Population pharmacokinetics and pharmacodynamic considerations of amodiaquine and desethylamodiaquine in Kenyan adults with uncomplicated malaria receiving artesunate-amodiaquine combination therapy

Abstract

Amodiaquine (AQ) is an antimalarial drug that was frequently combined with artesunate (AS) for the treatment of uncomplicated malaria due to Plasmodium falciparum and is now available as a fixed-dose combination. Despite its widespread use, the simultaneous pharmacokinetics in patients of AQ and its active metabolite, desethylamodiaquine (DAQ), were not characterized to date. The pharmacokinetics of AQ and DAQ in 54 adult patients receiving the AS/AQ combination were therefore investigated by the use of a population approach. AQ followed a 1-compartment model with first-order absorption and elimination, as well as a first-order and irreversible transformation into DAQ, which in turn followed a 2-compartment model with first-order elimination from its central compartment. The mean AQ apparent clearance and distribution volume were 3,410 liters/h and 39,200 liters, respectively. The mean terminal elimination half-life of DAQ was 211 h. Body weight was found to explain the interindividual variability of the apparent volume of distribution of AQ and the elimination rate constant of DAQ. A new dosage form consisting of a fixed-dose combination of AS and AQ was found to have no effect on the pharmacokinetic parameters of AQ and DAQ. All patients achieved parasite clearance within 4 days following the initiation of the treatment, which prevented investigation of the possible relationship between DAQ exposure and treatment outcome. This study provided the first simultaneous pharmacokinetic model for AQ and DAQ.

FIG. 1.

Representation of the structural pharmacokinetics model. AQ, amodiaquine; DAQ, desethylamodiaquine; ka, absorption rate constant; F, amodiaquine bioavailability; V/F_AQ, apparent distribution volume of amodiaquine; CL/F_AQ, apparent clearance of amodiaquine; ke, elimination rate constant of amodiaquine; Fm, fraction of amodiaquine converted to desethylamodiaquine; V_DAQc, central distribution volume of desethylamodiaquine; kel, elimination rate constant of desethylamodiaquine; k₃₄ and k₄₃, distribution rate constants between central and peripheral distribution volumes of desethylamodiaquine.

FIG. 2.

Observed versus population-predicted concentrations (ng/ml) of amodiaquine (W1) and desethylamodiaquine (W0). The black lines represent the identity (y = x) lines. L, liter.

FIG. 3.

Lack of residual trend on the weighted residuals (WRES) versus the different covariates: age (years); BW, body weight (kg); HB, hemoglobin (g/dl); ALA, alanine transaminase (unit/ml); sex (1 for men and 2 for women); and dose, dosage form (1 for fixed-dose combination and 2 for non-fixed-dose combination). Solid lines represent the Y = 0 line.

FIG. 4.

Weighted residuals (WRES) versus time after dose (h) or population-predicted concentrations (PRED, mg/liter) for amodiaquine (W1) and desethylamodiaquine (W0).

FIG. 5.

Visual predictive checks for amodiaquine (W1) and desethylamodiaquine (W0). The solid lines show the median values, and the dotted lines show the 95% confidence intervals. DV, observed concentrations (mg/liter); T1, time after dose (h).

FIG. 6.

Cumulative AUC of DAQ (A) and terminal half-life of DAQ (B) with respect to BW for both the non-FDC (open triangles) and the FDC (closed triangles) forms of administration.