Comparative Pharmacokinetic Assessment of Once-Daily Extended-Release and Twice-Daily Amantadine Formulations in Healthy Male Subjects Under Fasting Conditions.

Abstract

Background and objectives: Parkinson's disease (PD) affects a large population worldwide with millions of people losing motor function control. Although there is no recognized cure for PD, current medications aim to manage the symptoms and slow down the progression of the disease. Amantadine is one such treatment option that can be used in both early and late stages of PD. The current study aimed to assess the relative bioequivalence of two test prototypes (Ta and Tb) of amantadine extended-release (ER) oral formulation manufactured by Sun Pharmaceuticals Industries Limited with the reference immediate-release (IR) formulation (R) of amantadine hydrochloride manufactured by Morton Grove Pharmaceuticals Inc.

Methods: This was an open-label, balanced, randomized, three-treatment, six-sequence, three-period, single-dose once daily (OD) versus twice daily (BID), crossover relative bioavailability study in healthy adult male subjects under fasting condition with a total of 36 + 2 additional standby subjects meeting the eligibility criteria. The pharmacokinetic parameters including maximum concentration (C_max), time to achieve C_max (t_max), area under the plasma concentration-time curve from time zero to time t (AUC_0-t), area under the concentration-time curve from 0 to 24 h (AUC_0-24), area under the plasma concentration-time curve from time 0 to infinity (AUC_0-∞), and half-life (t_1/2) were assessed. Statistical analysis was performed using analysis of variance (ANOVA) and ratio of least square means (LSM) (log transformed) was used to calculate the relative bioequivalence of the test drugs with the reference drug. Safety monitoring was done by considering adverse and serious adverse events during the duration of the study.

Results: Both Ta and Tb formulations demonstrated similar systemic exposure to the reference product, meeting the criteria for bioequivalence within acceptable limits (80.00-125.00%). The ratios of LSM for log-transformed pharmacokinetic parameters (90% confidence interval [CI]) for Ta versus R were 100.02% (96.75-103.40%) for C_max, and 107.27% (102.75-112.00%) for AUC_0-t; and for Tb versus R were 93.92% (90.38-97.60%) for C_max, and 101.12% (96.73-105.71%) for AUC_0-t. There were no adverse or serious adverse events observed during the study.

Conclusion: These findings confirm the bioequivalence of the two test prototypes of amantadine ER formulation manufactured by Sun Pharmaceutical Industries Limited with the IR BID formulation of amantadine manufactured by Morton Grove Pharmaceuticals Inc. The pharmacokinetic equivalence supports the use of OD amantadine ER as an alternative to the BID IR formulation, with the potential to improve patient adherence due to reduced dosing frequency.