A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion
Journal Title: The AAPS Journal - Year 2015, Vol 17, Issue 4
Abstract
Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00–125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD’s within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion.
Authors and Affiliations
Wenlei Jiang, Fairouz Makhlouf, Donald J. Schuirmann, Xinyuan Zhang, Nan Zheng, Dale Conner, Lawrence X. Yu, Robert Lionberger
Keywords
Related Articles
- EP ID EP680973
- DOI 10.1208/s12248-015-9753-5
- Views 62
- Downloads 0
Impact of Osmotically Active Excipients on Bioavailability and Bioequivalence of BCS Class III Drugs
SAPP is commonly used as a food additive and mostly found in bakery products (40). SAPP can also be employed as an excipient for effervescent formulations to provide rapid disintegration of pharmaceutical products. In a...
Preparation of Alendronate Liposomes for Enhanced Stability and Bioactivity: In Vitro and In Vivo Characterization
Liposomes containing bisphosphonates have been shown to deplete circulating monocytes and reduce experimental restenosis. However, acceptable shelf life was not achieved, and the disruption extent and rate of the vesicle...
The Use of Clinical Utility Assessments in Early Clinical Development
A quickly realizable benefit of model-based drug development is in reducing uncertainty in risk/benefit, comprising individually of safety and effectiveness, two key attributes of a product evaluated for regulatory appro...
Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications
It is widely believed that acceptable bioequivalence studies of drugs with high within-subject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied t...
Reproductible production of a PEGylated dual-acting peptide for diabetes
A pEGylated glucagon-like peptide-1 (GLP-1) agonist and glucagon antagonist hybrid peptide was engineered as a potential treatment for type 2 diabetes. To support preclinical development of this PEGylated dual-acting pep...