11 research outputs found

    Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?

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    Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of ‘true’ paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated ‘true’ paediatric CLp values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLp predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on ‘true’ CLp. In the first scenario, the PE of AS0.75-based paediatric CLp predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLp predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age

    Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1-OH-midazolam in morbidly obese and weight loss surgery patients

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    This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1-OH-midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi-PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40-1.64) times higher compared to morbidly obese patients before surgery (P  0.05), with low values for both groups. The results of the semi-PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability.Pharmacolog

    Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

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    Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC24/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged 1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged Pharmacolog

    Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults

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    Background The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults. Methods Data from 19 obese adolescents [102.7 kg (62–149.5 kg)] and 20 morbidly obese adults [144 kg (112–186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW − WTfor age and length) was evaluated. Results The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called ‘excess weight’ model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed. Discussion We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents

    Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen

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    Introduction: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients. Methods: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106–193.1 kg] and body mass index [BMI] of 45.1 kg/m2 [40–55.2 kg/m2]) and eight non-obese patients (with a TBW of 69.4 kg [53.4–91.7] and BMI of 21.8 kg/m2 [19.4–27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM. Results: In morbidly obese patients, the median area under the plasma concentration–time curve from 0 to 8 h (AUC0–8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0–8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001). Conclusion: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment

    Kernel-Based Visual Hazard Comparison (kbVHC): a Simulation-Free Diagnostic for Parametric Repeated Time-to-Event Models

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    Repeated time-to-event (RTTE) models are the preferred method to characterize the repeated occurrence of clinical events. Commonly used diagnostics for parametric RTTE models require representative simulations, which may be difficult to generate in situations with dose titration or informative dropout. Here, we present a novel simulation-free diagnostic tool for parametric RTTE models; the kernel-based visual hazard comparison (kbVHC). The kbVHC aims to evaluate whether the mean predicted hazard rate of a parametric RTTE model is an adequate approximation of the true hazard rate. Because the true hazard rate cannot be directly observed, the predicted hazard is compared to a non-parametric kernel estimator of the hazard rate. With the degree of smoothing of the kernel estimator being determined by its bandwidth, the local kernel bandwidth is set to the lowest value that results in a bootstrap coefficient of variation (CV) of the hazard rate that is equal to or lower than a user-defined target value (CVtarget). The kbVHC was evaluated in simulated scenarios with different number of subjects, hazard rates, CVtarget values, and hazard models (Weibull, Gompertz, and circadian-varying hazard). The kbVHC was able to distinguish between Weibull and Gompertz hazard models, even when the hazard rate was relatively low (< 2 events per subject). Additionally, it was more sensitive than the Kaplan-Meier VPC to detect circadian variation of the hazard rate. An additional useful feature of the kernel estimator is that it can be generated prior to model development to explore the shape of the hazard rate function.Pharmacolog

    Kernel-Based Visual Hazard Comparison (kbVHC): a Simulation-Free Diagnostic for Parametric Repeated Time-to-Event Models

    No full text
    Repeated time-to-event (RTTE) models are the preferred method to characterize the repeated occurrence of clinical events. Commonly used diagnostics for parametric RTTE models require representative simulations, which may be difficult to generate in situations with dose titration or informative dropout. Here, we present a novel simulation-free diagnostic tool for parametric RTTE models; the kernel-based visual hazard comparison (kbVHC). The kbVHC aims to evaluate whether the mean predicted hazard rate of a parametric RTTE model is an adequate approximation of the true hazard rate. Because the true hazard rate cannot be directly observed, the predicted hazard is compared to a non-parametric kernel estimator of the hazard rate. With the degree of smoothing of the kernel estimator being determined by its bandwidth, the local kernel bandwidth is set to the lowest value that results in a bootstrap coefficient of variation (CV) of the hazard rate that is equal to or lower than a user-defined target value (CVtarget). The kbVHC was evaluated in simulated scenarios with different number of subjects, hazard rates, CVtarget values, and hazard models (Weibull, Gompertz, and circadian-varying hazard). The kbVHC was able to distinguish between Weibull and Gompertz hazard models, even when the hazard rate was relatively low (< 2 events per subject). Additionally, it was more sensitive than the Kaplan-Meier VPC to detect circadian variation of the hazard rate. An additional useful feature of the kernel estimator is that it can be generated prior to model development to explore the shape of the hazard rate function.Article / Letter to editorLeiden Academic Centre for Drug Researc

    Children in clinical trials: towards evidence-based pediatric pharmacotherapy using pharmacokinetic-pharmacodynamic modeling.

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    INTRODUCTION In pediatric pharmacotherapy, many drugs are still used off-label, and their efficacy and safety is not well characterized. Different efficacy and safety profiles in children of varying ages may be anticipated, due to developmental changes occurring across pediatric life. AREAS COVERED Beside pharmacokinetic (PK) studies, pharmacodynamic (PD) studies are urgently needed. Validated PKPD models can be used to derive optimal dosing regimens for children of different ages, which can be evaluated in a prospective study before implementation in clinical practice. Strategies should be developed to ensure that formularies update their drug dosing guidelines regularly according to the most recent advances in research, allowing for clinicians to integrate these guidelines in daily practice. Expert commentary: We anticipate a trend towards a systems-level approach in pediatric modeling to optimally use the information gained in pediatric trials. For this approach, properly designed clinical PKPD studies will remain the backbone of pediatric research

    Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?

    Get PDF
    Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of ‘true’ paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated ‘true’ paediatric CLp values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLp predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on ‘true’ CLp. In the first scenario, the PE of AS0.75-based paediatric CLp predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLp predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age.</p
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