生物学的同等性とバイオアベイラビリティのジャーナル

概要

Comparative Bioavailability of Two Tablet Formulations of Amifampridine with and without Food, and the Impact of Acetylator Status on the Pharmacokinetic Food Effect

Keith D. Gallicano*, Gary Ingenito, Ardeshir Khadang, Peter Boldingh

Background: Previous research has not evaluated whether the two pharmaceutically non-equivalent tablet products containing amifampridine, Ruzurgi^® (amifampridine) and Firdapse^® (amifampridine phosphate), are bioequivalent under fasted and fed conditions, and if acetylator status influences the magnitude of the food effect. Therefore, we compared the bioavailability of amifampridine tablet 10 mg relative to that of amifampridine phosphate tablet 10 mg (base equivalent) in the fed state following consumption of a high-fat meal and in the fasted state, and investigated the effect of food intake on the pharmacokinetics of amifampridine and its inactive 3-N-acetyl metabolite in subjects evaluated for slow or rapid/intermediate N-acetyltransferase 2 (NAT2) metabolizer status.

Methods: Twenty (20) healthy, adult male and female volunteers were enrolled in this open-label, randomized, four-treatment, two-sequence, four-period, crossover, single-dose, oral comparative bioavailability and food-effect study. Eighteen (18) individuals (Male: 10; Female: 8; Slow NAT2 metabolizer: 9; Rapid/intermediate NAT2 metabolizer: 9), completed all four periods. Plasma concentrations and pharmacokinetic characteristics of amifampridine and 3-N-acetyl amifampridine were determined by LC-MS/MS. Safety profiles of the two products were assessed from adverse events monitoring, medical examinations, and clinical laboratory tests.

Results: Compared to rapid/intermediate acetylators, slow acetylators had statistically significant 5.5- to 8.9-fold higher amifampridine C_max and AUC and a 1.8-fold longer t_½z (1.48 to 2.62 hours), and 22%-31% lower 3-N-acetyl amifampridine AUC and C_max. Metabolite t_½z values were similar between the two phenotypes (Rapid/intermediate: 3.50 hours; Slow: 3.66 hours). Under fasted and fed conditions, the 90% confidence intervals for the least-squares geometric mean ratios of the Test (Ruzurgi^®) to Reference (Firdapse^®) treatments were within the standard equivalence range (80%, 125%) for C_max, AUC_0-t and AUC_0-∞ parameters for amifampridine and metabolite. For rapid/intermediate acetylators, the high-fat meal significantly decreased amifampridine AUC by 34%-40%, and C_max by 69%. For slow acetylators, AUC was unaffected by food but C_max decreased by 39%. The single oral doses were well tolerated under fasted and fed conditions.

Conclusion and implications: Peak and total plasma exposures of amifampridine and its metabolite were equivalent between the two products following a single 10-mg dose in either the fasted or fed state. Therefore, dosing regimens of Ruzurgi^® and Firdapse^® can be considered interchangeable in the fasted and fed states.

A high-fat meal decreased peak and total plasma exposures of amifampridine and 3-N-acetyl amifampridine, but the effect was more pronounced on amifampridine for rapid/intermediate acetylators, indicating the importance of knowing an individual’s acetylator status to avoid potential underdosing either product with a high-fat meal.