory status epilepticus (SE) and severe traumatic brain injury (sTBI). Objectives: To investigate pentobarbital PK in SE and sTBI patients admitted to the paediatric intensive care unit (PICU) with population-based PK (PopPK) modelling and dosing simulations. Methods: Develop a PopPK model with non-linear mixed-effects modelling (NONMEM®) with retrospective data (n = 36; median age 1.3 years; median weight 10 kg; 178 blood samples) treated with continuous intravenous pentobarbital. An independent dataset was used for external validation (n = 9). Dosing simulations with the validated model evaluated dosing regimens. Results: A one-compartment PK model with allometrically scaled weight on clearance (CL; 0.75) and volume of distribution (V d; 1) captured data well. Typical CL and V d values were 3.59 L/70 kg/h and 142 L/70 kg, respectively. Elevated creatinine and C-reactive protein (CRP) levels significantly correlated to decreased CL, explaining 84% of inter-patient variability, and were incorporated in the final model. External validation using stratified visual predictive checks showed good results. Simulations demonstrated patients with elevated serum creatinine and CRP failed to achieve steady state yet progressed to toxic levels with current dosing regimens. Conclusions: The one-compartment PK model of intravenous pentobarbital described data well whereby serum creatinine and CRP significantly correlated with pentobarbital CL. Dosing simulations formulated adjusted dosing advice in patients with elevated creatinine and/or CRP. Prospective PK studies with pharmacodynamic endpoints, are imperative to optimise pentobarbital dosing in terms of safety and clinical efficacy in critically ill children.

Mycophenolate mofetil has an important role as immunosuppressive agent in solid organ transplant recipients. Exposure to the active mycophenolic acid (MPA) can be monitored using therapeutic drug monitoring. We present three cases in which MPA exposure severely decreased after oral antibiotic coadministration. By diminishing gut bacteria β-glucuronidase activity, oral antibiotics can prevent deglucuronidation of the inactive MPA-7-O-glucuronide metabolite to MPA and thereby possibly prevent its enterohepatic recirculation. This pharmacokinetic interaction could result in rejection, which makes it clinically relevant in solid organ transplant recipients, especially when therapeutic drug monitoring frequency is low. Routine screening for this interaction, preferably supported by clinical decision support systems, and pragmatic close monitoring of the MPA exposure in cases is advised.

Personalized medicine is currently hampered by the lack of flexible drug formulations. Especially for pediatric patients, manual compounding of personalized drug formulations by pharmacists is required. Three-Dimensional (3D) printing of medicines, which enables small-scale manufacturing at the point-of-care, can fulfill this unmet clinical need. This study investigates the feasibility of developing a 3D-printed tablet formulation at the point-of-care which complies to quality requirements for clinical practice, including bioequivalence. Development, manufacturing, and quality control of the 3D-printed tablets was performed at the manufacturing facility and laboratory of the department of Clinical Pharmacy and Toxicology at Leiden University Medical Center. Sildenafil was used as a model drug for the tablet formulation. Along with the 3D-printed tablets a randomized, an open-label, 2-period, crossover, single-dose clinical trial to assess bioequivalence was performed in healthy adults. Bioequivalence was established if areas under the plasma concentration curve from administration to the time of the last quantifiable concentration (AUC0-t) and maximum plasma concentration (Cmax) ratios were within the limits of 80.00–125.00%. The manufacturing process provided reproducible 3D-printed tablets that adhered to quality control requirements and were consequently used in the clinical trial. The clinical trial was conducted in 12 healthy volunteers. The 90% confidence intervals (CIs) of both AUC0-t and Cmax ratios were within bioequivalence limits (AUC0-t 90% CI: 87.28–104.14; Cmax 90% CI: 80.23–109.58). For the first time, we demonstrate the development of a 3D-printed tablet formulation at the point-of-care that is bioequivalent to its marketed originator. The 3D printing of personalized formulations is a disruptive technology for compounding, bridging the gap toward personalized medicine.

Temocillin is used for the treatment of various infections caused by Enterobacterales . The pharmacokinetic (PK)/pharmacodynamic (PD) index that is best correlated with the activity of beta-lactams is the percentage of time that the unbound concentration exceeds the MIC (% f T>MIC).

BACKGROUND: Sampling of blood at home to determine the concentration of drugs or other compounds can be effective in limiting hospital-based sampling. This could lower hospital visits and patient burden, improve the quality of life, and reduce health care costs. Dried blood spot (DBS) microsampling is often used for this purpose, wherein capillary blood, obtained by pricking the heel or finger, is used to measure different analytes. Although DBS has several advantages over venous blood sampling, it is not routinely implemented in clinical practice. To facilitate the bench to bedside transition, it is important to be aware of certain challenges that need to be considered and addressed. RESULTS: Here, important considerations regarding the implementation of DBS in clinical practice, the choice of patients, blood sampling, transport, and laboratory analysis are discussed. In addition, we share our experience and provide suggestions on how to deal with these problems in a clinical setting.

Transplant recipients may develop rejection despite having adequate tacrolimus whole blood predose concentrations (C0). The intra-immune cellular concentration is potentially a better target than C0. However, little is known regarding intracellular tacrolimus concentration in T-lymphocytes and monocytes. We investigated the tacrolimus concentrations in both cell types and their relation with the expression and activity of FK-binding protein (FKBP)-12 and P-glycoprotein (P-gp).. T-lymphocytes and monocytes were isolated from kidney transplant recipients followed by intracellular tacrolimus concentration measurement. FKBP-12 and P-gp were quantified with Western blot, flow cytometry, and the Rhodamine-123 assay. Interleukin-2 and interferon-γ in T-lymphocytes were measured to quantify the effect of tacrolimus.. Tacrolimus concentration in T-lymphocytes was lower than in monocytes (15.3 [8.5-33.4] versus 131.0 [73.5-225.1] pg/million cells; P0.001). The activity of P-gp (measured by Rhodamine-123 assay) was higher in T-lymphocytes than in monocytes. Flow cytometry demonstrated a higher expression of P-gp (normalized mean fluorescence intensity 1.5 [1.2-1.7] versus 1.2 [1.1-1.4]; P = 0.012) and a lower expression of FKBP-12 (normalized mean fluorescence intensity 1.3 [1.2-1.7] versus 1.5 [1.4-2.0]; P = 0.011) in T-lymphocytes than monocytes. Western blot confirmed these observations. The addition of verapamil, a P-gp inhibitor, resulted in a 2-fold higher intra-T-cell tacrolimus concentration. This was accompanied by a significantly fewer cytokine-producing cells.. T-lymphocytes have a higher activity of P-gp and lower concentration of the FKBP-12 compared with monocytes. This explains the relatively lower tacrolimus concentration in T-lymphocytes. The addition of verapamil prevents loss of intracellular tacrolimus during the cell isolation process and is required to ensure adequate intracellular concentration measurement.

Bodyweight-based tacrolimus dosing followed by therapeutic drug monitoring is standard clinical care after renal transplantation. However, after transplantation, a meager 38% of patients are on target at first steady-state and it can take up to 3 weeks to reach the target tacrolimus predose concentration (C0). Tacrolimus underexposure and overexposure is associated with an increased risk of rejection and drug-related toxicity, respectively. To minimize subtherapeutic and supratherapeutic tacrolimus exposure in the immediate post-transplant phase, a previously developed dosing algorithm to predict an individual’s tacrolimus starting dose was tested prospectively. In this single-arm, prospective, therapeutic intervention trial, 60 de novo kidney transplant recipients received a tacrolimus starting dose based on a dosing algorithm instead of a standard, bodyweight-based dose. The algorithm included cytochrome P450 (CYP)3A4 and CYP3A5 genotype, body surface area, and age as covariates. The target tacrolimus C0, measured for the first time at day 3, was 7.5–12.5 ng/mL. Between February 23, 2019, and July 7, 2020, 60 patients were included. One patient was excluded because of a protocol violation. On day 3 post-transplantation, 34 of 59 patients (58%, 90% CI 47–68%) had a tacrolimus C0 within the therapeutic range. Markedly subtherapeutic ( 20 ng/mL) tacrolimus concentrations were observed in 7% and 3% of the patients, respectively. Biopsy-proven acute rejection occurred in three patients (5%). In conclusion, algorithm-based tacrolimus dosing leads to the achievement of the tacrolimus target C0 in as many as 58% of the patients on day 3 after kidney transplantation.

International audience; The aim of this study was to define the therapeutic range for ribavirin (RBV) in transplant recipients with chronic hepatitis E virus (HEV) infection. In this retrospective multicentre cohort study, data of adult transplant recipients with chronic HEV infection, who had been treated with RBV monotherapy between 01-3-2008 and 01-08-2018, were included. ROC curve analyses were performed, and the half-maximal effective RBV concentration was calculated to determine a representative therapeutic range. In 96 patients, RBV monotherapy for a median of three months resulted in a sustained virologic response in 63.5% of the patients, while 88.5% of the patients developed anaemia. RBV plasma concentrations at steady state were significantly higher in clinical responders compared with clinical non-responders: median 1.96 (IQR 1.81-2.70) versus 0.49 (IQR 0.45-0.73) mg/L, P = .0004. RBV caused a dosedependent haemoglobin reduction with higher RBV plasma concentrations resulting in more haemoglobin reduction. The therapeutic range for RBV for chronic HEV infection in transplant recipients ranges between 1.8 and 2.3 mg/L.

The optimal dose regimen for intravenous (IV) treatment in children with severe acute asthma (SAA) is still a matter of debate. We assessed the efficacy of adding a salbutamol loading dose to continuous infusion with salbutamol in children admitted to a pediatric intensive care unit (PICU) with SAA. This multicentre, placebo-controlled randomized trial in the PICUs of four tertiary care children's hospitals included children (2-18 years) with SAA admitted between 2017 and 2019. Children were randomized to receive either a loading dose IV salbutamol (15 mcg/kg, max. 750 mcg) or normal saline while on continuous salbutamol infusion. The primary outcome was the asthma score (Qureshi) 1 h after the intervention. Analysis of covariance models was used to evaluate sensitivity to change in asthma scores. Serum concentrations of salbutamol were obtained. Fifty-eight children were included (29 in the intervention group). Median baseline asthma score was 12 (IQR 10-13) in the intervention group and 11 (9-12) in the control group (p = 0.032). The asthma score 1 h after the intervention did not differ significantly between the groups (p = 0.508, β-coefficient = 0.283). The median increase in salbutamol plasma levels 10 min after the intervention was 13 μg/L (IQR 5-24) in the intervention group and 4 μg/L (IQR 0-7) in the control group (p = 0.001). Side effects were comparable between both groups.We found no clinical benefit of adding a loading dose IV salbutamol to continuous infusion of salbutamol, in children admitted to the PICU with SAA. Clinically significant side effects from the loading dose were not encountered.• Pediatric asthma guidelines struggle with an evidence-based approach for the treatment of SAA beyond the initial steps of oxygen suppletion, repetitive administration of inhaled β2-agonists, and systemic steroids. • During an SAA episode, effective delivery of inhaled drugs is unpredictable due to severe airway obstruction.• This study found no beneficial effect of an additional loading dose IV salbutamol in children admitted to the PICU. • This study found no clinically significant side effects from the loading dose.

Aims: Tacrolimus is a critical dose drug and to avoid under- and overexposure, therapeutic drug monitoring is standard practice. However, rejection and drug-related toxicity occur despite whole-blood tacrolimus pre-dose concentrations ([Tac]blood) being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells; [Tac]cells) may better correlate with drug-efficacy. The aim of this study was to (1) investigate the relationship between [Tac]blood and [Tac]cells, (2) identify factors affecting the tacrolimus distribution in cells and whole-blood, and (3) study the relationship between [Tac]cells and clinical outcomes after kidney transplantation. Methods: A total of 175 renal transplant recipients were prospectively followed. [Tac]blood and [Tac]cells were determined at Months 3, 6 and 12 post-transplantation. Patients were genotyped for ABCB1 1199G>A and 3435C>T, CYP3A4 15389C>T, and CYP3A5 6986G>A. Data on rejection and tacrolimus-related nephrotoxicity and post-transplant diabetes mellitus were collected. Results: Correlations between [Tac]blood and [Tac]cells were moderate to poor (Spearman's r = 0.31; r = 0.41; r = 0.61 at Months 3, 6 and 12, respectively). The [Tac]cells/[Tac]blood ratio was stable over time in most patients (median intra-patient variability 39.0%; range 3.5%–173.2%). Age, albumin and haematocrit correlated with the [Tac]cells/[Tac]blood ratio. CYP3A5 and CYP3A4 genotype combined affected both dose-corrected [Tac]blood and [Tac]cells. ABCB1 was not significantly related to tacrolimus distribution. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes. Conclusions: The correlation between [Tac]blood and [Tac]cells is poor. Age, albumin and haematocrit correlate with the [Tac]cells/[Tac]blood ratio, whereas genetic variation in ABCB1, CYP3A4 and CYP3A5 do not. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes.

Background Therapeutic drug monitoring (TDM) of the two calcineurin inhibitors (CNIs), tacrolimus (TAC) and cyclosporine A (CsA), has resulted in improvements in the management of patients who have undergone solid organ transplantation. As a result of TDM, acute rejection rates and treatment-related toxicities have been reduced. Irrespective, acute rejection and toxicity still occur in patients who have undergone transplantation showing blood CNI concentrations within the therapeutic range. Moreover, the acute rejection rate is no longer decreasing. Hence, smarter TDM approaches are necessary. As CNIs exert their action inside T-lymphocytes, intracellular CNIs may be a promising candidate for improving therapeutic outcomes. Intracellular CNI concentration may be more directly related to drug effect and has been favorably compared with the standard, whole-blood TDM for TAC in liver transplant recipients. However, measuring intracellular CNIs concentrations is not without pitfalls at both the pre-analytical and analytical stages, and standardization appears essential in this area. To date, there are no guidelines for the TDM of intracellular CNI concentrations. Methods Under the auspices of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology and its Immunosuppressive Drug committees, a group of leading investigators in this field have shared experiences and have presented pre-analytical and analytical recommendations for measuring intracellular CNI concentrations.

Background Intravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer. Objective Our aim was to develop a population pharmacokinetic model to characterize the pharmacokinetic profile for intravenous salbutamol in children with status asthmaticus admitted to the pediatric intensive care unit (PICU), and to use this model to study the effect of different dosing schemes with and without a loading dose. Methods From 19 children (median age 4.9 years [range 9 months–15.3 years], median weight 18 kg [range 7.8–70 kg]) treated with continuous intravenous salbutamol at the PICU, plasma samples for R- and S-salbutamol concentrations (111 samples), as well as asthma scores, were collected prospectively at the same time points. Possible adverse reactions and patients’ clinical data (age, sex, weight, drug doses, liver and kidney function) were recorded. With these data, a population pharmacokinetic model was developed using NONMEM 7.2. After validation, the model was used for simulations to evaluate the effect of different dosing regimens with or without a loading dose. Results A two-compartment model with separate clearance for R- and S-salbutamol (16.3 L/h and 8.8 L/h, respectively) best described the data. Weight was found to be a significant covariate for clearance and volume of distribution. No other covariates were identified. Simulations showed that a loading dose can result in higher R-salbutamol concentrations in the early phase after the start of infusion therapy, preventing accumulation of S-salbutamol. Conclusions The pharmacokinetic model of intravenous R- and S-salbutamol described the data well and showed that a loading dose should be considered in children. This model can be used to evaluate the pharmacokinetic–pharmacodynamic relationship of intravenous salbutamol in children, and, as a next step, the effectiveness and tolerability of intravenous salbutamol in children with severe asthma. Electronic supplementary material The online version of this article (10.1007/s40262-019-00811-y) contains supplementary material, which is available to authorized users.

Contains fulltext : 220736.pdf (Publisher’s version ) (Closed access) Background Amlodipine is a widely used antihypertensive agent for the treatment of paediatric hypertension, but the commercially available tablets are not suitable to treat young patients, who need lower, flexible dosages and a liquid formulation. Objective To determine the pharmacokinetic properties of amlodipine and the acceptability of a standardised, extemporaneous oral solution. Method A newly developed liquid formulation of amlodipine was administered to hypertensive children between the age of 6 months and 11 years. Using a limited sampling strategy, population PK analysis was performed using nonlinear mixed effects modelling. Results Nine children, with a median age of 2.9 years (IQR 1.8-8.4), receiving stable amlodipine therapy in a median dose of 0.15 mg kg(-1) day(-1) (IQR 0.11-0.18), were switched to study medication. The population pharmacokinetic model was able to accurately predict the clearance of amlodipine in the study population. Based on the final model, clearance was reduced by 31.2% (RSE: 10%) in females. Patient reported outcomes on taste from a five-point hedonic scale were available for five patients, who scored the taste from positive to slightly negative. Conclusion The results from the PK study and the acceptability assessment show that the amlodipine oral solution presented in this study offers an appropriate treatment option for young children.

High-dose methotrexate (HD-MTX) is widely used in the treatment of non-Hodgkin lymphoma (NHL), but the pharmacokinetic properties of HD-MTX in Chinese adult patients with NHL have not yet been established through an approach that integrates genetic covariates. The purposes of this study were to identify both physiological and pharmacogenomic covariates that can explain the inter- and intraindividual pharmacokinetic variability of MTX in Chinese adult patients with NHL and to explore a new sampling strategy for predicting delayed MTX elimination. A total of 852 MTX concentrations from 91 adult patients with NHL were analyzed using the nonlinear mixed-effects modeling method. FPGS, GGH, SLCO1B1, ABCB1 and MTHFR were genotyped using the Sequenom MassARRAY technology platform and were screened as covariates. The ability of different sampling strategies to predict the MTX concentration at 72 h was assessed through maximum a posteriori Bayesian forecasting using a validation dataset (18 patients). A two-compartment model adequately described the data, and the estimated mean MTX clearance (CL) was 6.03 L/h (9%). Creatinine clearance (CrCL) was identified as a covariate for CL, whereas the intercompartmental clearance (Q) was significantly affected by the body surface area (BSA). However, none of the genotypes exerted a significant effect on the pharmacokinetic properties of MTX. The percentage of patients with concentrations below 0.2 µmol/L at 72 h decreased from 65.6 to 42.6% when the CrCL decreased from 90 to 60 ml/min/1.73 m2 with a scheduled dosing of 3 g/m2, and the same trend was observed with dose regimens of 1 g/m2 and 2 g/m2. Bayesian forecasting using the MTX concentrations at 24 and 42 h provided the best predictive performance for estimating the MTX concentration at 72 h after dosing. The MTX population pharmacokinetic model developed in this study might provide useful information for establishing personalized therapy involving MTX for the treatment of adult patients with NHL.

Background and Objective Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. Methods This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). Results At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. Conclusions The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers. Electronic supplementary material The online version of this article (10.1007/s40262-019-00831-8) contains supplementary material, which is available to authorized users.

Quantification of beta-lactam antibiotics can be performed by using liquid chromatography in combination with tandem mass spectrometry (MS/MS) or ultraviolet (UV) detection. Since beta-lactam antibiotics are known as highly polar analytes, using standard reversed phase chromatography will result in very early elution, which is often not desirable. Some retention is preferred to reduce matrix effects, because a high amount of non-retained molecular matrix species elute early from the column. For highly polar analytes, ultra-performance convergence chromatography (UPC

BACKGROUND: Initial algorithm-based dosing appears to be effective in predicting tacrolimus dose requirement. However, achieving and maintaining the target concentrations is challenging. Model-based follow-up dosing, which considers patient characteristics and pharmacological data, may further personalize treatment. This study investigated whether model-based follow-up dosing could lead to more accurate tacrolimus exposure than standard therapeutic drug monitoring (TDM) in kidney transplant recipients after an initial algorithm-based dose. METHODS: This simulation trial included patients from a prospective trial that received an algorithm-based tacrolimus starting dose followed by TDM. For every measured tacrolimus predose concentration (C0,obs), model-based dosing advice was simulated using the InsightRX software. Based on previous tacrolimus doses and C0 , age, body surface area, CYP3A4 and CYP3A5 genotypes, hematocrit, albumin, and creatinine, the optimal next dose, and corresponding tacrolimus concentration (C0,pred ) were predicted. RESULTS: Of 190 tacrolimus C0 values measured in 59 patients, 121 (63.7%; 95% CI 56.8-70.5) C0,obs were within the therapeutic range (7.5-12.5 ng/mL) versus 126 (66.3%, 95% CI 59.6-73.0) for C0,pred ( P = 0.89). The median absolute difference between the tacrolimus C0 and the target tacrolimus concentration (10.0 ng/mL) was 1.9 ng/mL for C0,obs versus 1.6 ng/mL for C0,pred . In a historical cohort of 114 kidney transplant recipients who received a body weight-based starting dose followed by TDM, 172 of 335 tacrolimus C0 (51.3%) were within the therapeutic range (10.0-15.0 ng/mL). CONCLUSIONS: The combination of an algorithm-based tacrolimus starting dose with model-based follow-up dosing has the potential to minimize under- and overexposure to tacrolimus in the early posttransplant phase, although the additional effect of model-based follow-up dosing on initial algorithm-based dosing seems small.

Immunosuppressive drugs have been key to the success of liver transplantation and are essential components of the treatment of inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). For many but not all immunosuppressants, therapeutic drug monitoring (TDM) is recommended to guide therapy. In this article, the rationale and evidence for TDM of tacrolimus, mycophenolic acid, the mammalian target of rapamycin inhibitors, and azathioprine in liver transplantation, IBD, and AIH is reviewed. New developments, including algorithm-based/computer-assisted immunosuppressant dosing, measurement of immunosuppressants in alternative matrices for whole blood, and pharmacodynamic monitoring of these agents is discussed. It is expected that these novel techniques will be incorporate into the standard TDM in the next few years.

BACKGROUND: Dried blood spots (DBSs) have gained recent popularity as a sampling method for therapeutic drug monitoring. For patients, DBS sampling has several advantages over venous blood sampling. However, technical issues primarily influenced by hematocrit levels, interfere with the implementation of this method in daily clinical practice. The results of concentration measurements of drugs that are influenced by hematocrit should be corrected for hematocrit levels. In this article, we developed a fast, nondestructive, near-infrared (NIR)-based method for measuring the hematocrit in DBSs. METHOD: Using a partial least squares algorithm, an NIR-based quantification method was developed for measuring hematocrit levels of 0.19-0.49 L/L. Residual venous blood of 522 patients was used to build this partial least squares model. The validity of the method was evaluated using 40 patient samples. DBSs were created by adding a small amount (50 µL) of blood on a Whatman filter paper and drying for 24 hours in a desiccator cabinet. The robustness was evaluated by measuring 24 additional samples with a high hemolysis, icterus, and lipemia (HIL) index. The hematocrit values obtained using a Sysmex XN hemocytometry analyzer were used as reference. RESULTS: The difference between hematocrit measurements obtained with NIR spectroscopy and a hemocytometry analyzer was

Breakthrough cytomegalovirus (CMV) disease during valganciclovir prophylaxis is rare but may cause significant morbidity and even mortality. In order to identify patients at increased risk the incidence of CMV disease was studied in a large population of renal transplant recipients who underwent a kidney transplantation in the Radboud University Medical Center between 2004 and 2015 (n = 1300). CMV disease occurred in 31/1300 patients. Multivariate binary linear regression analysis showed that delayed graft function (DGF) (p = 0.018) and rejection (p = 0.001) significantly and independently increased the risk of CMV disease, whereas CMV status did not. Valganciclovir prophylaxis was prescribed to 281/1300 (21.6%) high-risk patients (defined as CMV IgG-seronegative recipients receiving a kidney from a CMV IgG-seropositive donor (D+/R-)). Of these 281 patients, 51 suffered from DGF (18%). The incidence of breakthrough CMV disease in D + /R- patients with DGF was much higher than in those with immediate function (6/51 (11.8%) vs 2/230, (0.9%), p = 0.0006 Fisher's exact test), despite valganciclovir prophylaxis. This higher incidence of CMV disease could not be explained by a higher incidence of rejection (and associated anti-rejection treatment) in patients with DGF. D + /R- patients with DGF are at increased risk of developing CMV disease despite valganciclovir prophylaxis. These findings suggest that underexposure to ganciclovir occurs in patients with DGF. Prospective studies evaluating the added value of therapeutic drug monitoring to achieve target ganciclovir concentrations in patients with DGF are needed.

Twenty-five years after its approval by the FDA and EMA, tacrolimus remains the cornerstone of immunosuppressive treatment following solid organ transplantation [1,2]. The drug is highly effective ...

Dried blood spots (DBSs) have gained recent popularity as a sampling method for therapeutic drug monitoring. For patients, DBS sampling has several advantages over venous blood sampling. However, technical issues primarily influenced by hematocrit levels, interfere with the implementation of this method in daily clinical practice. The results of concentration measurements of drugs that are influenced by hematocrit should be corrected for hematocrit levels. In this article, we developed a fast, nondestructive, near-infrared (NIR)-based method for measuring the hematocrit in DBSs.Using a partial least squares algorithm, an NIR-based quantification method was developed for measuring hematocrit levels of 0.19-0.49 L/L. Residual venous blood of 522 patients was used to build this partial least squares model. The validity of the method was evaluated using 40 patient samples. DBSs were created by adding a small amount (50 µL) of blood on a Whatman filter paper and drying for 24 hours in a desiccator cabinet. The robustness was evaluated by measuring 24 additional samples with a high hemolysis, icterus, and lipemia (HIL) index. The hematocrit values obtained using a Sysmex XN hemocytometry analyzer were used as reference.The difference between hematocrit measurements obtained with NIR spectroscopy and a hemocytometry analyzer was15% for the 40 samples. The accuracy (≤9%) and precision (≤7%) for all the quality control samples were within the acceptance criteria of15%. The intraassay and interassay coefficient of variability was ≤3% and ≤6%, respectively, for the different quality control levels. There were no deviations in the measurements for the samples with high HIL indices. The stability of hematocrit in DBS was up to 14 days for all levels.We developed and validated a hematocrit model using NIR spectroscopy. This nondestructive, accurate, and reproducible method has a short analysis time (51 seconds), and can be used to analyze DBS samples stored for up to 2 weeks in a desiccator cabinet.

Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. Methods: Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models. Results: A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P

Background: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. Methods: A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. Results: As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. Conclusions: Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.

Background Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist. Objectives The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations. Methods Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n = 8), and German pediatric patients in a therapeutic drug monitoring service (n = 22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM®). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages. Results In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th–75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 µg/L [56.0–180.5 µg/L]) than in non-responders (58.0 µg/L [14.9–105.5 µg/L]), although non-significant (p = 0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders. Conclusions Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100–400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account. Electronic supplementary material The online version of this article (10.1007/s40262-020-00894-y) contains supplementary material, which is available to authorized users.

Purpose To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens. Methods Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC0–24/MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens. Results A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400–1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m2, and eGFR of 58.5 mL/min/1.73 m2. The median ƒAUC0–24 and ƒCmax were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC0–24/MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC0–24/MIC ratios. Conclusions The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure.

Purpose We developed a pharmacokinetic model of intravenous sildenafil in newborns with congenital diaphragmatic hernia (CDH) to achieve a target plasma concentration of over 50 μg/l. Methods Twenty-three CDH newborns with pulmonary hypertension (64 blood samples) received intravenous sildenafil. Patients received a loading dose of 0.35 mg/kg (IQR 0.16 mg/kg) for 3 h, followed by a continuous infusion of 1.5 mg/kg/day (IQR 0.1 mg/kg/day). For model development, non-linear mixed modeling was used. Inter-individual variability (IIV) and inter-occasion variability were tested. Demographic and laboratory parameters were evaluated as covariates. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were used for model validation. Results A two-compartment disposition model of sildenafil and a one-compartment disposition model of desmethyl sildenafil (DMS) was observed with IIV in sildenafil and DMS clearance and volume of distribution of sildenafil. NPDE and VPC revealed adequate predictability. Only postnatal age increased sildenafil clearance. This was partly compensated by a higher DMS concentration, which also has a therapeutic effect. In this small group of patients, sildenafil was tolerated well. Conclusions This model for sildenafil in CDH patients shows that concentration-targeted sildenafil dosing of 0.4 mg/kg in 3 h, followed by 1.6 mg/kg/day continuous infusion achieves appropriate sildenafil plasma levels.

Background Population pharmacokinetic (popPK) models for antibiotics are used to improve dosing strategies and individualize dosing by therapeutic drug monitoring. Little is known about the differences in results of parametric versus nonparametric popPK models and their potential consequences in clinical practice. We developed both parametric and nonparametric models of imipenem using data from critically ill patients and compared their results. Methods Twenty-six critically ill patients treated with intravenous imipenem/cilastatin were included in this study. Median estimated glomerular filtration rate (eGFR) measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 116 mL/min/1.73 m2 (interquartile range 104–124) at inclusion. The usual dosing regimen was 500 mg/500 mg four times daily. On average, five imipenem levels per patient (138 levels in total) were drawn as peak, intermediate, and trough levels. Imipenem concentration-time profiles were analyzed using parametric (NONMEM 7.2) and nonparametric (Pmetrics 1.5.2) popPK software. Results For both methods, data were best described by a model with two distribution compartments and the CKD-EPI eGFR equation unadjusted for body surface area as a covariate on the elimination rate constant (Ke). The parametric population parameter estimates were Ke 0.637 h−1 (between-subject variability [BSV]: 19.0% coefficient of variation [CV]) and central distribution volume (Vc) 29.6 L (without BSV). The nonparametric values were Ke 0.681 h−1 (34.0% CV) and Vc 31.1 L (42.6% CV). Conclusions Both models described imipenem popPK well; the parameter estimates were comparable and the included covariate was identical. However, estimated BSV was higher in the nonparametric model. This may have consequences for estimated exposure during dosing simulations and should be further investigated in simulation studies. Electronic supplementary material The online version of this article (10.1007/s40262-020-00859-1) contains supplementary material, which is available to authorized users.

Hepatitis E virus (HEV) is the most common cause of viral hepatitis worldwide. Genotypes 1 and 2 (GT1 and GT2) are mainly present in developing countries, while GT3 and GT4 are prevalent in developed and high-income countries. In the majority of cases, HEV causes a self-limiting hepatitis. GT3 and GT4 can be responsible for a chronic hepatitis that can lead to cirrhosis in immunocompromized patients, i.e. solid-organ- and stem-cell-transplant-patients, human immunodeficiency virus-infected patients, and patients receiving chemotherapy or immunotherapy. HEV has also been associated with extra-hepatic manifestations such as neurologic disorders (Guillain-Barré Syndrome and neuralgic amyotrophy) and kidney disease. In patients with chronic hepatitis, reduction of immunosuppression, when possible, is the first therapeutic option. In the remaining patients, ribavirin therapy has been shown to very efficient for treating HEV infection leading to a sustained virological response in nearly 80-85% of patients. However, the mechanism of action of ribavirin in this setting is still unknown, as is the impact of HEV RNA polymerase mutations. There are unmet needs with regard to the treatment of chronic HEV with ribavirin. These include the optimal dosing and duration of treatment, and the potential beneficial effects of therapeutic drug monitoring on the virological response and the incidence of side effects. In the present review, we will provide an overview of HEV epidemiology, its mode of transmission and clinical manifestations, as well as its treatment by ribavirin with a focus on the drug's pharmacokinetics and dosing.

Because of increasing antimicrobial resistance and the shortage of new antibiotics, there is a growing need to optimize the use of old and new antibiotics. Modelling of the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of antibiotics can support the optimization of dosing regimens. Antimicrobial efficacy is determined by susceptibility of the drug to the microorganism and exposure to the drug, which relies on the PK and the dose. Population PK models describe relationships between patients characteristics and drug exposure. This article highlights three clinical applications of these models applied to antibiotics: 1) dosing evaluation of old antibiotics, 2) setting clinical breakpoints and 3) dosing individualization using therapeutic drug monitoring (TDM). For each clinical application, challenges regarding interpretation are discussed. An important challenge is to improve the understanding of the interpretation of modelling results for good implementation of the dosing recommendations, clinical breakpoints and TDM advices. Therefore, also background information on PK/PD principles and approaches to analyse PK/PD data are provided.

Objectives To calculate the clavulanic acid exposure of oral amoxicillin/clavulanic acid dosing regimens, to investigate variability using a population pharmacokinetic model and to explore target attainment using Monte Carlo simulations. Methods Two groups of healthy male volunteers received amoxicillin/clavulanic acid tablets at the start of a standard meal on two separate days 1 week apart. One group (n = 14) received 875/125 mg q12h and 500/125 mg q8h and the other group (n = 15) received 500/125 mg q12h and 250/125 mg q8h. In total, 1479 blood samples were collected until 8-12 h after administration. Concentrations were analysed using non-compartmental (WinNonLin) and population pharmacokinetic (NONMEM) methods. Results Median Cmax and AUC0-8 were 2.21 mg/L (0.21-4.35) and 4.99 mg·h/L (0.44-8.31), respectively. In 40/58 daily concentration-time profiles, Cmax and AUC0-8 of the morning dose were higher than with later doses. The final population model included a lag time (0.447 h), first-order absorption (3.99 h-1 at 8:00 h, between-subject variability 52.8%, between-occasion variability 48.5%), one distribution compartment (33.0 L, between-subject variability 23.9%) and first-order elimination (24.6 L/h, between-subject variability 26.7%). Bioavailability (fixed at 1 at 8:00 h, between-occasion variability 28.2%) and absorption rate decreased over the day. For 97.5% of the simulated population after 125 mg q12h or q8h, %fT > Ct at 0.5 mg/L was 8.33% (q12h) and 15.2% (q8h), %fT > Ct at 1 mg/L was 0% (q12h + q8h), and fAUC0-24 was 3.61 (q12h) and 5.56 (q8h) mg·h/L. Conclusions Clavulanic acid absorption in healthy volunteers is highly variable. Bioavailability and absorption rate decrease over the day. The model developed here may serve to suggest clavulanic acid dosing regimens to optimize efficacy and prevent underdosing.

Tacrolimus (Tac) is well established as main immunosuppressant in most immunosuppressive regimens in solid organ transplantation. Due to the narrow therapeutic window, pre dose Tac levels (C0) are monitored in all patients receiving Tac to reach optimal therapeutic levels. Tac is metabolized in the liver and intestine by the cytochrome P450 3A (CYP3A) isoforms CYP3A4 and CYP3A5. We present a case of an African American woman who underwent a liver transplantation in which adequate Tac levels were difficult to accomplish due to differences in cytochrome P450 3A4/5 (CYP3A4/5) polymorphisms of the transplant recipient and the donor liver graft. This case report highlights that genotyping the liver transplant recipient and the donor liver graft might provide data which could be used to predict the tacrolimus metabolism post transplantation.

A population pharmacokinetic (PK) protein-binding model was developed to (1) predict free mycophenolic acid (fMPA) based on total MPA (tMPA) concentrations in renal transplant patients, to establish the therapeutic range of fMPA through pharmacokinetic-pharmacodynamic studies; and (2) provide a guideline for dosing mycophenolate mofetil (MMF). Full PK profiles of 56 patients (from five different occasions) during the first year after transplantation who were treated with oral MMF and cyclosporine, or macrolides (either tacrolimus or sirolimus), were analysed. fMPA protein-binding was modelled using nonlinear mixed effects modelling (NONMEM). The influence of physiological factors and coadministered immunosupressant was studied. A two-compartment model with first-order absorption and elimination, linear protein binding and enterohepatic circulation (EHC) best described the PK of MPA. Different recycling rate constants were considered depending on the coadministered immunosuppressant. The protein-binding rate constant (KB [relative standard error, RSE%]) increased nonlinearly with renal function according to K B = 43.1 (3.13)·(CLCR/59.51)0.394(10.66) h−1. Furthermore, fMPA plasma clearance, given by clearance of the free mycophenolic acid (CLfMPA), CLfMPA = 410 (RSE%3.00)·(1+CsA·0.594 (22.39)) L/h, was 59.4% greater in cyclosporine-treated patients than in macrolide-treated patients, leading to lower MPA exposures. External evaluation proved acceptable area under the plasma concentration-time curve and trough concentration predictions. A reliable protein-binding population PK model was developed for prediction of fMPA or tMPA from each other and for dose guiding in stable renal transplant recipients.

Introduction Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response. Method A population pharmacodynamic analysis using nonlinear mixed effect models was performed with data from 43 terminally ill patients. PK profiles were predicted by a previously described PK model and depth of sedation was measured using the Ramsay sedation score. Patient and disease characteristics were evaluated as possible covariates. The final model was evaluated using a visual predictive check (VPC). Results The effect of midazolam on the sedation level was best described by a differential odds model including a baseline probability, Emax model and inter individual variability (IIV) on the overall effect. The EC50 value was 68.7 ug/L for a Ramsay score of 3-5 and 117.1 ug/L for a Ramsay score of 6. Co-medication with haloperidol was the only significant covariate. The VPC of the final model showed good model predictability. Conclusion We were able to accurately describe the clinical response to midazolam. As expected there was large variability in response to midazolam. The use of haloperidol was associated with a lower probability of sedation. This may be a result of confounding by indication as haloperidol was used to treat delirium, and deliria has been linked to a more difficult sedation procedure.

Aims: Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. Because of large inter-individual variability (IIV), however, the time it takes to achieve adequate sedation varies widely. It would therefore greatly improve clinical care if an individualized dose could be determined beforehand. To find clinically relevant parameters for dose individualization, we performed a pharmacokinetic study on midazolam, 1OH-midazolam (1-OH-M) and 1OH-midazolam-glucuronide (1-OH-MG) in terminally ill patients. Methods: Using nonlinear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 192 samples from 45 terminally ill patients who received midazolam either orally or subcutaneously. The covariates analysed were patient characteristics, co-medication and blood chemistry levels. Results: The data were accurately described by a one compartment model for midazolam, 1-OH-M and 1-OH-MG. The population mean estimates for midazolam, 1-OH-M and 1-OH-MG clearance were 8.4 l h−1 (RSE 9%, IIV 49%), 45.4 l h−1 (RSE 12%, IIV 60.5%) and 5.1 l h−1 (RSE 11%, IIV 49.9%), respectively. 1-OH-MG clearance was correlated with the estimated glomular filtration rate (eGFR) explaining 28.4% of the IIV in 1-OH-MG clearance. In addition, low albumin levels were associated with decreased midazolam clearance, explaining 18.2% of the IIV. Conclusion: Our study indicates albumin levels and eGFR as relevant clinical parameters to optimize midazolam dosing in terminally ill patients. The correlation between low albumin levels and decreased midazolam clearance is probably a result of inflammatory response as high CRP levels were correlated in a similar way.

Aims: Elderly transplant recipients have a lower incidence of acute rejection, and a higher risk to die from infectious complications. A potential cause may be differences in the pharmacokinetics (PK) or pharmacodynamics (PD) of the immunosuppressive drugs they are taking. This study was designed to comprehensively evaluate the influence of age on the PK and PD of mycophenolic acid (MPA). Methods: In this study the PK and PD of MPA was studied in 26 elderly and 54 younger renal transplant recipients treated with mycophenolate mofetil and tacrolimus. Patients were sampled repetitively, both before and during the first 6 months after kidney transplantation. Age-related variability in MPA PK, baseline IMPDH activity, as well as MPA-induced IMPDH inhibition were studied. Results: The IMPDH activity pre-transplantation did not differ between elderly and younger patients. Neither IMPDH activity pre-transplantation nor maximum IMPDH inhibition was significantly correlated with the patients' age. The area under the MPA plasma concentration–time curve (AUC0–12h) and the area under the effect (IMPDH activity)–time curve (AEC0–12h) from 0 to 12 h were also not significantly different between the two groups. We found no significant differences in EC50 and Emax between elderly and younger patients. Conclusions: Age did not significantly affect the PK or PD of MPA. It is unlikely that the lower incidence of acute rejection in elderly patients, or the higher risk to die from a severe infection in elderly patients is due to different handling of MPA in the elderly.

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Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFN&gamma, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFN&gamma, ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell.