Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax

Abstract

Hydroxychloroquine (HCQ) is an antimalarial drug used as chemoprophylaxis against malaria caused by Plasmodium vivax in the Republic of Korea Army (ROKA). In this study, we evaluated the pharmacokinetics (PK) of HCQ and its metabolites and the relationship between the PK of HCQ and the effect of treatment of HCQ on vivax malaria in South Koreans. Three PK studies of HCQ were conducted with 91 healthy subjects and patients with vivax malaria. Plasma concentrations were analyzed by noncompartmental and mixed-effect modeling approaches. A two-compartment model with first-order absorption best described the data. The clearance and the central and peripheral volumes of distribution were 15.5 liters/h, 733 liters, and 1,630 liters, respectively. We measured the plasma concentrations of HCQ in patients with prophylactic failure of HCQ and compared them with the prediction intervals of the simulated concentrations for HCQ from the final PK model built in this study. In 71% of the patients with prophylactic failure, the plasma concentrations of HCQ were below the lower bounds of the 95% prediction interval, while only 8% of them showed higher levels than the upper bounds of the 95% prediction interval. We report that a significant cause of prophylactic failure among the individuals in ROKA was ascribed to plasma concentrations of HCQ lower than those predicted by the PK model. However, prophylactic failure despite sufficient plasma concentrations of HCQ was confirmed in several individuals, warranting continued surveillance to monitor changes in the HCQ susceptibility of Plasmodium vivax in the Republic of Korea.

Figures

FIG. 1.

Metabolism of HCQ.

FIG. 2.

Overall study flow.

FIG. 3.

Plasma concentrations (mean and standard deviation) of HCQ and its metabolites in the six healthy subjects in study Ia before and after the administration of a single oral dose of HCQ sulfate at 400 mg.

FIG. 4.

Diagnostic plots for the final population PK model of HCQ in the pharmacokinetic studies (studies Ia, Ib, and II). Solid line, fit by local regression (loess); dashed line, line of identity.

FIG. 5.

Comparison of the actual plasma concentrations of HCQ in 61 soldier patients in the clinical comparison study who were infected with malaria parasites despite chemoprophylaxis for longer than 4 weeks to the simulated plasma time-concentration profiles of HCQ after oral administration of HCQ sulfate with a prophylactic dose of 400 mg/week.