Objective: Evaluate amantadine exposure following Gocovri® (amantadine) extended release capsules dosing regimens in renal impairment, using pharmacokinetic (PK) modeling and simulations.

Background: Gocovri bedtime dosing provides therapeutic amantadine concentrations on morning awakening, and throughout the day to reduce dyskinesia and OFF in Parkinson’s disease (PD). Amantadine is excreted unchanged in the urine (>85%), with ~16 h mean elimination half-life in normal renal function. For all amantadine products, dose and/or dosing interval adjustment is recommended in moderate or severe renal impairment because elimination rate constant (ke) may be decreased >50%. Renal impairment is associated with older age, hypertension, and diabetes; based on population estimates, 20% of adults aged ≥65 years have at least moderate renal impairment.

Method: A one-compartment model was developed for single and multiple dose PK in healthy subjects; amantadine concentrations from a Gocovri trial in PD patients with no or mild renal impairment served as the reference population. Amantadine clearance across stages of renal impairment were derived from published sources. Exposures from approved, once daily bedtime Gocovri dosing regimens were simulated in PD patients with varying severity of renal impairment to match drug exposure in the reference population.

Results: A one-compartment model describes amantadine PK with Gocovri. In moderate-severe renal impairment, standard titration to a 274 mg Gocovri maintenance dose resulted in ~3 to 5-fold higher Cmax and ~5 to 11-fold higher AUC compared to the reference population. Time to steady-state was 4 days in normal subjects, 1 week in moderate, and ~1 month in severe renal impairment. Daily maintenance doses of 68.5 mg (severe impairment) and 137 mg (moderate impairment) resulted in exposure estimates similar to PD patients with no or mild renal impairment.

Conclusion: This model predicts substantially higher amantadine exposure in patients with moderate or severe renal impairment than seen in Gocovri PD trials, which excluded patients with eGFR <50 mL/min/1.73m2. In elderly PD patients, moderate or severe renal impairment may be common. Clinicians should consider potential for renal impairment and adjust Gocovri doses per labeling, to avoid drug accumulation and potential dose-related adverse events.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gocovri-dose-adjustment-in-elderly-parkinsons-patients-at-risk-for-renal-impairment-implications-from-an-exposure-simulation-model/