Pharmacokinetics, Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects.

Purpose: The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature-stable (PR2.2.1) formulations of rotigotine in healthy Chinese men.

Methods: In treatment period 1 of SP0913, subjects received a single application of rotigotine 2 mg/24 hours on day 1 followed by a washout period (days 2-6); treatment period 2 (days 6-14) involved multiple doses of rotigotine 2 mg/24 hours (days 7-9) followed by multiple doses of rotigotine 4 mg/24 hours (days 10-12), with patches applied for 24 hours each. In PD0011, subjects received a single dose (2 mg/24 hours) of each rotigotine formulation (PR2.2.1 and PR2.1.1) for 24 hours each in a crossover design. Blood samples were collected at scheduled time points to determine rotigotine plasma concentrations. Safety and tolerability were evaluated by adverse events monitoring.

Results: Twenty-four healthy Chinese subjects (12 males, 12 females) were enrolled and completed SP0913. Geometric mean plasma concentrations of unconjugated and total rotigotine increased to a plateau beginning at ∼8 hours (multiple dose) to 16 hours (single dose) postdose; no characteristic T was observed for unconjugated and total rotigotine. The respective geometric mean C, C, AUC from zero up to the last analytically quantifiable concentration, and AUC values for unconjugated and total rotigotine were similar when rotigotine 2 mg/24 hours was applied as a single dose or multiple-dose regimen. During the multiple-dose period, geometric mean C and AUC of both unconjugated and total rotigotine were ∼2-fold higher for rotigotine 4 mg/24 hours than for rotigotine 2 mg/24 hours. Forty-seven of 50 male Chinese subjects completed PD0011. Primary PK parameters for the room temperature-stable formulation of rotigotine were highly comparable to the cold-chain formulation. Common adverse events included application site pruritus, nausea, dizziness, and constipation (SP0913 only), with no clinically significant changes in other safety measures.

Implications: PK profiles and derived PK parameters of unconjugated and total rotigotine in healthy Chinese subjects were consistent with findings from other ethnic groups receiving single and multiple doses of the rotigotine transdermal patch. Single and repeated daily doses of the rotigotine transdermal patch were well tolerated. Room temperature-stable and cold-chain formulations were bioequivalent. ClinicalTrials.gov identifiers: NCT01675024 and NCT02070796.