Trends in Oral Drug Bioavailability Following Bariatric Surgery: Examining the Variable Extent of Impact on Exposure of Different Drug Classes

Changes to oral drug bioavailability have been observed post bariatric surgery. However, the magnitude and the direction of changes have not been assessed systematically to provide insights into the parameters governing the observed trends. Understanding these can help with dose adjustments. Analysis of drug characteristics based on a biopharmaceutical classification system is not adequate to … Continued

A Pregnancy Physiologically-based Pharmacokinetic (p-PBPK) Model for Disposition of Drugs Metabolized by CYP1A2, CYP3A4, and CYP2D6

Pregnant women are usually not part of the traditional drug development program. Pregnancy is associated with major biological and physiological changes that alter the pharmacokinetics (PK) of drugs. Prediction of the changes to drug exposure in this group of patients may help to prevent under- or overtreatment. We have used a pregnancy physiologically based pharmacokinetic … Continued

Mechanism-based Population Modeling of the Effects of Vildagliptin on GLP-1, Glucose, and Insulin in Patients with Type 2 Diabetes

The aim of this study was to build a mechanism-based population pharmacodynamic model to describe and predict the time course of active GLP-1, glucose and insulin in type 2 diabetic patients after treatment with various doses of vildagliptin. Vildagliptin concentrations, DPP-4 activity, active GLP-1, glucose and insulin concentrations from 13 type 2 diabetic patients after … Continued

Effects of the Moderate CYP3A4 Inhibitor, Fluconazole, on the Pharmacokinetics of Fesoterodine in Healthy Subjects

Available data suggest that fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors, such as ketoconazole. Currently, no information is available on whether dose adjustment is necessary when fesoterodine is administered with a moderate CYP3A4 inhibitor. This study shows that adjustment of fesoterodine dose is not warranted when … Continued

In Silico Prediction of Efavirenz and Rifampicin Drug-drug Interaction Considering Weight and CYP2B6 Phenotype

This study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight-based dosage recommendations used to counteract the rifampicin–efavirenz interaction. Efavirenz pharmacokinetics were simulated using a physiologically based … Continued

Assessment of Algorithms for Predicting Drug-drug Interactions Via Inhibition Mechanisms: Comparison of Dynamic and Static Models

The prediction of drug-drug interactions (DDIs) from in vitro data usually utilizes an average dosing interval estimate of inhibitor concentration in an equation-based static model. Simcyp®, a population-based ADME simulator, is becoming widely used for the prediction of DDIs and has the ability to incorporate the time-course of inhibitor concentration and hence generate a temporal … Continued

In Vitro and In Vivo Glucuronidation of Midazolam in Humans

Midazolam (MDZ) is a benzodiazepine used as a CYP3A4 probe in clinical and in vitro studies. A glucuronide metabolite of MDZ has been identified in vitro in human liver microsome (HLM) incubations. The primary aim of this study was to understand the in vivo relevance of this pathway. An authentic standard of N-glucuronide was generated from microsomal incubations and … Continued

Population Pharmacokinetics of Intravenous Pantoprazole in Pediatric Intensive Care Patients

What is already known about this subject The use of intravenous pantoprazole, a proton pump inhibitor, has been increasing in the paediatric intensive care unit. Despite this increased use, data on the disposition of intravenous pantoprazole in paediatric intensive care patients are very scarce. What this study adds Our population approach has determined the pharmacokinetic … Continued

Maraviroc: In Vitro Assessment of Drug-drug Interaction Potential

AIMS: To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug-drug interactions (DDIs). METHODS: Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. … Continued

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