Comparison of the bioavailabilities and anticoagulant activities of two warfarin formulations

Stirling, Yvonne; Howarth, D. J.; Stockley, R. J.; Bland, R.; Towler, C. M.; Harding, S. M.

doi:10.1111/j.1365-2141.1982.tb07287.x

Cited by 16 publications

(10 citation statements)

References 15 publications

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“…Food slightly decreases the rate but not the extent of absorption (Melander 1978); unchanged warfarin has not been recovered from stool (Aggeler & O'Reilly 1966). Using high performance liquid chromatography, peak plasma concentrations have been observed between 0.3 and 4 hours, but 1 study reports a secondary peak between 1 and 8 hours (Stirling et al 1982). …”

Section: Absorptionmentioning

confidence: 99%

Clinical Pharmacokinetic Considerations in the Control of Oral Anticoagulant Therapy

Shetty

Fennerty

Routledge

1989

Clinical Pharmacokinetics

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Aspects of the pharmacokinetics of warfarin that are clinically relevant are reviewed here. Since warfarin is normally completely absorbed, resistance to treatment due to impaired absorption is unusual, even in severe short bowel syndrome. Warfarin is highly albumin-bound; thus, hypoalbuminaemic states result in an increased free fraction of the drug and a decreased half-life but, as might be expected, there is no evidence of altered response at steady-state. Warfarin is completely metabolised by the liver to hydroxy-warfarins and warfarin alcohols, and although the latter have some biological activity they do not contribute significantly to the drug effect. No information is available concerning the metabolism of warfarin in chronic liver disease, but there is evidence of increased sensitivity due to impaired vitamin K-dependent clotting factor synthesis. Impaired renal function does not appear to alter the effect of warfarin. Lowered response to the drug may be secondary to poor compliance, kinetic resistance or pharmacodynamic resistance. These factors can be identified using algorithms based on population values for plasma warfarin concentrations and clearances at steady-state. The pharmacokinetics and pharmacodynamics of warfarin indicate that several days' overlap with heparin on initiation of warfarin, and gradual (rather than sudden) discontinuation of warfarin, might theoretically be necessary. 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. Because of the long elimination half-life of warfarin and the short elimination half-life of vitamin K, many days' treatment with phytomenadione may be required after warfarin overdose. The elimination half-life and therefore the duration of therapy may be reduced by regular oral cholestyramine, although the means by which the latter enhances warfarin elimination is still unknown.

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Section: Absorptionmentioning

confidence: 99%

Clinical Pharmacokinetic Considerations in the Control of Oral Anticoagulant Therapy

Shetty

Fennerty

Routledge

1989

Clinical Pharmacokinetics

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“…25 mg) in the absence or presence of steady-state treatment of the drug that has potential to interact with warfarin; the use of a higher single dose of warfarin allows greater potential to detect an interaction as well as reduces the exposure of healthy volunteers to a prolonged period of anticoagulation. In some published studies, the interaction of a drug with warfarin has been assessed by administration of a single lower (10-15 mg) oral dose of warfarin [13,14]. A 7% decrease in S-warfarin AUC could be demonstrated after a single 10-mg dose of warfarin.…”

Section: Introductionmentioning

confidence: 99%

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

Malhotra

Alvey

Gong

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drug-drug interactions with warfarin are common with potentially harmful consequences. Preclinical in vitro studies suggest that fesoterodine or 5-hydroxymethyl tolterodine are not likely to affect warfarin metabolism, but a lack of interaction has not been demonstrated in a clinical study. WHAT THIS STUDY ADDS• This study shows that the pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg, and that co-administration of warfarin 25 mg and fesoterodine 8 mg is safe and well tolerated. AIMSTo confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults. METHODSIn this open-label, two-treatment, crossover study, subjects (n = 14) aged 20-41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1-9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration-time curve from time 0 to infinity (AUC(0,•)), maximum plasma concentration (C max), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to Cmax (tmax), and half-life (t1/2) for S-and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUCINR), maximum INR (INRmax), area under the PT-time curve (AUCPT) and maximum PT (PTmax). RESULTSAcross all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92-100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings. CONCLUSIONSThe pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.

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“…In the initial phase of anticoagulation (i.e., the first weeks of therapy), the INR is exquisitely labile and its relationship to the plasma concentration of vitamin K-dependent coagulants is complex [9,10]. The risk of hemorrhage per 100 patient months is increased between 2-7 times in the first 3 months of therapy compared to patients on warfarin for greater than 1 year [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…The risk of hemorrhage per 100 patient months is increased between 2-7 times in the first 3 months of therapy compared to patients on warfarin for greater than 1 year [6][7][8]. Several previous studies indicate that the plasma concentration of native (i.e., functionally carboxylated) prothrombin may be a more accurate indicator of the likelihood of thromboembolic and hemorrhagic complications associated with warfarin therapy [9][10][11][12][13]. Therefore, we measured the concentration of multiple fragments of prothrombin in both the plasma and the urine to evaluate potentially superior markers for the monitoring of warfarin anticoagulation.…”

Section: Introductionmentioning

confidence: 99%

Comparison of plasma prothrombin and factor VII and urine prothrombin F1 concentrations in patients on long‐term warfarin therapy and those in the initial phase

et al. 1998

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Control of warfarin anticoagulation during the initial phase of therapy is difficult and empirically based. Plasma and urine samples were obtained from normal controls, patients under stable anticoagulation, and patients in the initial phase of anticoagulation. Total plasma prothrombin, des-carboxy (non-adsorbable with barium chloride) prothrombin, and native (total minus non-adsorbable) prothrombin were quantitated using Echis carinatus venom activation. Functional plasma factor VII (VII) was measured using a one-stage clotting assay. Total and des-carboxy urine prothrombin F1 (F1) were measured by ELISA. All urine F1 in normals and both anticoagulated groups was adsorbed by barium chloride. Plasma des-carboxy prothrombin concentration was similar for the two anticoagulated groups and did not correlate with 1/INR. Native prothrombin correlated with 1/INR in both the stable (r = 0.76) and initial phase (r = 0.74) groups. For any given INR, the subjects on stable anticoagulation had lower native prothrombin concentrations than the initial phase patients. Functional factor VII concentration also correlated significantly with 1/INR in both the stable (r = 0.64) and initial phase (r = 0.76) patients. Unlike native prothrombin, VII concentrations did not vary between the two cohorts for any given INR. Previous studies indicate that native prothrombin is a superior predictor of both hemorrhagic and thromboembolic complications during warfarin therapy. Our findings indicate that VII, and not prothrombin, may be the predominant factor monitored by the INR. This further supports the need to reevaluate the usefulness of the INR in the monitoring of warfarin therapy during the initial phase. Am.

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Comparison of the bioavailabilities and anticoagulant activities of two warfarin formulations

Cited by 16 publications

References 15 publications

Clinical Pharmacokinetic Considerations in the Control of Oral Anticoagulant Therapy

Clinical Pharmacokinetic Considerations in the Control of Oral Anticoagulant Therapy

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

Comparison of plasma prothrombin and factor VII and urine prothrombin F1 concentrations in patients on long‐term warfarin therapy and those in the initial phase

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