Pharmacokinetic Interactions between Primaquine and Chloroquine

Abstract

Chloroquine combined with primaquine has been the standard radical curative regimen for Plasmodium vivax and Plasmodium ovale malaria for over half a century. In an open-label crossover pharmacokinetic study, 16 healthy volunteers (4 males and 12 females) aged 20 to 47 years were randomized into two groups of three sequential hospital admissions to receive a single oral dose of 30 mg (base) primaquine, 600 mg (base) chloroquine, and the two drugs together. The coadministration of the two drugs did not affect chloroquine or desethylchloroquine pharmacokinetics but increased plasma primaquine concentrations significantly (P ≤ 0.005); the geometric mean (90% confidence interval [CI]) increases were 63% (47 to 81%) in maximum concentration and 24% (13 to 35%) in total exposure. There were also corresponding increases in plasma carboxyprimaquine concentrations (P ≤ 0.020). There were no significant electrocardiographic changes following primaquine administration, but there was slight corrected QT (QTc) (Fridericia) interval lengthening following chloroquine administration (median [range] = 6.32 [−1.45 to 12.3] ms; P < 0.001), which was not affected by the addition of primaquine (5.58 [1.74 to 11.4] ms; P = 0.642). This pharmacokinetic interaction may explain previous observations of synergy in preventing P. vivax relapse. This trial was registered at ClinicalTrials.gov under reference number NCT01218932.

Patients’ adherence and clinical effectiveness of a 14-day course of primaquine when given with a 3-day chloroquine in patients with Plasmodium vivax at the Thai–Myanmar border

“…Two, one, and four cases with outlier primaquine levels below the 1 st quartile on days 3, 7, and 14, respectively, could be due either to the non-adherence to primaquine doses or inadequate systemic drug exposure (due to impaired drug absorption or vomiting). The observed concentrationtime profile of primaquine was in agreement with other previous reports in similar populations indicating relatively short systemic exposure of primaquine in human blood(Na-Bangchang et al, 1994;Pukrittayakamee et al, 2014). Capillary sampling blood from a finger prick spot on filter paper (DBS) provides a valid tool for monitoring patients' adherence to therapy(Kissinger, 2011;Robijns et al, 2014) as it is simple, less invasive, and requires less experienced staff (finger puncture with a lancet) compared with the conventional venous blood collection.…”

“…to confirm exposure to primaquine would increase the sensitivity of adherence monitoring as the half-life of this metabolite is relatively longer (33 hours) (Pukrittayakamee et al, 2014). Unfortunately, measurement of carboxy-primaquine concentrations was not possible in the current study due to limitation of the analytical method used.…”

Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta

“…First is the fact that CQ's most important metabolites, desethylchloroquine and bisdesethylchloroquine, also bear lysosomotropic and alcalinyzing activities and can accumulate in plasma and other organs. Furthermore, CQ has a very long half-life (weeksmonths) which allows a greater total exposure [51][52][53][54]. However, the limitation set by the presence of the bloodbrain barrier (BBB) and efflux pumps expressed by glioma and endothelial cells, which hinder penetration and accumulation of several molecules to the CNS, needs to be accounted for.…”

In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

“…Whereas in most cases we identified synergism/additive effects between these drug combinations, there appeared to be some strain-specific differences that modulate the responses to the drug combinations, which warrants further studies on how P. falciparum strains from different geographical regions react to the drug combinations. Furthermore, the caveats due to the PQ versus the X dosing schedule and the pharmacokinetics/pharmacodynamics in vivo, which might not reflect the synergism we observed in vitro, must be addressed by further field studies (57). Taken as a whole, most of our PQ-X combinations, in both asexual and sexual stages, showed synergistic interactions in vitro, which supports the WHO recommendation of adding PQ as a gametocytocidal agent to ACTs, as well as the proposed PQ use in mass drug administration programs (2,58,59).…”