The Utility of a Population Approach in Drug-Drug Interaction Assessments: A Simulation Evaluation

Journal of Clinical Pharmacology
Diane D WangChuanpu Hu

Abstract

This study aims at evaluating the utility of the population pharmacokinetics approach in therapeutic protein drug-drug-interaction (DDI) assessment. Simulations were conducted for 2 representative victim drugs, methotrexate and trastuzumab, using a parallel-group design with and without the interaction drug. The effect of a perpetrator on the exposure of the victim drug is described as the ratio of clearance/apparent clearance of the victim drug given with or without the perpetrator. The power of DDI assessment was calculated as the percentage of runs with 90% confidence interval of the estimated DDI effect within 80% to 125% for the scenarios of no DDI, benchmarked with the noncompartmental approach with intensive sampling. The impact of the number of subjects, the number of sampling points per subject, sampling time error, and model misspecification on the power of DDI determination were evaluated. Results showed that with equal numbers of subjects in each arm, the population pharmacokinetics approach with sparse sampling may need about the same or a higher number of subjects compared to a noncompartmental approach in order to achieve similar power. Increasing the number of subjects, even if only in the study drug alone arm, ...Continue Reading

References

Jun 20, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Thorir D BjornssonUNKNOWN FDA Center for Drug Evaluation and Research (CDER)
May 4, 2005·Cancer Chemotherapy and Pharmacology·Rene BrunoPamela Klein
Sep 4, 2007·Journal of Clinical Pharmacology·Kathleen Seitz, Honghui Zhou
Dec 31, 2009·Pharmaceutical Statistics·Chuanpu HuHonghui Zhou
May 11, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Leslie J DickmannJ Greg Slatter
Nov 26, 2013·Journal of Clinical Pharmacology·Andrew T ChowUNKNOWN Population PK TPDI Working Group

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