A Bayesian Approach for Population Pharmacokinetic Modeling of Dihyroartemisinin

Dihydroartemisinin (DHA) is an active metabolite of artesunate (ARTS) and is highly effective in the treatment of malaria, a life threatening parasitic disease. ARTS causes rapid reduction in parasitemia and fever in patients with falciparum malaria and is associated with a radical cure rate of (> 90%) if administered for a period of 5-7 days. A phase I single oral dose escalation study in healthy volunteers was conducted to characterize the pharmacokinetics and to assess safety and tolerability of ARTS and DHA. The study was a randomized, double-blind placebo-controlled, staggered, parallel design to study ARTS doses from 2 to 5 mg/kg in 36 healthy Korean subjects. Plasma samples for pharmacokinetic assessment were obtained at regular time intervals and analyzed using a previously validated LC-MS method. Non-compartmental method of analysis was used for the determination of pharmacokinetic parameters using WinNonlin. Since ARTS is rapidly and almost completely converted to its active metabolite DHA, in this present study we are interested only in characterizing the pharmacokinetics of DHA by a Bayesian approach with PKBugs/WinBUGS using data from this completed phase I trial. Permission to use the dataset was obtained from Dr. L. Fleckenstein, the director of the Clinical Pharmacokinetics Lab, College of Pharmacy. In conclusion, using a Bayesian approach with a one-compartment structural model with first order input and elimination, the estimates for Cl/F, V/F, tlag, ke and ka for DHA were 130.06 L/hr, 195.98 L, 8.34 minutes, 0.664/hr and 1.271/hr respectively.