title: Bioequivalence of long half-life drugs--informative sampling determination--using truncated area in parallel-designed studies for slow sustained-release formulations.
abstract: A simulation study was done to determine if 72 h is the most informative sampling duration for bioequivalence (BE) determination in parallel-designed BE studies with drugs that have half-lives of at least 30 h. The impact of absorption and elimination half-lives on informative sampling was evaluated. Two-treatment parallel-designed BE studies using a one-compartment oral absorption model with half-lives of 30 and 350 h was simulated. Area under the curve (AUC) values were truncated at 12-360 h. Experimental BE data [median time to reach the maximum concentration (T(max) ) = 20 h and low clearance = 0.192 L/h) indicated a decrease and then an increase in the intrasubject variability [root mean square error (RMSE)] for truncated AUC as a function of time. Simulations supported these findings with the highest probability of passing the BE confidence interval criteria being between 60 and 96 h, depending on half-life and percent coefficient of variation. The 30-h simulation exhibited a minimum in RMSE at 24-h truncation that continued to increase up to 360 h, whereas the 350-h simulation exhibited a minimum at 60 h, which increased after 96 h. Power curves at the 350-h half-life showed higher probabilities of rejection of BE for true test/reference ratios greater than 0.9. For parallel-designed BE studies, sampling beyond 120 h will not affect the BE decision and therefore is unnecessary.
authors.affiliation: Pfizer Laboratories, Division of Global Clinical Pharmacology, Pharmacometrics, New York, New York, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Tahtawy
authors.forename: Ferrin
authors.initials: F
authors.lastname: Harrison
authors.forename: Jeanne Fourie
authors.initials: JF
authors.lastname: Zirkelbach
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Jackson
mesh_terms: D019540:Area Under Curve; D003692:Delayed-Action Preparations; D006207:Half-Life; D010599:Pharmacokinetics; D013810:Therapeutic Equivalency
chemical_list: D003692:Delayed-Action Preparations