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 Ò ) was an effective and generally well-tolerated ondemand 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 Ò ] and SC-APO-GO [APO-go Ò PEN]) were evaluated in a randomized, threeway 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 C 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

A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease

“…18 Importantly in the current study, QT prolongation was not observed at apomorphine C max , despite administration of apomorphine sublingual film doses exceeding those needed to achieve FULL "ON," perhaps owing to the slower rate of absorption of sublingual versus subcutaneous apomorphine. 18 There was a nonlinear relationship between C max and dose, likely due to high interpatient variability. This relationship may have also been influenced by route of administration, which requires adequate moisture in the oral cavity to facilitate dissolution of the sublingual film.…”

“…In a pharmacokinetic comparative bioavailability study, apomorphine sublingual film had a lower C max compared with subcutaneous apomorphine formulations at similar exposures 18 . Importantly in the current study, QT prolongation was not observed at apomorphine C max , despite administration of apomorphine sublingual film doses exceeding those needed to achieve FULL “ON,” perhaps owing to the slower rate of absorption of sublingual versus subcutaneous apomorphine 18 . There was a nonlinear relationship between C max and dose, likely due to high interpatient variability.…”

“…17 A prior study found that maximum plasma concentration (C max ) was lower and time to C max (T max ) was longer for apomorphine sublingual film compared with subcutaneous apomorphine formulations, while overall systemic apomorphine exposure was similar. 18 The pharmacokinetic properties of apomorphine sublingual film may contribute to a more favorable safety profile than other apomorphine formulations, as similar overall exposure is achieved without a rapid early rise in drug concentration. In a pivotal study, apomorphine sublingual film demonstrated a significant improvement in the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III motor examination score at 30 minutes postdose compared with placebo (least squares [LS] mean difference -7.6, P = 0.0002).…”

“…Apomorphine sublingual film, a novel sublingual formulation of apomorphine, is approved for the acute, intermittent treatment of “OFF” episodes associated with PD 17 . A prior study found that maximum plasma concentration (C max ) was lower and time to C max (T max ) was longer for apomorphine sublingual film compared with subcutaneous apomorphine formulations, while overall systemic apomorphine exposure was similar 18 . The pharmacokinetic properties of apomorphine sublingual film may contribute to a more favorable safety profile than other apomorphine formulations, as similar overall exposure is achieved without a rapid early rise in drug concentration.…”

Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease

“…There have been attempts to develop alternate modes of administration, but to date, all have failed primarily due to subcutaneous tissue side effects. APL-130277 is a new formulation of apomorphine that consists of a sublingual, bilayer film formulation, first registered in Canada in 2020 and FDA approved as treatment for unpredictable OFF episodes [ 96 , 97 ]. A 12-week, Phase 3, DBRCT involving patients with OFF episodes despite stable anti-PD treatment evaluated sublingual apomorphine (dose range of 10–30 mg) and reported significantly greater self-rated full ON response within 30 min versus placebo, corroborated by a nominally significant full ON response using home-dosing diaries.…”