Clinical Pharmacokinetics and Pharmacodynamics of Warfarin

  title={Clinical Pharmacokinetics and Pharmacodynamics of Warfarin},
  author={Nick H G Holford},
  journal={Clinical Pharmacokinetics},
  • N. Holford
  • Published 1 November 1986
  • Medicine, Biology
  • Clinical Pharmacokinetics
SummaryThe simplest complete system accounting for the time-course of changes in the prothrombin time induced by warfarin requires the combination of 4 independent models: 1.A pharmacokinetic model for the absorption, distribution, and elimination of warfarin. Warfarin is essentially completely absorbed, reaching a maximum plasma concentration between 2 and 6 hours. It distributes into a small volume of distribution (10 L/70kg) and is eliminated by hepatic metabolism with a very small clearance… 
Clinical Pharmacokinetic Considerations in the Control of Oral Anticoagulant Therapy
The pharmacokinetics and pharmacodynamics of warfarin indicate that several days’ overlap with heparin on initiation ofwarfarin, and gradual (rather than sudden) discontinuation of warFarin, might theoretically be necesssary, however, those studies which have been performed have indicated that a long overlap and gradual discontinuation are not associated with greater safety or efficacy of the drug.
Pharmacodynamic and Stereoselective Pharmacokinetic Interactions between Zileuton and Warfarin in Humans
Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfar in order to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics.
Pharmacokinetic-Pharmacodynamic Investigation of a Possible Interaction Between Steady-State Temocapril and Warfarin in Healthy Subjects
No clinically relevant effect of temocapril on the pharmacokinetics and pharmacodynamics of warfarin was detected in healthy subjects.
Pharmacodynamics of warfarin in cats.
Wide inter-individual variations in both pharmacokinetics and pharmacodynamic response suggest that a more optimal dosing of warfarin may be possible with the development of individual pharmacokinetic/pharmacodynamic algorithms, analogous to those currently employed in human patients.
Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin.
There was a significant correlation between the estimated formation clearance of (S)-7-hydroxywarfarin and the clearance of(S)- warfarin, which accounted for much of the variability in the latter, and for the first time a stereoselective assay was employed.
Relationship between pharmacokinetics and pharmacodynamics of tinzaparin (logiparin), a low molecular weight heparin, in dogs.
It is concluded that sigmoid Emax models adequately describe the C versus E relationship after s.c. and i.v. doses of 3H-tinzaparin in dogs and that the interindividual variation of the pharmacodynamic parameters derived from this model was relatively small.
The Disposition of The Enantiomers of Warfarin Following Chronic Administration to Rats: Relationship to Anticoagulant Response
The results appear consistent with the possibility of there being a saturable binding site in the microsomal fraction of the liver, with a capacity of approximately 4·0 μg g−1 protein.
The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype.
R)- warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin and VKORC1 genotype is a covariate of the relative R/S potency relationship.
Modeling INR data to predict maintenance fluindione dosage.
A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state, and prescription rules for fluindione were derived retrospectively on the 73 patients in this study.


Kinetics of pharmacologic effects in man: The anticoagulant action of warfarin
The prothrombinopenic effect of warfarin as a function of time after drug administration can be predicted effectively by use of a mathematical relationship based on the dose or the initial concentration of the drug, the rate constants forwarfarin elimination and for prothROMbin complex activity decline, and the slope of the log‐plasma concentration‐response plot for the drug.
Pharmacokinetics and pharmacodynamics of warfarin at steady state.
It is suggested that plasma protein binding may reflect the interaction between warfarin and its effector site in the hepatocyte.
Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man
S Warfarin is a more potent anticoagulant than R warfarin in man and the plasma T½ of R but not of S was significantly longer after multiple dosing than after a single dose.
Phenylbutazone-warfarin interaction in man: further stereochemical and metabolic considerations.
The pharmacokinetics and urinary metabolic profile of R and S-warfarin, following administration of a 1.5 mg/kg oral dose of racemic warfarin and 4 days into an oral regimen of 100 mg phenylbutazone three times a day, and the stereoselective reduction of S- and R-warFarin, to their respective SS and RS-alcohols, is also substantially inhibited during phenyl butazone administration are investigated.
Pharmacokinetics of warfarin in the nephrotic syndrome and effect on vitamin K-dependent clotting factors.
The behavior of warfarin, a drug tightly bound to albumin, was studied in patients with nephrotic syndrome (NS) to assess the influence of hypoalbuminemia on its pharmacokinetics and its effect on
Studies on Coumarin Anticoagulant Drugs: Initiation of Warfarin Therapy Without a Loading Dose
The results provide a rational basis for the induction of prophylactic anticoagulant therapy without large loading doses of warfarin and should reduce the danger of hemorrhage in patients who are sensitive to the drug because of advanced age, sepsis, liver disease, congestive heart failure, or recent surgery or trauma.
Clinical Pharmacokinetics of Oral Anticoagulants
There are several well established pharmacokinetic drug interactions with warfarin and there is a wide awareness of the drugs most likely to reduce anticoagulant effects by enzyme induction and alternative drugs can be used.
Pharmacokinetics of warfarin enantiomers: A search for intrasubject correlations
The Maintenance dose of racemic warfarin required by an individual patient may be a useful predictor of the maintenance dose of S(−)‐warfarin which will produce a comparable degree of anticoagulation, and no such predictability is evident with respect to R(+)‐warFarin.
Comparison of the bioavailabilities and anticoagulant activities of two warfarin formulations
The clinical study in patients confirmed that the old and new formulations of Marevan are interchangeable on a dose for dose basis and the greatest changes in factors II, VII and X were observed after the first dose of warfarin.
Kinetics of warfarin absorption in man
The rate of warfarin absorption was rapid as guided by a consideration of the oral plasma concentration time curve in 8 subjects; peak drug concentrations in plasma were reached by 25 to 60 minutes after oral dosing.