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


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.
Simpson
Julie A
JA
Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia. Julie.Simpson@cancervic.org.au
Hughes
Dyfrig
D
Manyando
Christine
C
Bojang
Kalifa
K
Aarons
Leon
L
Winstanley
Peter
P
Edwards
Geoffrey
G
Watkins
William A
WA
Ward
Steve
S
D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003622:Dapsone / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy*; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000187:drug effects; D002727:Proguanil / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011446:Prospective Studies; D014227:Triazines / Q000097:blood / Q000493:pharmacokinetics*
D000962:Antimalarials; D014227:Triazines; C026009:cycloguanil; C007030:chlorproguanil; D003622:Dapsone; D002727:Proguanil