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 byPlasmodium 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.

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

“…Interestingly, although there is fairly extensive literature on the pharmacokinetics of chloroquine in humans, there is relatively limited information from animal studies. Pharmacokinetic studies of chloroquine in both animal models and in human subjects indicate that chloroquine has quite a long half-life (Mzayek et al, 2007;Lim et al, 2009;Karunajeewa et al, 2010;Moore et al, 2011), indicating that drug clearance is unlikely to be a limiting factor in the potential capacity of chloroquine to suppress of autophagy. However, the maximal concentrations of chloroquine achieved in the plasma fall only within the range of 1.5 and 3 mM, even with daily administration of the drug, concentrations which are unlikely to be sufficient to effectively interfere with autophagy (based on the concentrations required for autophagy inhibition in cell culture).…”

Resurgence of Plasmodium vivax Malaria in the Republic of Korea during 2006–2007

“…14 Prophylactic failure cases with high enough plasma concentrations of hydroxychloroquine have constantly occurred possibly because of the mass chemoprophylaxis, 15 and chloroquine-resistant P. vivax malaria cases have been recently reported in ROK, 16 suggesting a scale down of chemoprophylaxis. Continuous surveillance and monitoring are warranted to prevent further expansion of P. vivax malaria in ROK.…”

Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma

“…HCQ pharmacokinetics are characterized by an extremely prolonged terminal half-life (up to 40 d) and a very large volume of distribution, in part due to the partitioning of the drug into red blood cells and strong binding to heme proteins. 17,18 In humans, HCQ is rapidly and almost completely absorbed following an oral dose with approximately 50% being bound to plasma proteins. Three HCQ metabolites have been identified, including N-desethylchloroquine, desethylhydroxychloroquine (DHCQ), and bidesethylchloroquine.…”