Enantiospecific pharmacokinetics and drug–drug interactions of primaquine and blood-stage antimalarial drugs
| Autor: | Joel Tarning, Kalayanee Chairat, Borimas Hanboonkunupakarn, Daniel Blessborn, Warunee Hanpithakpong, Podjanee Jittamala, Sasithon Pukrittayakamee, Nicholas J. White, Nicholas P. J. Day |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Adult Male Primaquine medicine.medical_treatment 030231 tropical medicine 030106 microbiology Population Dihydroartemisinin Artesunate Pharmacology 03 medical and health sciences chemistry.chemical_compound Antimalarials Young Adult 0302 clinical medicine Pharmacokinetics Piperaquine Malaria Vivax Medicine Humans Pharmacology (medical) Drug Interactions education Original Research Pyronaridine education.field_of_study Antiinfective agent Cross-Over Studies business.industry Middle Aged Thailand Artemisinins Healthy Volunteers 3. Good health Infectious Diseases chemistry Quinolines Drug Therapy Combination Female business medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy |
| ISSN: | 1460-2091 0305-7453 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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