Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria

George O Adjei; Kim Kristensen; Bamenla Q Goka; Lotte C G Hoegberg; Michael Alifrangis; Onike P Rodrigues; Jørgen A L Kurtzhals

doi:10.1128/AAC.00673-07

Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria

George O Adjei, Kim Kristensen, Bamenla Q Goka, Lotte C G Hoegberg, Michael Alifrangis, Onike P Rodrigues, Jørgen A L Kurtzhals

40 Citations (Scopus)

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.

Original language	English
Journal	Antimicrobial Agents and Chemotherapy
Volume	52
Issue number	12
Pages (from-to)	4400-6
Number of pages	6
ISSN	0066-4804
DOIs	https://doi.org/10.1128/AAC.00673-07
Publication status	Published - 2008

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Adjei, G. O., Kristensen, K., Goka, B. Q., Hoegberg, L. C. G., Alifrangis, M., Rodrigues, O. P., & Kurtzhals, J. A. L. (2008). Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria. Antimicrobial Agents and Chemotherapy, 52(12), 4400-6. https://doi.org/10.1128/AAC.00673-07

Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria. / Adjei, George O; Kristensen, Kim; Goka, Bamenla Q et al.
In: Antimicrobial Agents and Chemotherapy, Vol. 52, No. 12, 2008, p. 4400-6.

Research output: Contribution to journal › Journal article › Research › peer-review

Adjei, GO, Kristensen, K, Goka, BQ, Hoegberg, LCG, Alifrangis, M, Rodrigues, OP & Kurtzhals, JAL 2008, 'Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria', Antimicrobial Agents and Chemotherapy, vol. 52, no. 12, pp. 4400-6. https://doi.org/10.1128/AAC.00673-07

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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.",

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T1 - Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria

AU - Adjei, George O

AU - Kristensen, Kim

AU - Goka, Bamenla Q

AU - Hoegberg, Lotte C G

AU - Alifrangis, Michael

AU - Rodrigues, Onike P

AU - Kurtzhals, Jørgen A L

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1128/AAC.00673-07

DO - 10.1128/AAC.00673-07

M3 - Journal article

C2 - 18779360

SN - 0066-4804

VL - 52

SP - 4400

EP - 4406

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 12

ER -

Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria

Abstract

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