DDMODEL00000308: Population pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs in healthy volunteers

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Short description:
Population pharmacokinetic properties of primaquine and carboxyprimaquine following administration of racemic primaquine given alone and in combination with commonly used antimalarial drugs.
Original code
  • Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs.
  • Chairat K, Jittamala P, Hanboonkunupakarn B, Pukrittayakamee S, Hanpithakpong W, Blessborn D, White NJ, Day NPJ
  • The Journal of antimicrobial chemotherapy, 11/2018, Volume 73, Issue 11, pages: 3102-3113
  • Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • 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.
Joel Tarning
Context of model development: Variability sources in PK and PD (CYP, Renal, Biomarkers);
Long technical model description: A detailed explanation of the model can be found in the published manuscript, Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs (published in Journal of Antimicrobial Chemotherapy).;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Despite its extensive use as a partner drug with other antimalarials, there are few studies of primaquine drug-drug interactions. The objective of this study was to characterize the pharmacokinetic properties of racemic and enantiomeric primaquine and carboxyprimaquine, following administration of racemic primaquine, and to investigate interactions with the three blood-stage antimalarial drug combinations using non-linear mixed-effects population pharmacokinetic modelling.;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Anti-infectives;
Annotations are correct.
This model is not certified.
  • Model owner: Joel Tarning
  • Submitted: Oct 3, 2019 7:53:47 AM
  • Last Modified: Oct 3, 2019 7:53:47 AM
Revisions
  • Version: 4 public model Download this version
    • Submitted on: Oct 3, 2019 7:53:47 AM
    • Submitted by: Joel Tarning
    • With comment: Updated model annotations.
 
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