Integration of absorption, distribution, metabolism, and elimination genotyping data into a population pharmacokinetic analysis of nevirapine.

Objectives: The aim of this analysis was to show the applicability of a newly developed algorithm to assess the influence of genetic variants and other covariates on nevirapine's drug disposition. The algorithm combines high-throughput genotyping data and nonlinear mixed effects modeling methods.

Methods: Patients, who participated in the 2NN pharmacokinetic sub study, were reconsented and reenrolled into a clinical trial for genotyping analysis.

Integration of high-throughput genotyping data into pharmacometric analyses using nonlinear mixed effects modeling.

Objectives: High-throughput genotype (HTG) platforms allow the simultaneous screening of many single nucleotide polymorphisms (SNP) across many genes per sample for a reasonable price. This analysis presents an algorithm for the implementation of HTG data in nonlinear mixed effect (NLME) modeling techniques, including model evaluation. The suitability of the developed algorithm is tested by applying it to four simulated data sets representing various genotype-phenotype relationships.

Quantitative pharmacology approach in Alzheimer's disease: efficacy modeling of early clinical data to predict clinical outcome of tesofensine.

Effective therapeutic options for Alzheimer's disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process.

Semi-mechanistic population pharmacokinetic drug-drug interaction modelling of a long half-life substrate and itraconazole.

Background: For compounds with a long elimination half-life, the evaluation of a drug-drug interaction (DDI) study can be challenging. The standard analytical approach of a non-compartmental analysis (NCA) might not be able to detect the full interaction potential and may lead to a significant underestimation of the interaction. The most appropriate method for data analysis might be a semi-mechanistic population pharmacokinetic modelling approach.

A quantitative enterohepatic circulation model: development and evaluation with tesofensine and meloxicam.

Background And Objective: Drugs undergoing enterohepatic circulation (EHC) are associated with typical pharmacokinetic characteristics such as multiple-peak phenomenon in the plasma concentration-time profile and prolongation of the apparent elimination half-life (t((1/2))). Currently, versatile pharmacokinetic models are lacking that could test the hypothesis of an EHC for observed multiple-peak phenomenon in pharmacokinetic profiles and its quantitative contribution. The aim of this analysis was to accomplish a model that is able to describe typical plasma concentration-time profiles of compounds undergoing EHC using data from intravenous studies of tesofensine and meloxicam.

Effective integration of systems biology, biomarkers, biosimulation and modelling in streamlining drug development.

The European Federation of Pharmaceutical Sciences (EUFEPS) has long established itself as leaders in the field of interdisciplinary meetings to discuss issues that face drug development. It's ever popular and well attended "Optimizing Drug Development" series has tackled numerous issues, most recent of which have been drug interactions, getting the dose right, candidate selection, and biomarkers (Lesko et al., 2000; Rolan et al.

Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease.

Aims: To develop a population pharmacokinetic model for NS2330 and its major metabolite M1 based on data from a 14 week proof of concept study in patients with Alzheimer's disease, and to identify covariates that might influence the pharmacokinetic characteristics of the drug and/or its metabolite.

Methods: Plasma data from 320 subjects undergoing multiple oral dosing, and consisting of 1969 NS2330 and 1714 metabolite concentrations were fitted simultaneously using NONMEM.

Results: Plasma concentration-time profiles of NS2330 and M1 were best described by one-compartment models with first-order elimination for both compounds.

Population pharmacokinetic modelling of BIBN 4096 BS, the first compound of the new class of calcitonin gene-related peptide receptor antagonists.

Pharmacokinetics (PK) of the calcitonin gene-related (CGRP) peptide receptor antagonist BIBN 4096 BS, the first compound of this new class tested in humans, has been evaluated combining the data from a phase I study performed in healthy volunteers and a phase IIa study conducted in migraine patients. A total of 94 individuals with a total of 556 plasma samples contributed to the analysis. Subjects received a single dose of 0.