Pharmacokinetics of multiple escalating doses of GBR12909 in healthy volunteers

Objective: To characterize the pharmacokinetics of multiple escalating oral doses of GBR12909, a selective dopamine uptake inhibitor candidate drug to treat cocaine addiction, in healthy adults. Methods: Twelve healthy adult male and female subjects (mean age: 36 years; mean weight: 77kg) completed the study. GBR12909 was administered orally at 25, 50, 75 and 100 mg once daily for 11 days. Predose blood samples were obtained on Days 1, 3, 5, 8, 9, 10 and 11. Serial blood samples up to 120 hours were obtained on Day 11. Plasma concentration-time data were analyzed by noncompartmental methods using WinNonlin. ANOVA method was applied to the dose normalized pharmacokinetic (PK) parameters to determine the dose dependency in the pharmacokinetics of GBR12909. Results: The plasma concentrations at a dose of 25 mg were below the limit of quantitation at most time points and, therefore, were excluded from PK analyses. Trough concentrations indicate that steady-state conditions were achieved by 10 days. The mean (%CV) PK parameters of GBR12909 are shown below. 50 mg 75 mg 100 mg Cmax, ng/mL 27.5(77) 41.1(57) 80.4(66) Tmax, h 1.3(41) 1.3(50) 1.4(29) AUC(0-24), ng·h/mL 176.1(80) 248.1(62) 426.4(86) CL/F, L/h 416.9(59) 386.7(46) 373.6(64) Results from ANOVA did not indicate any major deviations from linearity in GBR12909 PK parameters. Conclusions: Following oral administration, GBR12909 is vapidly absorbed and the pharmacokinetics are highly variable. 11 days of once daily dosing appears to result in steady-state conditions. In the dose range studied the PK parameters of GBR12909 were linear.