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

Abstract

Background: 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 anti-malarial dosing in key target population groups.

Methods: A 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.

Results: The 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 AUC_0-∞) 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 AUC_0-∞ was not significantly associated with age. No significant safety concerns were identified.

Conclusions: Efficacy 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.

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

Fig. 1

Trial profile of artesunate-amodiaquine fixed-dose combination treated Ghanaian patients with uncomplicated P. falciparum malaria

Fig. 2

A plot of the median (IQR) capillary whole blood amodiaquine (AQ) concentrations versus time overlaid with log-transformed y-axis plot of median (interquartile range) capillary whole blood amodiaquine concentrations (ng/ml) versus time in Ghanaian patients of all ages treated with 3-day course of artesunate-amodiaquine

Fig. 3

A plot of the median capillary whole blood desethylamodiaquine (DEAQ) concentrations versus time profile overlaid with log-transformed y-axis plot of the median (interquartile range) capillary whole blood desethylamodiaquine concentrations versus time in Ghanaian patients of all ages treated with 3-day course of artesunate-amodiaquine

Fig. 4

A scatter plot showing the correlation between the area under the capillary whole blood concentration–time curve of desethylamodiaquine (AUC0-∞) and the day 7 desethylamodiaquine (DEAQ) concentrations

Fig. 5

Box and whisker plots of log scale observed Day 3 amodiaquine concentrations by treatment response