IntroductionIn February 2018, OS320—an amantadine extended-release (ER) tablet formulation with once-daily morning administration—was approved for the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions in adults. The purpose of this study was to describe three phase 1 studies that assessed the pharmacokinetics (PK) and bioavailability of amantadine ER in healthy adult volunteers.MethodsStudy 1 was an open-label, four-treatment, single-dose, crossover study comparing amantadine ER 129, 193, and 258 mg tablets with an equivalent dose of immediate-release (IR) amantadine 40 mg/5 mL syrup. Study 2 was an open-label, single-dose, crossover food-effect study with amantadine ER 258 mg. Study 3 was an open-label, multiple-dose, crossover study comparing amantadine ER and amantadine IR syrup.ResultsAmantadine ER displayed a steady release of amantadine, with the peak amantadine concentration occurring at ~ 7.5 h postdose or in the middle of the day (following a morning dose) with steady-state administration. Administration of amantadine ER 258 mg with a high-fat meal did not affect amantadine bioavailability. Amantadine plasma exposure increased proportionally with increasing doses, and at steady state, amantadine exposure from an amantadine ER 258-mg tablet was bioequivalent to twice-daily 129-mg amantadine IR syrup.ConclusionThe PK profile of amantadine ER 129-mg, 193-mg, and 258-mg tablets allows for once-daily dosing in the morning; the 24-h average amantadine plasma concentration is equivalent to that for the same daily dose of IR amantadine administered twice daily.FundingOsmotica Pharmaceutical US LLC.

Background An extended-release formulation of amantadine (Osmolex ER™, Osmotica Pharmaceutical US LLC) was approved in February 2018 to treat Parkinson’s disease and drug-induced extrapyramidal reactions in adults. Objectives To determine the pharmacokinetic profile of extended-release amantadine in subjects with varying degrees of renal impairment. Methods Adults with normal renal function (creatinine clearance > 89 mL/min/1.73 m 2 ), moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m 2 ), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m 2 ) received a single 129-mg dose (160 mg amantadine hydrochloride) of extended-release amantadine. Blood and urine samples for pharmacokinetic analysis were taken at scheduled intervals. A two-compartment pharmacokinetic population model was employed to determine optimum extended-release amantadine dosing in subjects with renal impairment. Results Following a single oral dose of the 129-mg extended-release amantadine tablet, amantadine plasma concentration increased slowly, reaching a peak at approximately 11 h. Amantadine elimination was reduced in subjects with renal impairment. Renal clearance decreased from 10,965 to 2618 mL/h in subjects with severe renal impairment compared to those with normal renal function. Pharmacokinetic modeling and simulation methods were used to recommend the oral administration of 129-mg extended-release amantadine tablets at intervals of 24, 48, 72, 96, 120, or 168 h depending on the degree of renal function. Conclusions Renal impairment was associated with reduced amantadine clearance. Based on pharmacokinetic modeling and simulations, dose regimens were recommended for subjects with impaired renal function to provide systemic amantadine exposure similar to subjects with normal renal function taking a once-daily extended-release amantadine tablet. Electronic supplementary material The online version of this article (10.1007/s40263-019-00651-1) contains supplementary material, which is available to authorized users.