Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers

Aims To describe the Population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis. Methods The Population consisted of 135 male Thai soldiers (mean age 218.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesu nate for 3 days plus doxycycline for 7 days to remove any pre-existing mala ria infections. After the treatment regime, 104 soldiers (drug group) recei ved a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were r e-treated with artesunate for 3 days plus doxycycline for 7 days followed b y a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg taf enoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis Plasma tafenoquine concentr ations were measured by h.p.l.c. Population pharmacokinetic modelling was p erformed using NONMEM. Results A one-compartment model was found best to describe the pharmacokine tics of tafenoquine after oral administration. Age and weight influenced vo lume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficie nt impact to warrant change in dosing. The population estimates of the firs t-order absorption rate constant (K-a), CL/F and V/F were 0.694 h(-1), 3.20 1 h(-1) and 1820 1, respectively. The intersubject variability in these pa rameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respec tively. The absorption and elimination half-lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%. Conclusions The population pharmacokinetics of orally administered tafenoqu ine have been determined in Thai soldiers under field conditions. This info rmation, together with its known potent antimalarial activity, portends wel l for the application of tafenoquine as a useful prophylactic drug or for s hort-term radical treatment of vivax malaria.