Objective: To demonstrate the unique shape and pharmacokinetic (PK) profile of Gocovri® (amantadine) extended release (ER) capsules by using metrics pertinent to ER dosage forms.

Background: Gocovri, dosed at bedtime, has been demonstrated to reduce dyskinesia and OFF in Parkinson’s disease (PD). The recommended bedtime dosing may seem unexpected for an ER product that is needed for symptoms primarily occurring in the daytime, such as amantadine. Typical PK metrics of Cmax, Tmax, and AUC may be inadequate to differentiate the shape of PK curves from different ER products. An expanded understanding of metrics pertinent to ER dosage forms will help highlight the rationale for Gocovri bedtime dosing.

Method: Single and multiple-dose Gocovri PK in healthy volunteers was analyzed by noncompartmental methods. The shape of the Gocovri PK curves up to Cmax and sustenance of plasma concentrations were characterized by partial AUC (pAUC to assess overnight exposure), apical concentrations (Cap) within a dosing interval, (mean of concentrations within 25% of Cmax), and dose-independent parameters Trise (time for concentration to rise above pre-dose concentration) and plateau time (Tpla, duration that concentrations are maintained ≥75% of Cmax).

Results: Following a single dose of Gocovri, pAUC0-4 was 0.5% and pAUC0-8 was 8% of the total exposure, consistent with delayed and slow-release kinetics. Based on subject-level analysis of Gocovri PK, steady-state median Trise was 4 h and plateau concentrations were attained 4.5 hours after QHS dose and sustained (Tpla) for a median duration of 14 h over each dosing interval (11 h of awake period). Trough concentrations occurred ~24 h after dosing and persisted for 2-4 h after the next dose. Estimated amantadine Cap with 137 mg Gocovri QHS was 476±148 ng/mL (mean±SD) compared to Cmax of 558±146 ng/mL.

Conclusion: In order to illustrate the shape of the Gocovri PK profile, metrics of early drug exposure, duration of sustained exposure, and profile flatness are required. Bedtime dosing of Gocovri results in delayed, slow rise in concentrations that are high in the morning and sustained throughout the day while minimizing nighttime exposure. This unique PK profile may contribute to the pharmacodynamic effects of Gocovri in reducing both dyskinesia and OFF time.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analysis-of-the-shape-of-the-gocovri-steady-state-pk-profile-implications-for-an-extended-release-product/