Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax.
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.
Lim
Hyeong-Seok
HS
Department of Pharmacology, Ulsan University College of Medicine, Songpa-gu, Seoul, Republic of Korea.
Im
Jeong-Soo
JS
Cho
Joo-Youn
JY
Bae
Kyun-Seop
KS
Klein
Terry A
TA
Yeom
Joon-Sup
JS
Kim
Tae-Seon
TS
Choi
Jae-Seon
JS
Jang
In-Jin
IJ
Park
Jae-Won
JW
D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008288:Malaria / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010966:Plasmodium vivax / Q000187:drug effects*
D000962:Antimalarials; D006886:Hydroxychloroquine