Amantadine Delayed-Release/Extended-Release Capsules Show More Benefit Compared With Other Formulations

In a first, but indirect, comparison of the 3 available formulations of amantadine for the treatment of Parkinson disease, only the delayed-release/extended-release formulation (Gocovri) resulted in improvements in both in OFF time and dyskinesia.

Results of an indirect treatment comparison of the 3 available formulations of amantadine—immediate-release tablets, immediate-release/extended-release tablets (Osmolex; Supernus Pharmaceuticals), delayed-release/extended-release capsules (Gocvori; Adamas/Supernus)—suggest that only treatment with the delayed-release/extended-release capsules resulted in significant improvements in both in OFF time and dyskinesia among patients with Parkinson disease (PD).1

Ultimately, the investigators, including Wolfgang H. Oertel, MD, PhD, professor of neurology, Hertie Senior Research Professor, Philips University of Marburg, concluded that the results of this assessment warrant further exploration. “The improvements seen with amantadine [delayed-release/extended-release] could have resulted from the high early morning amantadine concentrations not observed for the other two formulations,” Oertel et al wrote.

The results were presented in a poster at the 2022 Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress in Washington, DC, June 17-19. Using predicted multiple-dose pharmacokinetic profiles of the different formulations, amantadine delayed-release/extended-release—administered in a dose of 274 mg at 10:00 PM—showed a markedly higher concentration between the hours of 6:00 AM and 10:00 AM, above 1200 ng/mL.

“The bedtime administration of amantadine [delayed-release/extended-release] provided significantly higher concentrations in the morning hours (6:00-10:00 AM) than morning-administered amantadine [immediate-release/extended-release] or amantadine [immediate-release] administered 2 to 3 times per day,” Oertel and colleagues wrote. They also noted that, additionally, the dissolution profiles of the 3 amantadine formulations were consistent with the curves displayed in the pharmacokinetic modeling.

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The assessments included a pooled dataset from 5 total studies that included 303 patients: 1 of amantadine delayed-release/extended-release (n = 100), 2 of the immediate-release/extended-release formulation (n = 150), and 2 of the immediate-release formulation (n = 53). Each of these studies included placebo groups, with a total of 218 patients in those groups. At baseline, Unified Dyskinesia Rating Scale (UDysRS) scores were 40.6 (±13.2), 40.4 (±13.3), and 30.9 (±12.5) for the delayed-release/extended-release, immediate-release/extended-release, and immediate-release formulation groups, respectively. The respective baseline OFF times were 3.0 hours (±2.3), 3.6 hours (±2.2), and 6.4 hours (±2.9).

As for efficacy in treating dyskinesia, the trio of formulations were assessed using the UDysRS scores. All told, the delayed-release/extended-release formulation showed improvement in treatment difference effects of 27.3% on UDysRS scores and 36.1% in OFF time, compared with improvements of 13.3% and 1.4%, respectively, with the immediate-release/extended-release formulation and of 16.8% and 6.4%, respectively, with the immediate-release formulation.

In hours, those results translated to reductions of 10.1 hours on UDysRS scores and 1.0 hours of OFF time with the delayed-release/extended-release formulation. For the immediate-release/extended-release formulation, there was a 5.3-hour reduction on UDysRS and a reduction 0.1 hours of OFF time, and for the immediate-release formulation, there were reductions of 5.8 hours and 0.4 hours on the same measures, respectively.

“Amantadine [immediate-release] demonstrated a significant improvement in UDysRS total score but not OFF time,” the investigators wrote. “In addition to significant reductions in OFF time and UDysRS scores, amantadine [delayed-release/extended-release] also demonstrated significant reduction in ON time with troublesome dyskinesia” though those data points were not included in the poster.

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REFERENCE
1. Oertel WH, Pahwa R, Hauser RA, Sale M, Went GT. Analysis of amantadine formulations for OFF and dyskinesia in Parkinson disease. Presented at: ATMRD Congress; June 17-19, 2022; Washington, DC.