Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Guanfacine Extended-Release Formulation in Healthy Japanese and Caucasian Male Adults.

BACKGROUND AND OBJECTIVE: Guanfacine extended-release (guanfacine XR) could be a useful treatment option for children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). As an initial step in the development in Japan, the pharmacokinetics, safety and tolerability were assessed in healthy Japanese and non-Hispanic Caucasian adults.

METHODS: A Phase 1, double-blind, randomized, placebo-controlled, single- and multiple-oral dose escalation study of guanfacine XR was conducted. Healthy Japanese and Caucasian subjects received guanfacine XR 1 mg orally in the morning on Day 1. Following safety assessments, subjects subsequently received guanfacine XR 1 mg (Days 4-8), 2 mg (Days 9-13), 3 mg (Days 14-18), and 4 mg (Days 19-23) once daily, followed by a taper-down period. Single- and multiple-dose pharmacokinetic parameters were estimated based on plasma concentration-time data and urine concentration data of guanfacine by non-compartmental analysis.

RESULTS: A total of 30 male subjects (15 Japanese and 15 Caucasian, active:placebo = 12:3) were enrolled. Of those receiving guanfacine XR, 11/12 (91.7%) subjects in each active drug group completed the study. Following multiple doses, the mean area under the plasma concentration-time curves of guanfacine were 9-22% greater for Caucasian subjects than Japanese subjects in the 1-3 mg dose range and 54% greater for the 4 mg. Guanfacine XR was generally well tolerated by both ethnic groups, with most adverse events being mild in both groups. There were no serious or severe adverse events during the study and no adverse events led to withdrawal from the study.

CONCLUSIONS: Exposure to guanfacine in Japanese subjects tended to be lower than in Caucasian subjects. Guanfacine XR was generally well tolerated and safety profiles were similar for Japanese and Caucasian subjects.