Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria

Malaria Journal

Bernhards Ogutu¹  Katya Mauff²  Sandra Castel³  Paolo Denti⁴  Lubbe Wiesner⁴  Karen I. Barnes⁴  Elizabeth N. Allen⁴  Lesley J. Workman⁴  Thomas A. Anyorigiya⁵  Alexander Dodoo⁶  David Dosoo⁷  Kwaku-Poku Asante⁷  Abraham Oduro⁸  Frank Atuguba⁹  Abraham Hodgson^1,10  Fred Binka^1,11  Seth Owusu-Agyei^1,11 

[1] Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya;Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa;UCT/MRC Collaborating Centre for Optimising Antimalarial Therapy (CCOAT), University of Cape Town, Cape Town, South Africa;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa;UCT/MRC Collaborating Centre for Optimising Antimalarial Therapy (CCOAT), University of Cape Town, Cape Town, South Africa;Navrongo Health Research Centre, Navrongo, Ghana;Ghana Standards Authority, Accra, Ghana;Kintampo Health Research Centre, Kintampo, Ghana;Navrongo Health Research Centre, Navrongo, Ghana;Navrongo Health Research Centre, Navrongo, Ghana;Dodowa Health Research Centre, Dodowa, Ghana;Navrongo Health Research Centre, Navrongo, Ghana;Research and Development Division, Ghana Health Service, Accra, Ghana;University for Health and Allied Sciences, Ho, Volta Region, Ghana;

关键词: Amodiaquine;    Artesunate;    Fixed-dose combination;    Pharmacokinetics;    P. falciparum;    Ghana;    Infants;    Young children;    Underweight-for-age;    Parasite density;   

DOI  :  10.1186/s12936-020-03553-6

来源: Springer

【 摘 要 】

BackgroundAccurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups.MethodsA sensitive and selective LC–MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine.ResultsThe day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1–4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78–0.98), p = 0.021]. Amodiaquine exposure (median AUC0-∞) was significantly higher in infants (4201 ng h/mL) and children aged 1–5 years (1994 ng h/mL) compared to older children and adults (875 ng h/mL, p = 0.001), even though infants received a lower mg/kg amodiaquine dose (median 25.3 versus 33.8 mg/kg in older patients). Desethylamodiaquine AUC0-∞ was not significantly associated with age. No significant safety concerns were identified.ConclusionsEfficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.

【 授权许可】

CC BY