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

Felix Agbo; Stuart H Isaacson; Ramon Gil; Yu-Yuan Chiu; Scott J Brantley; Parul Bhargava; Bradford Navia

doi:10.1007/s40120-021-00251-6

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

Neurol Ther. 2021 Dec;10(2):693-709. doi: 10.1007/s40120-021-00251-6. Epub 2021 May 15.

Authors

Felix Agbo¹, Stuart H Isaacson², Ramon Gil³, Yu-Yuan Chiu⁴, Scott J Brantley⁵, Parul Bhargava^{6

7}, Bradford Navia⁶

Affiliations

¹ Clinical Pharmacology, Modeling and Simulation, Sunovion Pharmaceuticals Inc., One Bridge Plaza North, Suite 510, Fort Lee, NJ, 07024, USA. Felix.Agbo@sunovion.com.
² Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA.
³ Parkinson's Disease Treatment Center of Southwest Florida, Port Charlotte, FL, USA.
⁴ Clinical Pharmacology, Modeling and Simulation, Sunovion Pharmaceuticals Inc., One Bridge Plaza North, Suite 510, Fort Lee, NJ, 07024, USA.
⁵ Nuventra, Inc., Durham, NC, USA.
⁶ Sunovion Pharmaceuticals Inc., Marlborough, MA, USA.
⁷ Merck & Co, Inc., North Wales, PA, USA.

Abstract

Introduction: 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).

Methods: 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.

Results: Median time to maximum plasma concentration (t_max) 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 (C_max) 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 C_max, respectively). Apomorphine sulfate exposure was ~ three-fold higher for APL versus SC-APO and SC-APO-GO by AUC_∞ and C_max.

Conclusion: In patients with PD and "OFF" episodes, APL demonstrated lower C_max and relative bioavailability but similar exposures (AUCs) versus SC apomorphine within the approved dose range.

Trial registration: ClinicalTrials.gov, NCT03292016.

Keywords: APL; APL-130277; Apomorphine sublingual film; Bioavailability; Exposure; Parkinson’s disease; Pharmacokinetics; Subcutaneous apomorphine; “OFF” episodes.

Associated data

ClinicalTrials.gov/NCT03292016