Bioequivalence of Long Half-Life Drugs - Informative Sampling Determination -Parallel Designed Studies
- Corresponding Authors:
- Dr. Andre J. Jackson
Office of Clinical Pharmacology
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire
Dr., Silver Spring, MD, 20993, USA
E-mail: [email protected]
Received Date: March 29, 2011; Accepted Date: April 15, 2011; Published Date: April 19, 2011
Citation: El-Tahtawy A, Harrison F, Zirkelbach JF, Jackson AJ (2011) Bioequivalence of Long Half-Life Drugs - Informative Sampling Determination -Parallel Designed Studies. J Bioequiv Availab 3: 056-061. doi: 10.4172/jbb.1000059
Copyright: © 2011 El-Tahtawy A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Objective: To determine if 72 hours is the most informative sampling duration for the bioequivalence (BE) determination for drugs with half-lives > 30 h when using a parallel study design. Methods: Two-treatment parallel-designed BE studies were simulated. A one-compartment oral absorption model with half-lives of 30 h and 350 h (clearance = 0.224 or 0.019 L/h), distribution volume = 9.7 L, and inter-subject variability for clearance of 75-250% was simulated. The test/reference ratio for fraction available was investigated at 1.0 and 1.25, while the rate constants for absorption (Ka) were simulated at a test/reference ratio of 1 and 4. AUC values truncated at 12-360 h were calculated. Experimental parallel BE studies drugs were also investigated. Key findings: Experimental BE data indicated a decrease and then an increase in the root mean square error (RMSE) or variability as a function of time. Simulations supported these findings with the highest probability of passing the CI being between times 24 and 120 h depending on Ka, half-life, and inter-subject variability. Based on this work, a reduction in the sampling duration of parallel-designed BE studies is recommended. Experimental BE data indicated a decrease and then an increase in the RMSE. The 30-h half-life simulations exhibited a minimum in RMSE that rose to a plateau at 350 h. There was an increase in the probability of rejecting BE with longer sampling times for the 30-h simulations showing a maximum near 300 h while the 350-h half-life simulations showed no maximum. Conclusion: For parallel-designed BE studies, sampling beyond 120 h will not change the BE decision and therefore is unnecessary.