Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy chlorproguanil/dapsone

To determine the population pharmacokinetics of chlorproguanil, dapsone and the active metabolite of chlorproguanil, chlorcycloguanil; and to estimate the duration of parasitocidal activity for chlorpoguanil/dapsone against Plasmodium falciparum isolates of varying sensitivity.

Rich and sparse pharmacokinetic data were collected prospectively from: healthy volunteers (n=48) and adults (n=65) and children (n=68) suffering from P. falciparum malaria. All subjects received 2.0 mg kg-1 of chlorproguanil and 2.5 mg kg-1 of dapsone.

The population pharmacokinetic parameter estimates for chlorproguanil were ka=00.09 h-1 (intersubject variability was 44%), CL/F=51.53 l h-1 (57%), CLD/F=54.67 l h-1, V1/F=234.40 l (50%) and V2/F=1612.75 l; for dapsone were ka=00.93 h-1, CL/F=1.99 l h-1 (72%) and V/F=76.96 l (48%); and for chlorcycloguanil were CLm/Fm=3.72 l h-1 kg-1 (67%) and Vm/Fm=12.76 l kg-1 (64%). For dapsone, CL/F and V/F were both significantly positively correlated with body weight. For a 10-kg child, the mean duration of parasitocidal activity for chlorproguanil/dapsone against the three most susceptible P. falciparum strains was 4.5 days [5th and 95th percentiles 2.4, 7.3] for W282; 5.9 days (3.6, 9.7) for ItG2F6; and 6.1 days (3.7, 10.1) for K39. For an isolate with the ile-164-leu mutation, V1/S, activity ranged from 0.8 days (0.0, 3.3) for a 10-kg child to 1.8 days (0.0, 4.0) for a 60-kg adult.

Plasmodium falciparum malaria has no effect on the pharmacokinetic parameters for chlorproguanil, dapsone or chlorcycloguanil. Chlorproguanil/dapsone will probably prove to be ineffective against parasite strains with the mutation ile-164-leu, were these to become prevalent in Africa.