Population pharmacokinetic analysis of apomorphine sublingual film or subcutaneous apomorphine in healthy subjects and patients with Parkinson's disease

Apomorphine is an on-demand treatment of "OFF" episodes in patients with Parkinson's disease (PD). A joint parent-metabolite population pharmacokinetic (PK) model characterized apomorphine and apomorphine-sulfate following administration of apomorphine sublingual film (APL) and two formulations of subcutaneous apomorphine. Overall, 2485 samples from 87 healthy subjects and 71 patients with PD and "OFF" episodes were analyzed using nonlinear mixed-effects modeling. Apomorphine PK was adequately described by a two-compartment model with first-order transit absorption via both routes of administration and first-order metabolism to apomorphine-sulfate with one-compartment disposition and first-order elimination. Bioavailability of apomorphine sublingual film was similar to 18% relative to subcutaneous apomorphine. Among covariates tested, only body weight had a large effect on apomorphine exposure (maximum plasma concentration and area under the concentration-time curve [AUC(0-infinity)]), with greater weight resulting in lower exposure. Model-predicted apomorphine exposure was similar between apomorphine sublingual film 30 mg and subcutaneous apomorphine 5 mg (median AUC(0-24), 66.7 ng center dot h/mL, geometric mean ratio of 0.99; 90% confidence interval [CI], 0.96-1.03) and was comparable between apomorphine sublingual film 35 mg and subcutaneous apomorphine 6 mg (median AUC(0-24), 75.4 and 80.0 ng center dot h/mL, respectively; geometric mean ratio of 0.94; 90% CI, 0.90-0.97) administered every 2 h for a maximum of 5 doses per day. In a typical patient with PD, predicted apomorphine exposure increased with increasing doses of apomorphine sublingual film; however, the increase was less than dose proportional. Similar apomorphine exposure was predicted in patients with mild renal impairment versus normal renal function. PK properties of apomorphine sublingual film support its administration for a wide range of patients with PD and "OFF" episodes, regardless of demographic and clinical characteristics. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Pharmacokinetic (PK) properties of apomorphine sublingual film (APL-130277; APL), an on-demand treatment for "OFF" episodes in patients with Parkinson's disease (PD), have not been previously described comprehensively. WHAT QUESTION DID THIS STUDY ADDRESS? A population PK model of apomorphine and its inactive metabolite, apomorphine sulfate, was developed to characterize PK properties of APL and two formulations of subcutaneous apomorphine. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Compared with subcutaneous apomorphine, APL has a relative bioavailability of similar to 18%. Increase in apomorphine exposure (peak plasma concentration and area under the concentration-time curve [AUC0- -8]) was less than dose proportional with no obvious difference in elimination half-life across the dose range studied. Model-predicted apomorphine exposure at higher doses of APL (30-35 mg) was comparable to subcutaneous apomorphine (5-6 mg) across a range of patient characteristics tested as covariates, including mild renal impairment; greater body weight resulted in lower exposure. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Sublingual apomorphine PK properties support administration of APL as an on-demand treatment for a wide range of patients with PD and "OFF" episodes.