Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug–drug interaction studies for CYP2C9

Klein, Kerenaftali; Gueorguieva, Ivelina; Aarons, Leon

doi:10.1007/s10928-011-9235-z

Cited by 6 publications

(12 citation statements)

References 47 publications

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“…S-warfarin is metabolized by the polymorphic CYP2C9 enzyme and hence is the substrate selected to investigate the drug-drug interactions for CYP2C9 by the US Food and Drug Administration (FDA), while R-warfarin is metabolized by a combination of CYP isoforms including CYP1A2 and CYP 3A4. It has also been reported that the anticoagulant action of racemic warfarin is mostly due to the S-warfarin and to predict any drug-drug interaction requires only the monitoring of S-warfarin (Klein et al, 2012).…”

Section: Figurementioning

confidence: 99%

Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

John

John²,

Wu³

et al. 2013

British J Pharmacology

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Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats. EXPERIMENTAL APPROACHTwo groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg -1 racemic warfarin i.v., and the test group (n = 13) 1 mg·kg -1 of racemic warfarin followed by 25 mg·kg -1 ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods. KEY RESULTSETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine. CONCLUSION AND IMPLICATIONSOur data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance. Abbreviations

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Section: Figurementioning

confidence: 99%

Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

John

John²,

Wu³

et al. 2013

British J Pharmacology

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“…PDDIs often are between drugs that are metabolized by the same cytochrome P450 (CYP450) enzymes, and/or due to the administration of drugs that inhibit or induce these enzymes systems (Spriet et al, 2009;Klein, Gueorguieva, Aarons, 2012;Mouly, Meune, Bergmann, 2009). Drugs metabolized by this route include midazolam, tacrolimus, cyclosporine, and phenytoin, all of which are widely used in the ICU.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of potential drug-drug interactions in the intensive care unit of a Brazilian teaching hospital

Rodrigues

Stahlschmidt

Granja

et al. 2017

Braz. J. Pharm. Sci.

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Patients in intensive care unit are prescribed large numbers of drugs, highlighting the need to study potential Drug-Drug Interactions in this environment. The aim of this study was to delineate the prevalence and risk of potential drug-drug interactions between medications administered to patients in an ICU. This cross-sectional observational study was conducted during 12 months, in an adult ICU of a teaching hospital. Inclusion criteria were: prescriptions with 2 or more drugs of patients admitted to the ICU for > 24 hours and age of ≥18 years. Potential Drug-Drug Interactions were quantified and classified through Micromedex TM database. The 369 prescriptions included in this study had 205 different drugs, with an average of 13.04 ± 4.26 (mean ± standard deviation) drugs per prescription. Potential Drug-Drug Interactions were identified in 89% of these, with an average of 5.00 ± 5.06 interactions per prescription. Of the 405 different pairs of potentially interacting drugs identified, moderate and major interactions were present in 74% and 67% of prescriptions, respectively. The most prevalent interaction was between dipyrone and enoxaparin (35.8%), though its clinical occurrence was not observed in this study. The number of potential Drug-Drug Interactions showed significant positive correlations with the length of stay in the intensive care unit, and with the number of prescribed drugs. Acknowledging the high potential for Drug-Drug Interactions in the ICU represents an important step toward improving patient safety and best therapy results.Uniterms: Potential drug-drug interactions. Intensive care unit. Patient safety. University hospitals.

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“…Most studies used chiral high-performance liquid chromatography (HPLC) to measure the plasma concentrations of S-warfarin or S-warfarin and R-warfarin. [19][20][21][22] Klein et al 23 did not mention any bioanalysis method or sample type used to estimate warfarin concentration.…”

Section: Bioanalytical Methodsmentioning

confidence: 99%

Various Factors Influencing the Enantiomers of Warfarin Pharmacokinetics: A Systematic Review of Population Pharmacokinetics

Mahaboob,

Ganesh,

Arun

et al. 2023

Journal of Pharmacology and Pharmacotherapeutics

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Warfarin is the most commonly prescribed anticoagulant medication. Warfarin’s pharmacokinetics (PK) in its enantiomeric form have been reported to be highly variable. Five population pharmacokinetic model studies for warfarin were identified in this systematic review. This review summarized these studies and reported on various factors affecting warfarin PK. Most studies reported a one-compartment model with first-order absorption and elimination for both S-warfarin and R-warfarin. Warfarin disposition has been reported to be influenced by various factors, including gender, age, genetic variation, body surface area (BSA), concurrent drug, weight, and ethnicity. So, all of these factors must be considered when addressing this pharmacokinetic variability. These models should undergo an external evaluation to confirm their generalizability and to support model-informed dosing in clinical settings.

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Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug–drug interaction studies for CYP2C9

Cited by 6 publications

References 47 publications

Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

Prevalence of potential drug-drug interactions in the intensive care unit of a Brazilian teaching hospital

Various Factors Influencing the Enantiomers of Warfarin Pharmacokinetics: A Systematic Review of Population Pharmacokinetics

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