Detailed Evaluation of Pharmacokinetic-based Drug-drug Interaction Data Contained in New Drug and Biologic License Applications of Drugs Approved by the U.S. FDA in 2015

Presented at ASCPT conference, March 2017, Washington, DC, USA
Jingjing Yu, Zhu Zhou, Katie Owens, Tasha K. Ritchie, and Isabelle Ragueneau-Majlessi

2017 ASCPT Poster Presentation – 2015 NDA Review

Abstract

The aim of the present work was to perform a systematic analysis of metabolism, transport, and drug interaction data available in New Drug Applications (NDAs) and Biologic License Applications (BLAs) of drugs approved in 2015, and highlight significant findings.

Key Findings From Preclinical and Clinical Drug Interaction Studies Presented in New Drug and Biological License Applications Approved by the Food and Drug Administration in 2014

Drug Metab Dispos. 2016 Jan; 44(1); 83-101.
Published online 2015 Sep 30

Abstract

Regulatory approval documents contain valuable information, often not published, to assess the drug-drug interaction (DDI) profile of newly marketed drugs. This analysis aimed to systematically review all drug metabolism, transport, pharmacokinetics, and DDI data available in the new drug applications and biologic license applications approved by the U.S. Food and Drug Administration in 2014, using the University of Washington Drug Interaction Database, and to highlight the significant findings. Among the 30 new drug applications and 11 biologic license applications reviewed, 35 new molecular entities (NMEs) were well characterized with regard to drug metabolism, transport, and/or organ impairment and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, when NMEs were considered as victim drugs, 16 NMEs had at least one in vivo DDI study with a clinically significant change in exposure (area under the time-plasma concentration curve or Cmax ratio ≥2 or ≤0.5), with 6 NMEs shown to be sensitive substrates of cytochrome P450 enzymes (area under the time-plasma concentration curve ratio ≥5 when coadministered with potent inhibitors): paritaprevir and naloxegol (CYP3A), eliglustat (CYP2D6), dasabuvir (CYP2C8), and tasimelteon and pirfenidone (CYP1A2). As perpetrators, seven NMEs showed clinically significant inhibition involving both enzymes and transporters, although no clinically significant induction was observed. Physiologically based pharmacokinetic modeling and pharmacogenetics studies were used for six and four NMEs, respectively, to optimize dosing recommendations in special populations and/or multiple impairment situations. In addition, the pharmacokinetic evaluations in patients with hepatic or renal impairment provided useful quantitative information to support drug administration in these fragile populations.