Comparison of Three Oral Amantadine Formulations: A Population Pharmacokinetic Study
Zhao Wang1, Roberto Gomeni2, Robert Hauser3, Rajesh Pahwa4, Olivier Rascol5, Asfiha Gebre1, Gianpiera Ceresoli-Borroni6, Jonathan Rubin6
1Supernus Pharmaceuticals Inc, 2Pharmacometrica, 3Movement Disorders Center, 4University of Kansas Medical Center, 5Departments of Clinical Pharmacology and Neurosciences-CIC9302/INSERM 825, 6Supernus Pharmaceuticals
Objective:

Compare exposure parameters of three amantadine (AMT) formulations using an integrated population pharmacokinetic (PK) model.

Background:

Currently, three distinct AMT products are available in the US to treat manifestations of Parkinson’s disease [PD]: the original immediate-release (IR) formulation (AMT-IR, [Symmetrel] administered 2-3 times daily), and two extended-release (ER) formulations; one with an IR component (AMT-IR/ER [Osmolex ER], administered once/day morning) and one with delayed-release technology (AMT-DR/ER [Gocovri], administered once/day bedtime)). While differences in drug-release mechanisms and indications render the products non-interchangeable, little comparative PK data exist.

Design/Methods:

Data from three phase 1 (PK healthy control) and one phase 2 (PD patient) studies (including 5906 PK measurements from 125 subjects) were used to develop a population PK model. Covariates included age, BMI, weight, and creatinine clearance. The model was then used to generate predicted steady state AMT concentration-time profiles at recommended product maintenance dosages.

Results:

Drug absorption was formulation specific. Drug disposition was adequately described by a one‑compartment model with first-order elimination. Creatinine clearance and body mass were shown to impact amantadine PK. Median model-predicted, steady-state Cmax (ng/mL) for the maintenance dosages: AMT-IR 81mg BID, AMT-IR 81 mg TID, AMT-IR/ER 193mg, AMT-IR/ER 258mg and AMT‑DR/ER 274mg, were: 667, 979, 770, 1014, and 1109, respectively; median model-predicted, steady-state AUC0‑24 (ng/mL*hr) were: 12494, 18262, 14191, 18439, and 21575, respectively. Concentrations were higher over the first half of the waking day for AMT‑DR/ER vs. AMT-IR and were more similar for AMT-IR/ER vs. AMT-IR. 

Conclusions:
Model-generated PK data confirm lack of product interchangeability reported in US product prescribing information. The higher plasma AMT concentrations in the morning and first half of the day with AMT-DR/ER are consistent with its indication for levodopa-related OFF episodes and dyskinesia as people with PD often wake up in an OFF state, and dyskinesia typically emerges following morning levodopa dosing.
10.1212/WNL.0000000000206190