Farkad Ezzet & Jeffrey Eisele
Artemether and Benflumetol are two efficacious and well tolerated anti malarial drugs developed and registered in China. The concomitant administration of the two compounds (co-artemether) combines the advantage of the fast onset of action due to artemether and the long duration of action due to benflumetol. The treatment of co-artemether comprises four doses administered at 0, 8, 24 and 48 hours.
Plasma concentration profiles (around 25 plasma samples taken during a period of 2-4 weeks) of benflumetol in 48 patients (24 in each of two trials) suffering from P. falciparum infection allowed inference to be made with regard to benflumetolÃs kinetics, and its within and between subject variability.
With a two compartment model and elimination occurring from the central compartment, the half-life of the second phase of elimination is estimated to be about 90 hours, thus requiring over 18 days for the body to eliminate benflumetol. The half-life of the first order absorption process is about 2.8 hours, thus requiring approximately 14 hours to absorb most of benflumetolÃs tablet plus two hours lag time before onset of absorption. More importantly, there appears to be a clear trend towards increasing availability over the four doses. The bioavailability fraction at the forth dose is estimated to be about three times higher than that of the first dose. However, the between subject coefficient of variation of the bioavailability seemed to decrease from 95% to 60%. These changes in availability are possibly a result of a confounded effect of improved patient condition and food intake. The lipophilic character of benflumetol may explain improved absorption with food.
The above analyses were carried out using NONMEM and NLME.
Reference: PAGE 5 (1996) Abstr 558 [www.page-meeting.org/?abstract=558]
Poster: oral presentation