Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria.
A trial was conducted in 32 Thai children with uncomplicated multidrug-resistant falciparum malaria to assess the efficacy, safety and pharmacokinetics of atovaquone and proguanil; plasma concentrations of atovaquone, proguanil and its metabolite, cycloguanil, were measured in a subset of 9 children. The children received atovaquone (17 mg/kg/d for 3 d) plus proguanil (7 mg/kg/d for 3 d). Twenty-six children who had only Plasmodium falciparum infection and remained in hospital for 28 d were assessed for drug efficacy. The combination regimen produced a cure rate of 100%. Parasite and fever clearance times were 47 h (range 8-75) and 50 h (range 7-111), respectively. Atovaquone and proguanil were rapidly absorbed, with median time to peak concentrations of 6 h (range 6-24) and 6 h (range 6-12), respectively. Peak concentrations of cycloguanil were achieved between 6 and 12 h (median 6) after administration of proguanil. Mean peak plasma concentration of atovaquone on day 3 was 5.1 micrograms/mL (SD = 2.1). The day 3 mean peak plasma concentration of proguanil was 306 ng/mL (SD = 108) compared with 44.3 ng/mL (SD = 27.3) for cycloguanil. Mean values for the AUC (area under plasma concentration-time curve) were 161.8 micrograms/mL.h (SD = 126.9) for atovaquone, 4646 ng/mL.h (SD = 1226) for proguanil, and 787 ng/mL.h (SD = 397) for cycloguanil. Terminal elimination half-lives of atovaquone, proguanil and cycloguanil were estimated as 31.8 h (SD = 8.9), 14.9 h (SD = 3.3) and 14.6 h (SD = 2.6), respectively. No major adverse effect was attributable to the study drugs. Atovaquone/proguanil combination is safe and highly effective, and should be especially valuable for treatment of multidrug-resistant falciparum malaria.
Department of Tropical Paediatrics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
A
A
Sabchareon
P
P
Attanath
P
P
Phanuaksook
P
P
Chanthavanich
Y
Y
Poonpanich
D
D
Mookmanee
T
T
Chongsuphajaisiddhi
B M
BM
Sadler
Z
Z
Hussein
C J
CJ
Canfield
D B
DB
Hutchinson
D000962:Antimalarials / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053626:Atovaquone; D002648:Child; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009285:Naphthoquinones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018512:Parasitemia / Q000188:drug therapy*; D002727:Proguanil / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011446:Prospective Studies; D014227:Triazines / Q000493:pharmacokinetics
D000962:Antimalarials; D009285:Naphthoquinones; D014227:Triazines; C026009:cycloguanil; D002727:Proguanil; D053626:Atovaquone