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

摘要

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 ~ 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 [AUC0–∞]), 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 AUC0–24, 66.7 ng•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 AUC0–24, 75.4 and 80.0 ng•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.