Clin Pharmacokinet
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Randomized Controlled Trial
Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban.
Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population. ⋯ The paediatric PBPK model developed here allowed an exploratory analysis of the pharmacokinetics of rivaroxaban in children to inform the dosing regimen for a clinical study in paediatric patients.
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Milrinone is the drug of choice for the treatment and prevention of low cardiac output syndrome (LCOS) in paediatric patients after open heart surgery across Europe. Discrepancies, however, among prescribing guidance, clinical studies and practice pattern require clarification to ensure safe and effective prescribing. However, the clearance prediction equations derived from classical pharmacokinetic modelling provide limited support as they have recently failed a clinical practice evaluation. Therefore, the objective of this study was to evaluate current milrinone dosing using physiology-based pharmacokinetic (PBPK) modelling and simulation to complement the existing pharmacokinetic knowledge and propose optimised dosing regimens as a basis for improving the standard of care for paediatric patients. ⋯ The PBPK drug-disease model for milrinone in paediatric patients with and without LCOS after open heart surgery highlights that age, disease and surgery differently impact the pharmacokinetics of milrinone, and that current milrinone dosing for LCOS is suboptimal to maintain the therapeutic target range across the entire paediatric age range. Thus, optimised dosing strategies are proposed to ensure safe and effective prescribing.
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Randomized Controlled Trial Multicenter Study
Population pharmacokinetics of sifalimumab, an investigational anti-interferon-α monoclonal antibody, in systemic lupus erythematosus.
Sifalimumab is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes a majority of the subtypes of human interferon-α. Sifalimumab is being evaluated as a treatment for systemic lupus erythematosus (SLE). The primary objectives of this analysis were (a) to develop a population pharmacokinetic model for sifalimumab in SLE; (b) to identify and quantitate the impact of patient/disease characteristics on pharmacokinetic variability; and (c) to evaluate fixed versus body weight (WT)-based dosing regimens. ⋯ A two-compartment population pharmacokinetic model adequately described sifalimumab pharmacokinetics. The estimated typical pharmacokinetic parameters were similar to other monoclonal antibodies without target mediated elimination. Although the population pharmacokinetic analysis identified some statistically significant covariates, they explained <7 % between-subject variability in pharmacokinetic parameters indicating that these covariates are not clinically relevant. The population pharmacokinetic analysis also demonstrated the feasibility of switching to fixed doses in phase IIb clinical trials of sifalimumab.
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Review
The role of pharmacogenetics in drug disposition and response of oral glucose-lowering drugs.
The primary goal of type 2 diabetes mellitus (T2DM) disease management is improvement of quality of life and prevention of complications. One way to achieve these goals is improving glycemic control by using different types of oral glucose-lowering medications. Currently seven different pharmacological oral glucose-lowering drug classes are available, each with its own mechanism of action and characteristics regarding absorption, distribution, metabolism, and elimination. ⋯ This review comprises current knowledge on genetic variants affecting both pharmacokinetics and pharmacodynamics of oral glucose-lowering drugs. Included variants are located in genes coding for drug transporters, i.e., the organic anion-transporting family and the organic cation transporter family; genes involved in metabolism, i.e., cytochrome P450 superfamily; genes coding for drug receptors; T2DM-associated genes; and genes identified by genome-wide association studies (GWASs). Furthermore, this review provides insight into current status and future directions for personalized medicine in T2DM.
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Randomized Controlled Trial
Population pharmacokinetic analysis for hydrocodone following the administration of hydrocodone bitartrate extended-release capsules.
Hydrocodone is a semi-synthetic narcotic analgesic and antitussive. Although hydrocodone products have been on the market for over 50 years, relatively little is known about its pharmacokinetics. Additionally, there are no published reports of population pharmacokinetic analyses for hydrocodone. Furthermore, current labeling of hydrocodone-containing products provides little guidance in terms of the impact of patient descriptors on the pharmacokinetics of hydrocodone. The objectives of this analysis were to develop a population pharmacokinetic model that characterizes the pharmacokinetics of hydrocodone following single and multiple oral doses of hydrocodone extended-release capsules (hydrocodone bitartrate ER capsules) in healthy subjects and patients, to examine the impact of patient descriptors on pharmacokinetic parameters and to assess the dose-proportionality of hydrocodone pharmacokinetic. ⋯ A linear model for hydrocodone elimination provided an adequate fit to the observed data over the entire dose range, which supports that hydrocodone bitartrate ER capsules exhibit dose-proportional pharmacokinetics. The formulation of hydrocodone bitartrate ER capsules results in absorption profiles that are variable across and within subjects. Despite the variability in absorption profiles, a relatively simple model provided an adequate fit to the data. Creatinine clearance and BSA were statistically significant predictors of the apparent oral clearance and apparent oral volume of distribution. Absorption characteristics of hydrocodone bitartrate ER capsules should still allow effective plasma concentrations of hydrocodone to be reached quickly and for effective concentrations to be maintained for a long period.