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

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.

Fig. 1

Plasma apomorphine concentration time data for a APL 20 mg, b APL 25 mg, and c APL 30 mg and corresponding doses of SC-APO and SC-APO-GO. APL apomorphine sublingual film, SC-APO subcutaneous apomorphine injection, SC-APO-GO subcutaneous apomorphine prefilled injection pen, SD standard deviation. ^a Data were missing for one patient at the 6-h time point

Fig. 2

Plot of individual apomorphine a C_max and b AUC_last values vs. dose of apomorphine sublingual film, SC-APO, and SC-APO-GO. Symbols denote the individual values and the line denotes the mean. APL apomorphine sublingual film, AUC_last area under the concentration-time curve from time 0 to the last measurable plasma concentration, C_max maximum plasma concentration, SC-APO subcutaneous apomorphine injection, SC-APO-GO subcutaneous apomorphine prefilled injection pen

Fig. 3

Plot of apomorphine AUC_last for a SC-APO vs. APL with substitution of missing SC-APO data for SC-APO-GO, b SC-APO vs. APL without substitution of missing SC-APO data for SC-APO-GO, and c SC-APO-GO vs. SC-APO. The black line denotes the linear regression line and the equation represents the slope. APL apomorphine sublingual film, AUC_last area under the concentration-time curve from time 0 to the last measurable plasma concentration, SC-APO subcutaneous apomorphine injection, SC-APO-GO subcutaneous apomorphine prefilled injection pen