Abstract Details

Title Population Pharmacokinetics Model of Apomorphine/Apomorphine-Sulphate Administered as a Sublingual Film or Subcutaneously in Healthy Subjects and Patients With Parkinson’s Disease

Topic Movement Disorders

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-034

Objective A population pharmacokinetics (popPK) model was developed to characterize the PK of apomorphine and its major metabolite, apomorphine-sulfate, in healthy subjects and patients with Parkinson’s disease (PD) following administration of apomorphine sublingual film (APL) and subcutaneously injected apomorphine.

Background APL was demonstrated to be safe and effective for the acute, intermittent treatment of “OFF” episodes in a Phase 3 study of patients with PD.

Design/Methods 2302 PK samples from 87 healthy subjects and 60 patients with PD and 1012 samples from 90 healthy subjects/patients with PD were analyzed for apomorphine/apomorphine-sulfate from 9 studies (5 Phase 1, 3 Phase 2, 1 Phase 3) using nonlinear mixed effects modeling (NONMEM®, version 7.3). Selected covariates were evaluated using stepwise forward selection/backward elimination.

Results Final PK models of apomorphine/apomorphine-sulfate were adequately described by a two-/one-compartment model, with first-order input and elimination. Bioavailability of APL was ~15% relative to subcutaneous apomorphine. Mean apomorphine systemic clearance and central volume of distribution were 190 L/h and 260 L, respectively. Covariates of dose, contact time under the tongue, body weight, and gender had <1.5-fold change in area under the concentration-time curve and maximum plasma concentration (C_max). Simulations predicted that 35 mg APL every 2 hours for 5 doses achieved ~50% the apomorphine C_max and ~2-fold higher apomorphine-sulfate C_max compared with the same regimen of 6 mg subcutaneous apomorphine. Simulations indicated that patients with mild renal impairment had similar apomorphine/apomorphine-sulfate exposure to those with normal renal function following APL administration. Apomorphine/apomorphine-sulfate exposure increased with increasing APL dose; however, the increase was less than dose proportional.

Conclusions A popPK model described comparable and differentiated PK characteristics of apomorphine/apomorphine-sulfate following sublingual and subcutaneous administrations.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Bradford A. Navia, MD, PhD (Aprinoia Therapeutics)	No disclosure on file
	No disclosure on file

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