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


METHODS
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.


RESULTS
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-infinity) was 64.6, 151 and 400 ng.h/ml and C(max) 48.9, 106 and 224 ng/ml respectively; DHA AUC(0-infinity) was 538, 1,445 and 3,837 ng.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.


CONCLUSIONS
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 In addition, the CPG-DDS combination has been withdrawn from clinical use.
Miller
Ann K
AK
Clinical PK Modelling & Simulation, Quantitative Sciences, GlaxoSmithKline, Mailcode UW2350, King of Prussia, PA, 19406, USA. ann.k.miller@gsk.com
Bandyopadhyay
Nibedita
N
Wootton
Daniel G
DG
Duparc
Stephan
S
Kirby
Paula L
PL
Winstanley
Peter A
PA
Ward
Stephen A
SA
D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D037621:Artemisinins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077332:Artesunate; D003622:Dapsone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005714:Gambia; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism*; D008295:Malawi; D008297:Male; D008875:Middle Aged; D021261:Parasitic Sensitivity Tests; D002727:Proguanil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D013997:Time Factors
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C519882:chloroguanil, dapsone drug combination; D000077332:Artesunate; C039060:artenimol; C007030:chlorproguanil; D003622:Dapsone; D002727:Proguanil