Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs
<strong>Objectives</strong> 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. <strong>Methods</strong>...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2018
|
| _version_ | 1826266933475934208 |
|---|---|
| author | Chairat, K Jittamala, P Hanboonkunupakarn, B Pukrittayakamee, S Hanpithakpong, W Blessborn, D White, N Day, N Tarning, J |
| author_facet | Chairat, K Jittamala, P Hanboonkunupakarn, B Pukrittayakamee, S Hanpithakpong, W Blessborn, D White, N Day, N Tarning, J |
| author_sort | Chairat, K |
| collection | OXFORD |
| description | <strong>Objectives</strong> 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. <strong>Methods</strong> 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. <strong>Results</strong> 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. <strong>Conclusions</strong> 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. |
| first_indexed | 2024-03-06T20:46:28Z |
| format | Journal article |
| id | oxford-uuid:36165bcd-6023-4f0e-a9b8-6b816147edff |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:46:28Z |
| publishDate | 2018 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:36165bcd-6023-4f0e-a9b8-6b816147edff2022-03-26T13:35:41ZEnantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:36165bcd-6023-4f0e-a9b8-6b816147edffEnglishSymplectic Elements at OxfordOxford University Press2018Chairat, KJittamala, PHanboonkunupakarn, BPukrittayakamee, SHanpithakpong, WBlessborn, DWhite, NDay, NTarning, J<strong>Objectives</strong> 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. <strong>Methods</strong> 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. <strong>Results</strong> 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. <strong>Conclusions</strong> 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. |
| spellingShingle | Chairat, K Jittamala, P Hanboonkunupakarn, B Pukrittayakamee, S Hanpithakpong, W Blessborn, D White, N Day, N Tarning, J Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs |
| title | Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs |
| title_full | Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs |
| title_fullStr | Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs |
| title_full_unstemmed | Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs |
| title_short | Enantiospecific pharmacokinetics and drug-drug interactions of primaquine and blood-stage antimalarial drugs |
| title_sort | enantiospecific pharmacokinetics and drug drug interactions of primaquine and blood stage antimalarial drugs |
| work_keys_str_mv | AT chairatk enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs AT jittamalap enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs AT hanboonkunupakarnb enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs AT pukrittayakamees enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs AT hanpithakpongw enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs AT blessbornd enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs AT whiten enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs AT dayn enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs AT tarningj enantiospecificpharmacokineticsanddrugdruginteractionsofprimaquineandbloodstageantimalarialdrugs |