Pharmacokinetics and Comparative Bioavailability of Apomorphine Sublingual Film and Subcutaneous Apomorphine Formulations in Patients with Parkinson’s Disease and “OFF” Episodes: Results of a Randomized, Three-Way Crossover, Open-Label Study

Springer Science and Business Media LLC - 2021
Felix Agbo1, Stuart H. Isaacson2, Ramon Gil3, Yu-Yuan Chiu1, Scott J. Brantley4, Parul Bhargava5,6, Bradford Navia6
1Clinical Pharmacology, Modeling and Simulation, Sunovion Pharmaceuticals Inc., Fort Lee, USA
2Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, USA
3Parkinson’s Disease Treatment Center of Southwest Florida, Port Charlotte, USA
4Nuventra, Inc, Durham, USA
5Merck & Co., Inc, North Wales, USA
6Sunovion Pharmaceuticals Inc., Marlborough, USA

Tóm tắt

In a pivotal study, apomorphine sublingual film (APL; KYNMOBI®) was an effective and generally well-tolerated on-demand treatment of “OFF” episodes in patients with Parkinson’s disease (PD), approved across the dose range of 10–30 mg. Pharmacokinetics and comparative bioavailability of APL and two subcutaneous (SC) apomorphine formulations (SC-APO [APOKYN®] and SC-APO-GO [APO-go® PEN]) were evaluated in a randomized, three-way crossover, open-label study (NCT03292016). Patients with PD and “OFF” episodes received an open-label randomized sequence of single doses of SC-APO and SC-APO-GO at the currently prescribed dose (2/3/4/5 mg) and APL doses with similar plasma exposure (15/20/25/30 mg) with ≥ 1-day washout between formulations. Plasma pharmacokinetics of apomorphine and apomorphine sulfate (major inactive metabolite) were measured 0–6 h postdose. Median time to maximum plasma concentration (tmax) of apomorphine was 0.63–0.75 h for APL and 0.25–0.38 h for SC-APO and SC-APO-GO. Geometric mean maximum plasma concentration (Cmax) of apomorphine was 4.31–11.2 ng/ml across APL doses and was generally lower compared with SC apomorphine formulations within dose groups. Area under the concentration-time curve from time 0 to infinity (AUC∞) was similar across apomorphine formulations within most dose groups. Relative bioavailability of APL was ~ 17% of SC apomorphine by AUC∞; SC-APO and SC-APO-GO had similar bioavailability (98% and 83% by AUC∞ and Cmax, respectively). Apomorphine sulfate exposure was ~ three-fold higher for APL versus SC-APO and SC-APO-GO by AUC∞ and Cmax. In patients with PD and “OFF” episodes, APL demonstrated lower Cmax and relative bioavailability but similar exposures (AUCs) versus SC apomorphine within the approved dose range. ClinicalTrials.gov, NCT03292016.

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