Журнал биоэквивалентности и биодоступности

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Bioequivalence of Long Half-Life Drugs - Informative Sampling Determination -Parallel Designed Studies

Ahmed El-Tahtawy, Ferrin Harrison, Jeanne Fourie Zirkelbach and Andre J. Jackson

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.