REPETITIVE DOSING OF ARTEMISININ AND QUININE AGAINST PLASMODIUM-FALCIPARUM IN-VITRO - A SIMULATION OF THE IN-VIVO PHARMACOKINETICS

Plasmodium falciparum (F32) parasites were exposed to artemisinin and quinine for 3 and 4 h, respectively, once or twice daily and for 3, 5 or 7 days. Between the peaks the parasites were exposed to trough conc entrations. Continuous drug exposure was also assessed for comparison. After drug exposure, the cultures were extended for an observation pe riod of up to 30 days to assess the viability of the parasites remaini ng after drug exposure. For artemisinin, a critical threshold concentr ation of 3 x 10(-8) M was required for growth inhibition. Dosing twice daily for at least 5 days was also critical. Prolonging the duration of drug exposure to 7 days further increased the efficacy. For quinine the results were quite different. The concentration dependency of the efficacy was more gradual. On the other hand dosing once daily appear ed to be nearly as effective as twice daily and radical clearance was obtained even after 3 days of exposure at peak concentrations of 10(-5 ) M. A concentration of 10(-6) M provided the same effect if the durat ion was extended to 7 days. There was a strong similarity between esti mated concentrations of free unbound drug required for radical clearan ce in vitro and those empirically required for clinical efficacy in vi vo. This suggests that the in vitro model represents an appropriate mo del for estimating drug efficacy and pharmacodynamics if the in vitro system is adapted to simulate in vivo pharmacokinetics. (C) 1997 Elsev ier Science B.V.