Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border

Abstract

Background: A three-day course of chloroquine remains a standard treatment of Plasmodium vivax infection in Thailand with satisfactory clinical efficacy and tolerability although a continuous decline in in vitro parasite sensitivity has been reported. Information on the pharmacokinetics of chloroquine and its active metabolite desethylchloroquine are required for optimization of treatment to attain therapeutic exposure and thus prevent drug resistance development.

Methods: The study was conducted at Mae Tao Clinic for migrant worker, Tak province, Thailand. Blood samples were collected from a total of 75 (8 Thais and 67 Burmeses; 36 males and 39 females; aged 17-52 years) patients with mono-infection with P. vivax malaria [median (95 % CI) admission parasitaemia 4898 (1206-29,480)/µL] following treatment with a three-day course of chloroquine (25 mg/kg body weight chloroquine phosphate over 3 days). Whole blood concentrations of chloroquine and desethylchloroquine were measured using high performance liquid chromatography with UV detection. Concentration-time profiles of both compounds were analysed using a population-based pharmacokinetic approach.

Results: All patients showed satisfactory response to standard treatment with a three-day course of chloroquine with 100 % cure rate within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred. A total of 1045 observations from 75 participants were included in the pharmacokinetic analysis. Chloroquine disposition was most adequately described by the two-compartment model with one transit compartment absorption model into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. First-order elimination from the central compartment of chloroquine and desethylchloroquine was assumed. The model exhibited a strong predictive ability and the pharmacokinetic parameters were estimated with adequate precision.

Conclusion: The developed population-based pharmacokinetic model could be applied for future prediction of optimal dosage regimen of chloroquine in patients with P. vivax infection.

Fig. 1

A two-compartment model (central and peripheral) with a one transit compartment model for the absorption of chloroquine into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. CQ is chloroquine compartments and DCQ represents desethylchloroquine compartments. k represents the rate constant between different compartments

Fig. 2

Goodness of fit plots of chloroquine. Plots of the observed versus population predicted concentrations (a) and observed versus individual predicted concentrations (b). Weighed individual residuals versus individual predictions (c) and weighed residuals versus time (d). The black line is a non-parametric smoother describing the trend and the black line is the line of unity

Fig. 3

Goodness of fit plots of desethylchloroquine. Plots of the observed versus population predicted concentrations (a) and observed versus individual predicted concentrations (b). Weighed individual residuals versus individual predictions (c) and weighed residuals versus time (d). The black line is a non-parametric smoother describing the trend and the black line is the line of unity

Fig. 4

Plots from the visual predictive check for chloroquine (a) and desethylchloroquine (b) observations. The middle solid lines represent the median of simulated predictions by the final model. The dashed black lines represent the corresponding percentiles for the true observations. The black dots are the true observations and the grey shaded areas are the 95 % confidence intervals for the simulations. The decline in the upper percentiles of desethylchloroquine is due to base line values in the subjects