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

Aims

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.

Methods

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.

Results

The population pharmacokinetic parameter estimates for chlorproguanil were k(a) = 00.09 h(-1) (intersubject variability was 44%), CL/F = 51.53 l h(-1) (57%), CLD/F = 54.67 l h(-1), V-1/F = 234.40 l (50%) and V-2/F = 1612.75 l; for dapsone were k(a) = 00.93 h(-1), CL/F = 1.99 l h(-1) (72%) and V/F = 76.96 l (48%); and for chlorcycloguanil were CLm/F-m = 3.72 l h(-1) kg(-1) (67%) and V-m/F-m = 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 [5(th) and 95(th) 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.

Conclusions

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.