Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing

Abstract

Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.

Keywords: NONMEM; dose optimization; malaria; pediatrics.

FIG 1

Structure of the PK model of amodiaquine and desethylamodiaquine. Abbreviations: F, oral bioavailability; K_TR, first-order transit rate constant; K_a, absorption rate constant; AQ, amodiaquine; DEAQ, desethylamodiaquine; CL, clearance; Vc, central volume of distribution; Q, Q₁, and Q₂, intercompartmental clearances; Vp, Vp₁, and Vp₂, peripheral volumes of distribution.

FIG 2

Visual predictive check of the final model describing the plasma concentrations of amodiaquine (AQ) and desethylamodiaquine (DEAQ) versus time in uncomplicated malaria patients from Thailand (THA), Kenya (KEN), Uganda (UGA), Burkina Faso (BKF), and Ghana (GHA). Open circles are the observed data points; solid and dashed lines are the 50th, 5th, and 95th percentiles of the observed data; shaded areas are the simulated (n = 1,000) 95% confidence interval for the same percentile. The y axis represents the plasma concentration on the log scale. Censored data points below the lower limit of quantification were imputed as LLOQ/2 and included in the calculation of percentiles for the observed and the simulation data. The VPC for amodiaquine for both Thailand and Kenya was cut at times of 90 and 60 h, respectively, since beyond these times the concentrations from both observed and simulated data were below the LLOQ.

FIG 3

Clearance maturation for amodiaquine (red line) and desethylamodiaquine (blue line) expressed as a fraction of adult clearance predicted from the PK model plotted against postnatal age (assuming that birth occurred at term). The dashed lines indicate the section of the maturation curve that falls in the age range below that observed in the study data and are therefore based on an extrapolation.

FIG 4

Simulation results of current recommended and optimized dose regimens for amodiaquine. (A and C) Day 7 plasma desethylamodiaquine concentration (A) and maximum concentration of desethylamodiaquine (C) based on the current recommended dose regimen. (B and D) Predicted desethylamodiaquine day 7 concentration for the optimized dose regimen designed to achieve a concentration ≥75% above the threshold value (B) and C_max of desethylamodiaquine for the optimized dose regimen (D). The black dashed and solid lines in panels A and B are the median and 80% value of median of the simulated day 7 plasma desethylamodiaquine concentration for the typical patient (representing the expected exposure level from the current dosing recommendation), respectively, and the red lines in panels C and D represents the C_max upper threshold (575 ng/ml). Simulations for each weight are presented as a box plot for the median and 25th and 75th percentiles, with whiskers representing the 5th and 95th percentiles. The boxes in gray indicate that the simulation for that age range is based on an extrapolation, since no PK data for children of that age were available.