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Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy chlorproguanil/dapsone
Author(s) -
Simpson Julie A.,
Hughes Dyfrig,
Manyando Christine,
Bojang Kalifa,
Aarons Leon,
Winstanley Peter,
Edwards Geoffrey,
Watkins William A.,
Ward Steve
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02567.x
Subject(s) - dapsone , pharmacokinetics , metabolite , pharmacodynamics , population , pharmacology , medicine , biology , gastroenterology , immunology , environmental health
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 CL m / 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.