Publication: Enantiospecific pharmacokinetics and drug–drug interactions of primaquine and blood-stage antimalarial drugs
Issued Date
2018-01-01
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ISSN
14602091
03057453
03057453
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2-s2.0-85055184925
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Antimicrobial Chemotherapy. Vol.73, No.11 (2018), 3102-3113
Suggested Citation
Kalayanee Chairat, Podjanee Jittamala, Borimas Hanboonkunupakarn, Sasithon Pukrittayakamee, Warunee Hanpithakpong, Daniel Blessborn, Nicholas J. White, Nicholas P.J. Day, Joel Tarning Enantiospecific pharmacokinetics and drug–drug interactions of primaquine and blood-stage antimalarial drugs. Journal of Antimicrobial Chemotherapy. Vol.73, No.11 (2018), 3102-3113. doi:10.1093/jac/dky297 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/47164
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Title
Enantiospecific pharmacokinetics and drug–drug interactions of primaquine and blood-stage antimalarial drugs
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Abstract
© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.