ARTEMISININ KINETICS AND DYNAMICS DURING ORAL AND RECTAL TREATMENT OFUNCOMPLICATED MALARIA

Objective: To compare parasite clearance times after oral and rectal a dministration of artemisinin in adults with uncomplicated malaria and to relate pharmacodynamics with artemisinin kinetics and to disclose a ny pharmacokinetic changes during treatment, Methods: Thirty male Viet namese patients with falciparum malaria were randomized to treatment w ith 500 mg artemisinin daily by either the oral or rectal route of adm inistration. Parasite densities in capillary blood were determined by microscopy every 4 to 6 hours. Artemisinin plasma concentrations on th e first and last day of treatment were determined by HPLC and unbound fractions in plasma were determined by ultrafiltration, Results: Mean parasite clearance times and 95% confidence intervals (95% CI) were 25 (95% CI, 16 to 33) and 29 (95% CI, 23 to 35) hours during oral and re ctal treatment, respectively. The bioavailability after rectal relativ e to oral artemisinin was 30%, Artemisinin areas under the plasma conc entration-time curve (AUC) on the fifth (last) day of oral or rectal t reatment were 30% (95% CI, 4% to 56%) and 40% (95% CI, -6% to 91%), re spectively, of those after the first dose, The fraction unbound in pla sma was 15% (95% CI, 12% to 19%), increasing marginally during treatme nt. No relationship was found between main clinical end points and dru g exposure, although indices for the rapidity of response onset were l ower after oral treatment and correlated to unbound AUC values (r(s) = -0.7; P < 0.001). Conclusions: The similarity in parasite clearance t imes despite lower drug levels during rectal treatment suggests that i nitial oral doses map be unnecessarily high, The singular time depende ncy of artemisinin pharmacokinetics, attributed to autoinduction of dr ug elimination, has possible implications for combination chemotherapy , Decreasing artemisinin concentrations during treatment may partly ex plain recrudescences and increase the risk for resistance development.