title: Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria.
abstract: Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite of AQ, in plasma between patients with different variants of the cytochrome P4502C8 (CYP2C8) gene. A two-compartment model was fitted to 169 plasma DEAQ concentrations from 103 Ghanaian children aged 1 to 14 years with uncomplicated malaria treated either with AQ alone (n = 15) or with AS plus AQ (n = 88). The population clearance of DEAQ appeared to increase nonlinearly with body weight, and the central volume of distribution of DEAQ was higher (P < 0.001) in the AS-plus-AQ group than in the AQ-only group. The maximum plasma DEAQ concentration was higher (P < 0.001), and the population distribution half-life was shorter (P < 0.01), in the AQ-only group than in the AS-plus-AQ group. The total areas under the plasma DEAQ concentration-time curves (P = 0.68) and elimination half-lives (P = 0.39) were similar for the two groups. There was a high frequency (0.179) of the non-wild-type allele of CYP2C8, but no differences between CYP2C8 genotypes with regard to AQ efficacy or safety were evident. The sample size, however, was limited, so monitoring of AQ toxicity in the study area is still indicated. The nonlinear clearance of DEAQ and the wide variability in kinetic parameters have safety implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination.
authors.affiliation: Department of Child Health, Korle Bu Teaching Hospital, Accra, Ghana.
authors.forename: George O
authors.initials: GO
authors.lastname: Adjei
authors.forename: Kim
authors.initials: K
authors.lastname: Kristensen
authors.forename: Bamenla Q
authors.initials: BQ
authors.lastname: Goka
authors.forename: Lotte C G
authors.initials: LC
authors.lastname: Hoegberg
authors.forename: Michael
authors.initials: M
authors.lastname: Alifrangis
authors.forename: Onike P
authors.initials: OP
authors.lastname: Rodrigues
authors.forename: Jorgen A L
authors.initials: JA
authors.lastname: Kurtzhals
mesh_terms: D000655:Amodiaquine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use; D000077332:Artesunate; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D065727:Cytochrome P-450 CYP2C8; D004359:Drug Therapy, Combination; D005260:Female; D005869:Ghana; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000655:Amodiaquine; D000077332:Artesunate; C047386:desethylamodiaquine; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8
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