Pharmacokinetics, safety, and tolerability of varenicline in healthy adolescent smokers: a multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

Abstract Background: Varenicline is approved as an aid to smoking cessation in adults aged ≥18 years. Objective: The goal of this study was to characterize the multiple-dose pharmacokinetics, safety, and tolerability of varenicline in adolescent smokers. Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled healthy 12− to 16-year-old smokers (≥3 cigarettes daily) into high-body-weight (>55 kg) and low-body-weight (≤55 kg) groups. Subjects were randomized to receive 14 days of treatment with a high dose of varenicline, a low dose of varenicline, or placebo. The varenicline doses in the high-body-weight group were 1 mg BID and 0.5 mg BID; the varenicline doses in the low-body-weight group were 0.5 mg BID and 0.5 mg once daily. The apparent renal clearance (CL/F) and volume of distribution (V/F) of varenicline and the effect of body weight on these parameters were estimated using nonlinear mixed-effects modeling. Results: The high-body-weight group consisted of 35 subjects (65.7% male; 77.1% white; mean age, 15.2 years). The low-body-weight group consisted of 37 subjects (37.8% male; 48.6% white; mean age, 14.3 years). The pharmacokinetic parameters of varenicline were dose proportional over the dose range from 0.5 to 2 mg/d. The CL/F for a 70-kg adolescent was 10.4 L/h, comparable to that in a 70-kg adult. The estimated varenicline V/F was decreased in individuals of small body size, thus predicting a varenicline C max ~30% greater in low-body-weight subjects than in high-body-weight subjects. In high-body-weight subjects, steady-state varenicline exposure, as represented by the AUC 0–24 , was 197.0 ng · h/mL for varenicline 1 mg BID and 95.7 ng · h/mL for varenicline 0.5 mg BID, consistent with values reported previously in adult smokers at the equivalent doses. In low-body-weight subjects, varenicline exposure was 126.3 ng · h/mL for varenicline 0.5 mg BID and 60.1 ng · h/mL for varenicline 0.5 mg once daily, values at the lower end of the range observed previously in adults at doses of 1 mg BID and 0.5 mg BID, respectively. Among high-body-weight subjects, adverse events (AEs) were reported by 57.1% of subjects in both the high- and low-dose varenicline groups and by 14.3% of subjects in the placebo group; among low-body-weight subjects, AEs were reported by 64.3%, 73.3%, and 12.5% of subjects in the high-dose varenicline, low-dose varenicline, and placebo groups, respectively. The most common AEs were nausea, headache, vomiting, and dizziness. Psychiatric AEs that were considered treatment related included abnormal dreams in 2 subjects and mild, transient anger in 1 subject. Of the AEs reported by ≥1 subject in any treatment group, ≥92% were mild in intensity. No subject discontinued the study because of an AE. Conclusions: Varenicline steady-state exposure in study subjects weighing >55 kg was similar to that observed previously in adults. The body-weight effect on varenicline pharmacokinetics, which resulted in higher exposure in individuals of smaller body size (≤55 kg), was adequately offset by administration of half the varenicline dose recommended in adults. Varenicline was generally well tolerated during the 14-day treatment period. Clinical Trials Identification Number: NCT00463918.