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- Title
Evaluating Within‐Subject Variability for Narrow Therapeutic Index Drugs.
- Authors
Jayachandran, Priya; Okochi, Hideaki; Frassetto, Lynda A.; Park, Wansu; Fang, Lanyan; Zhao, Liang; Benet, Leslie Z.
- Abstract
The US Food and Drug Administration (FDA) reference‐scaled average bioequivalence approach scales the bioequivalence (BE) limits of narrow therapeutic index drugs (NTIDs) to the intrasubject or within‐subject variability (WSV) of the reference‐listed drug. A clinical study was conducted to evaluate the WSV of warfarin (Coumadin), 10 mg, administered to 10 healthy volunteers exhibiting similar cytochrome P450 2C9 and vitamin K epoxide reductase alleles on 3 study days. Individual intrasubject coefficients of variation for maximum plasma concentration and area under the curve (0‐72 hour) ranged from 3.7–15% and from 4.3–16.2%, respectively (R‐warfarin) and from 5.4–19.1% and from 2.5–11.9%, respectively (S‐warfarin). Two BE tests were performed on a WSV distribution obtained by bootstrapping 1,000 replicates of the clinical data, yielding passing rates of 95–97% for the mean comparison and 84–87% for the variability comparison. The variability comparison passing rate was lower than expected for an NTID product tested against itself, but it may provide further assurance of BE.
- Subjects
UNITED States. Food &; Drug Administration; THERAPEUTIC equivalency in drugs; THERAPEUTICS; CYTOCHROMES; ALLELES
- Publication
Clinical Pharmacology & Therapeutics, 2019, Vol 105, Issue 2, p411
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1002/cpt.1293