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

Simpson, J. A., Hughes, D., Manyando, C., Bojang, K., Aarons, L., Winstanley, P., Edwards, Geoffrey, Watkins, W. A. and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (2006) 'Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy chlorproguanil/dapsone'. British Journal of Clinical Pharmacology, Vol 61, Issue 3, pp. 289-300.

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	chlorcycloguanil chlorproguanil dapsone pharmacodynamics plasmodium falciparum population pharmacokinetics plasmodium-falciparum malaria sulfadoxine-pyrimethamine young-children dapsone africa glucuronidation efficacy
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials QV Pharmacology > QV 38 Drug action. QX Parasitology > Protozoa > QX 135 Plasmodia
Faculty: Department:	Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI):	https://doi.org/10.1111/j.1365-2125.2005.02567.x
Depositing User:	Martin Chapman
Date Deposited:	13 Jul 2011 13:52
Last Modified:	17 Jul 2020 10:57
URI:	https://archive.lstmed.ac.uk/id/eprint/1593

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