Population Pharmacokinetics of Antimalarial Naphthoquine in Combination with Artemisinin in Tanzanian Children and Adults: Dose Optimization

Abstract

The combination antimalarial therapy of artemisinin-naphthoquine (ART-NQ) was developed as a single-dose therapy, aiming to improve adherence relative to the multiday schedules of other artemisinin combination therapies. The pharmacokinetics of ART-NQ has not been well characterized, especially in children. A pharmacokinetic study was conducted in adults and children over 5 years of age (6 to 10, 11 to 17, and ≥18 years of age) with uncomplicated malaria in Tanzania. The median weights for the three age groups were 20, 37.5, and 55 kg, respectively. Twenty-nine patients received single doses of 20 mg/kg of body weight for artemisinin and 8 mg/kg for naphthoquine, and plasma drug concentrations were assessed at 13 time points over 42 days from treatment. We used nonlinear mixed-effects modeling to interpret the data, and allometric scaling was employed to adjust for the effect of body size. The pharmacokinetics of artemisinin was best described by one-compartment model and that of naphthoquine by a two-compartment disposition model. Clearance values for a typical patient (55-kg body weight and 44.3-kg fat-free mass) were estimated as 66.7 L/h (95% confidence interval [CI], 57.3 to 78.5 L/h) for artemisinin and 44.2 L/h (95% CI, 37.9 to 50.6 L/h) for naphthoquine. Nevertheless, we show via simulation that patients weighing ≥70 kg achieve on average a 30% lower day 7 concentration compared to a 48-kg reference patient at the doses tested, suggesting dose increases may be warranted to ensure adequate exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01930331.).

Keywords: dose optimization; malaria; population pharmacokinetics.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG 1

Structural presentation of the final model describing population pharmacokinetics for artemisinin and naphthoquine in Tanzanian malaria patients. F, oral bioavailability; Ktr, first-order transit rate constant; Ka, absorption rate constant; CL, clearance; Vc, central volume of distribution; Q, intercompartmental clearances; Vp, peripheral volumes of distribution. *, peripheral compartments apply only to naphthoquine.

FIG 2

Visual predictive check of the final model describing the plasma concentration of artemisinin versus time in uncomplicated malaria patients from Tanzania. Open circles are the observed data points, solid and dashed lines are the 50th, 5th, and 95th percentiles of the observed data, and shaded areas are the simulated (n = 1,000) 95% confidence intervals for the same percentiles.

FIG 3

Visual predictive check of the final model describing the plasma concentrations of naphthoquine versus time in uncomplicated malaria patients from Tanzania. Open circles are the observed data points, solid and dashed lines are the 50th, 5th, and 95th percentiles of the observed data, and shaded areas are the simulated (n = 1,000) 95% confidence interval for the same percentile.

FIG 4

Simulation results of day 7 plasma naphthoquine concentration (A) and maximum concentration of naphthoquine (B). Results from the current recommended dose are in coral, and those from the optimized dose regimen are in blue. The purple line in panel A is the median, the dashed lines are the 5th and 95th percentiles of the simulated efficacy target, respectively, and the red line in panel B represents the target Cmax (156 ng/mL). Simulations of weight are presented as a distribution plot: the median is represented by the black line, the thick shading represents the 25th and 75th percentiles, and the lighter shading represents the 5th and 95th percentiles.