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Pharmacokinetics of chlorproguanil, dapsone, artesunate and their major metabolites in patients during treatment of acute uncomplicated Plasmodium falciparum malaria

Miller, A. K., Bandyopadhyay, N., Wootton, D. G., Duparc, S., Kirby, P. L., Winstanley, P. A. and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (2009) 'Pharmacokinetics of chlorproguanil, dapsone, artesunate and their major metabolites in patients during treatment of acute uncomplicated Plasmodium falciparum malaria'. European Journal of Clinical Pharmacology, Vol 65, Issue 10, pp. 977-987.

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Abstract

Chlorproguanil (CPG)-dapsone (DDS)-artesunate was in development for the treatment of uncomplicated Plasmodium falciparum malaria. The pharmacokinetics of CPG, DDS, artesunate and their metabolites chlorcycloguanil (CCG), monoacetyl dapsone (MADDS) and dihydroartemisinin (DHA) were investigated in patients with P. falciparum given CPG-DDS alone or plus artesunate. Adult patients from Malawi and The Gambia taking part in a phase II clinical trial were randomised to receive a 3-day treatment of CPG-DDS alone (2/2.5 mg/kg/day) or plus 1, 2 or 4 mg/kg/day artesunate. Blood samples for pharmacokinetic analysis were collected up to 24 h post-first dose. The pharmacokinetic analysis included 115 patients. For CPG, there was no significant effect of artesunate on C-max or AUC(0-24), except the 90% confidence interval (CI) for AUC(0-24) for the 4 mg/kg artesunate dose was slightly below that for the standard bioequivalence range (90% CI 0.78, 1.11); this was not considered clinically relevant. Artesunate increased the CCG AUC(0-24) by 6-17% and C-max by 0-16%. Artesunate had no significant effect on the rate or extent of absorption of DDS. For MADDS, artesunate increased the AUC(0-24) by 13-47% and C-max by 8-45%. For 1, 2 and 4 mg/kg artesunate dosing, artesunate AUC(0-a) was 64.6, 151 and 400 ng center dot h/ml and C-max 48.9, 106 and 224 ng/ml respectively; DHA AUC(0-a) was 538, 1,445 and 3,837 ng center dot h/ml and C-max 228, 581 and 1,414 ng/ml respectively. Using a power model, the point estimates of slope were greater than 1 for artesunate AUC(0-t) by 16% and C-max by 5% and for DHA by 39 and 21% respectively. Artesunate did not significantly affect CPG or DDS pharmacokinetics. For CCG and MADDS, small to moderate increases in exposure with artesunate dosing were observed. There was a greater than proportional increase in artesunate and DHA exposure with increasing artesunate dose. These effects are not considered to be clinically relevant. It should be noted that the CPG-DDS-artesunate programme has now been stopped following unacceptable haematological toxicity in patients with glucose-6-phosphate dehydrogenase deficiency during a phase III trial. In addition, the CPG-DDS combination has been withdrawn from clinical use.

Item Type: Article
Additional Information: The original publication is available at www.springerlink.com
Uncontrolled Keywords: Pharmacokinetics Malaria Chlorproguanil-dapsone Artesunate Antimalarial combination therapy Phase-III trial Oral artesunate Sulfadoxine-pyrimethamine Artemisinin derivatives Artemether-lumefantrine African children Healthy-subjects Dihydroartemisinin Bioavailability Volunteers
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
QX Parasitology > Protozoa > QX 135 Plasmodia
QV Pharmacology > QV 34 Experimental pharmacology (General)
QV Pharmacology > QV 38 Drug action.
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1007/s00228-009-0672-1
Depositing User: Mary Creegan
Date Deposited: 28 Jun 2010 10:21
Last Modified: 06 Feb 2018 12:59
URI: http://archive.lstmed.ac.uk/id/eprint/328

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