Abstract
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.
Highlights
Accurate 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 antimalarial dosing in key target population groups
This study aimed to characterize the pharmacokinetic and pharmacodynamic (PK/PD) profile of amodiaquine when given with artesunate as a fixed-dose combination to treat uncomplicated P. falciparum malaria in non-pregnant patients of all ages, including infants, malnourished young children and those with a high parasitaemia
Study procedures Patients were given a fixed-dose combination of artesunate-amodiaquine (Coarsucam®/Artesunate plus amodiaquine (ASAQ) Winthrop; Sanofi-Aventis, Maphar Laboratories, Morocco) with water based on World Health Organization (WHO) recommended dosage regimens by body weight to achieve an artesunate target of 4 mg/kg body weight and amodiaquine target of 10 mg/kg body weight of amodiaquine base once daily for 3 days [3]
Summary
Accurate 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 antimalarial dosing in key target population groups. Effective malaria treatment requires that the frequency and dose of anti-malarial drugs is adequate to provide sufficient drug concentrations over time to kill all parasites in all key target populations [11]. Despite extensive use of amodiaquine for many years, previously as a monotherapy and currently in combination with artesunate for the treatment of uncomplicated falciparum malaria [13, 14] and in combination with sulfadoxine-pyrimethamine for Seasonal Malaria Chemoprevention [15, 16], pharmacokinetic data are limited for the parent compound amodiaquine and in key target populations such as very young and malnourished children and patients with uncomplicated hyperparasitaemia [17,18,19,20,21,22,23]
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