Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
J Antimicrob Chemother. 2018 Nov 1;73(11):3102-3113. doi: 10.1093/jac/dky297.
Characterization of the pharmacokinetic properties of the enantiomers of primaquine and carboxyprimaquine following administration of racemic primaquine given alone and in combination with commonly used antimalarial drugs.
Enantiomeric pharmacokinetics were evaluated in 49 healthy adult volunteers enrolled in three randomized cross-over studies in which a single dose of primaquine was given alone and then, after a suitable washout period, in combination with chloroquine, dihydroartemisinin/piperaquine or pyronaridine/artesunate. Non-linear mixed-effects modelling was used to characterize pharmacokinetics and assess the impact of drug-drug interactions.
The volume of distribution of racemic primaquine was decreased by a median (95% CI) of 22.0% (2.24%-39.9%), 24.0% (15.0%-31.5%) and 25.7% (20.3%-31.1%) when co-administered with chloroquine, dihydroartemisinin/piperaquine and pyronaridine/artesunate, respectively. The oral clearance of primaquine was decreased by a median of 19.1% (14.5%-22.8%) when co-administered with pyronaridine/artesunate. These interactions were enantiospecific with a relatively higher effect on (+)-S-primaquine than on (-)-R-primaquine. No drug-drug interaction effects were seen on the pharmacokinetics of either carboxyprimaquine enantiomer.
Population pharmacokinetic models characterizing the enantiospecific properties of primaquine were developed successfully. Exposure to primaquine, particularly to the (+)-S-primaquine but not the carboxy metabolites, increased by up to 30% when co-administered with commonly used antimalarial drugs. A better mechanistic understanding of primaquine metabolism is required for assessment of its efficacy and haematological toxicity in humans.
描述单独给予和与常用抗疟药物联合给予消旋体伯氨喹后，伯氨喹对映体的药代动力学特性。
在三项随机交叉研究中，共招募了 49 名健康成年志愿者，评估了伯氨喹对映体的药代动力学。在这些研究中，志愿者单次给予伯氨喹，然后在适当的洗脱期后，分别联合给予氯喹、双氢青蒿素/哌喹或咯萘啶/青蒿琥酯。采用非线性混合效应模型来描述药代动力学并评估药物相互作用的影响。
当与氯喹、双氢青蒿素/哌喹和咯萘啶/青蒿琥酯联合使用时，消旋体伯氨喹的分布容积中位数（95%CI）分别降低了 22.0%（2.24%-39.9%）、24.0%（15.0%-31.5%）和 25.7%（20.3%-31.1%）。当与咯萘啶/青蒿琥酯联合使用时，伯氨喹的口服清除率中位数降低了 19.1%（14.5%-22.8%）。这些相互作用具有对映体特异性，对（+）-S-伯氨喹的影响相对高于（-）-R-伯氨喹。两种羧基伯氨喹对映体的药代动力学均未观察到药物相互作用的影响。
成功开发了描述伯氨喹对映体特异性性质的群体药代动力学模型。当与常用抗疟药物联合使用时，伯氨喹，尤其是（+）-S-伯氨喹的暴露量增加了 30%，但羧基代谢物的暴露量没有增加。需要更深入的了解伯氨喹的代谢机制，以评估其在人体内的疗效和血液学毒性。
