Effect of Modafinil at Steady State on the Single‐Dose Pharmacokinetic Profile of Warfarin in Healthy Volunteers

@article{Robertson2002EffectOM,
  title={Effect of Modafinil at Steady State on the Single‐Dose Pharmacokinetic Profile of Warfarin in Healthy Volunteers},
  author={Philmore Jr. Robertson and Edward T. Hellriegel and Sanjay Arora and Michael T. Nelson},
  journal={The Journal of Clinical Pharmacology},
  year={2002},
  volume={42},
  url={https://api.semanticscholar.org/CorpusID:29223738}
}
The results indicate that the marked suppression of CYP2C9 activity in vitro does not translate into a similar effect clinically, however, limitations arising from investigation of single doses of warfarin preclude global conclusions about the potential for more subtle interactions after chronic Warfarin administration.
View on Wiley
ncbi.nlm.nih.gov
25 Citations
Highly Influential Citations
1
Background Citations
5
Methods Citations
2

25 Citations

Clinical Pharmacokinetic Profile of Modafinil

The results show that modafinil is a moderately long-lived drug that is well absorbed and extensively metabolised, and has potential to affect the pharmacokinetics of drugs that are metabolised by certain CYP enzymes.

The Impact of R10-Hydroxywarfarin on CYP2C9-Mediated S-Warfarin Metabolism

10-hydroxywarfarin is a major circulating metabolite of warfarin following multiple dosing, and it is proposed that it may reach high enough plasma concentrations at steady-state to produce a significant impact on the disposition and pharmacological response of S-warFarin.

Drug‐Drug Interactions Between Warfarin and Psychotropics: Updated Review of the Literature

Clinicians should monitor a patient's international normalized ratio (INR) closely to ensure it remains within therapeutic range, and interactions between warfarin and psychotropic drugs are important and likely underrecognized.

Interaction Profile of Armodafinil with Medications Metabolized by Cytochrome P450 Enzymes 1A2, 3A4 and 2C19 in Healthy Subjects

Armodafinil did not induce CYP1A2 but was a moderate inducer of CYP3A4 and a moderate inhibitor of CYp2C19 in healthy subjects and was generally well tolerated when administered with caffeine, midazolam or omeprazole.

Effect of Herbal Medicines on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects

Two clinical studies conducted as part of this research found that warfarin has an important role in treating people with heart disease, yet it has a narrow therapeutic range, is highly bound to plasma proteins, and is metabolised by cytochrome P450, which creates the potential for life-threatening interactions with other drugs and foods leading to excessive bleeding.

Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation).

Prediction of in vivo drug clearance from in vitro data. I: Impact of inter-individual variability

The Simcyp® Population-Based ADME Simulator was used to predict median drug clearances and their associated variance from in vitro data and regardless of whether microsomal binding was considered, the predicted fold variability fell within 2-fold of the observed variability.

Prediction of the Clearance of Eleven Drugs and Associated Variability in Neonates, Infants and Children

The in silico prediction of pharmacokinetic behaviour in paediatric patients is not intended to replace clinical studies, however, it provides a valuable aid to decision-making with regard to first-time dosing in children and study design.

Optimized Cocktail Phenotyping Study Protocol Using Physiological Based Pharmacokinetic Modeling and In silico Assessment of Metabolic Drug–Drug Interactions Involving Modafinil

This work sought to develop an optimized ICPP mDDI study protocol to evaluate the potential magnitude and clinical relevance of mDDIs using a physiologically based pharmacokinetic modeling approach.

Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects

Modafinil is a nonamphetamine nootropic drug with an increasingly therapeutic interest due to its different sites of action and behavioral effects in comparison to cocaine or amphetamine, and its psychotropic and cognitive effects are also attractive in several other pathologies and conditions that affect sleep structure, induce fatigue and lethargy, and impair cognitive abilities.

23 References

The Effect of Orlistat on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Volunteers

Orlistat administered at doses of 120 mg three times daily did not significantly alter the pharmacokinetics and pharmacodynamics of a single 30‐mg oral dose of warfarin in healthy volunteers.

Investigation of multiple dose citalopram on the pharmacokinetics and pharmacodynamics of racemic warfarin.

Citalopram produced no change in the pharmacokinetics of (R)- and (S)-warfarin, indicating that citaloprams does not alter the metabolism of warfarin mediated via CYP1A2, CYP3A4 and CYP2C9, and is not considered to be of importance in the clinical setting.

Effect of the Endothelin‐Receptor Antagonist Bosentan on the Pharmacokinetics and Pharmacodynamics of Warfarin

Bosentan treatment led to a statistically significant reduction of the maximal prothrombin time (PTmax) and the AUC0‐120h of PT and factor VII activity compared to placebo, on average, by 23% to 38%, which could be explained by an increase in the elimination of the pharmacologically more active S‐enantiomer.

The effect of multiple doses of donepezil HCl on the pharmacokinetic and pharmacodynamic profile of warfarin.

It is suggested that donepezil may be safely co-administered with warfarin without the need for dose modification and pharmacokinetic parameters, Rmax and AUC(PT), were also unchanged by concomitant administration ofdonepezil.

Losartan Does Not Affect the Pharmacokinetics and Pharmacodynamics of Warfarin

The lack of pharmacokinetic or pharmacodynamic interaction between warfarin and losartan observed in this investigation suggests that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

A Double‐Blind, Placebo‐Controlled, Ascending‐Dose Evaluation of the Pharmacokinetics and Tolerability of Modafinil Tablets in Healthy Male Volunteers

The pharmacokinetic and safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.

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.

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.

In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.

Human P450 metabolism of warfarin.