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Journal of Clinical Pharmacology, 2004; 44:388-393
© 2004 the American College of Clinical Pharmacology

DRUG INTERACTIONS

The Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor, Are Unaffected by a Single Dose of Alcohol

Troy C. Sarich, PhD, Susanne Johansson, MSc, Kajs-Marie Schützer, MD, PhD, Ulrika Wall, MD, PhD, Eva Kessler, MSc, Renli Teng, PhD and Ulf G. Eriksson, PhD

From Experimental Medicine, AstraZeneca, Wilmington, Delaware, and Mölndal, Sweden.

Address for reprints: Troy C. Sarich, PhD, Experimental Medicine, AstraZeneca LP, C4C-123, P.O. Box 15437, 1800 Concord Pike, Wilmington, DE 19850.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Ximelagatran—a direct thrombin inhibitor rapidly converted to its active form, melagatran, after oral administration—is being developed for the prevention and treatment of thromboembolic disease. The pharmacokinetics, pharmacodynamics, and tolerability/safety of ximelagatran following a single 36-mg oral dose of ximelagatran ± a single oral dose of alcohol (0.5 and 0.6 g ethanol/kg to women and men, respectively) were assessed in a randomized, open-label, twoway crossover study (n = 26). The 90% confidence intervals (CIs) and least squares mean estimates for the ratio of ximelagatran plus alcohol to ximelagatran alone for melagatran AUC (1.04 [90% CI = 1.00-1.08]) and Cmax (1.08 [90% CI = 1.03-1.14]) fell within the bounds demonstrating no interaction. Alcohol did not alter the melagatran-induced prolongation of the activated partial thromboplastin time or the good tolerability/safety profile of ximelagatran. In conclusion, the pharmacokinetics, pharmacodynamics, and tolerability/safety of oral ximelagatran were not affected by alcohol.

Key Words: Ximelagatran • pharmacokinetics • pharmacodynamics • safety/tolerability • thromboembolic disease • anticoagulants • alcohol

Thromboembolic disease is the primary cause of death in Western industrialized societies and has been characterized as a major public health problem.1,2 Anticoagulants—namely, injectable heparins and the oral coumarins such as warfarin—inhibit or prevent thrombus formation, growth, and embolization and are effective in the prevention and treatment of thromboembolic disease.1 Despite their antithrombotic efficacy and the need for effective intervention, anticoagulants are generally underused, particularly for indications requiring outpatient and/or long-term administration.3,4 Reasons for the underutilization of heparins include the requirement for subcutaneous administration and the risk of thrombocytopenia. Use of warfarin is limited because of its narrow therapeutic window, the requirement for routine coagulation monitoring and frequent dose adjustment, and interactions with food, alcohol, and numerous medications.5,6

Ximelagatran, an oral direct thrombin inhibitor (oral DTI), is currently under development for the prevention and treatment of thromboembolic disease and has a promising pharmacokinetic and pharmacodynamic profile compared with those of currently available anticoagulants. After oral administration, ximelagatran is rapidly absorbed and converted via two minor intermediates to its active form, melagatran.7,8 Melagatran binds with high affinity to both free and clot-bound thrombin to prevent the conversion of fibrinogen to fibrin9,10 and has also been shown to inhibit thrombin generation, platelet activation, and thrombus formation in humans.11-13 The majority of systemic melagatran is renally eliminated,7,8,14 and ximelagatran and its metabolites are not substrates of and do not inhibit any of the major cytochrome P450 isoenzymes.15 The pharmacokinetics of melagatran have been shown to be stable over time following repeated dosing with oral ximelagatran in patients with atrial fibrillation.16

In randomized, double-blind studies, treatment with ximelagatran has resulted in superior reductions in the frequency of venous thromboembolic events compared with the low-molecular weight heparins dalteparin (METHRO II trial) and enoxaparin (EXPRESS study) in patients undergoing total hip or knee replacement, as well as compared with warfarin in patients undergoing total knee replacement (EXULT A trial).17-19 Using fixed-dose administration without coagulation monitoring, a statistically significant reduction in the risk of venous thromboembolic events was achieved in the ximelagatran arm (2.8%) compared to the placebo arm (12.6%) during long-term (18-month) secondary prophylaxis of venous thromboembolism.20 Furthermore, ximelagatran was shown to be statistically noninferior to well-controlled warfarin in the prevention of stroke and systemic embolic events in patients with atrial fibrillation.21 Ximelagatran is also being investigated for the treatment of deep vein thrombosis with or without pulmonary embolism.22,23

Alcohol is frequently consumed in combination with prescription medications. In a survey of 311 independently living residents of retirement communities, 38% reported consumption of alcohol during treatment with prescription medication(s) known to interact with alcohol.24 The oral anticoagulant warfarin was among the top 10 high-risk medications taken by these respondents. It is reported that alcohol consumption during warfarin therapy can result in fluctuations (increase or decrease) in the international normalized ratio (INR).25,26 However, consumption of fortified wine over 21 days by 7 healthy volunteers did not alter the effect of warfarin.27

Alcohol can affect the pharmacokinetics of concurrently administered drugs by, for example, delaying gastric emptying to slow drug absorption or by inducing liver enzymes to affect drug metabolism.28 As it is likely that ximelagatran will be administered concomitantly with alcohol, the current study was conducted to assess the potential effect of a single dose of alcohol on the pharmacokinetics, pharmacodynamics, and tolerability/safety of ximelagatran.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Healthy men and women volunteers ages 20 to 40 years and with a body mass index (BMI) from 19 to 27 kg/m2 were eligible for the study. Exclusion criteria included any significant clinical illness (as judged by the investigator) within 2 weeks before the first dose of study medication; pregnancy or planned pregnancy; use of prescription medicines (except contraceptives), acetylsalicylic acid, or nonsteroidal anti-inflammatory drugs within 2 weeks before the first dose of study medication; use of over-the-counter drugs (except acetaminophen/paracetamol), vitamins, herbals, or minerals within 1 week before the first dose of study medication; and the requirement for concomitant medication (except for contraceptives and occasional acetaminophen/paracetamol) through the duration of the study. All volunteers provided written informed consent.

Study Design
This randomized, open-label, two-way crossover study was conducted at a single center in Sweden. The study protocol was approved by the Swedish Medical Agency and the local independent ethics committee (IEC) in Lund, Sweden. The study was conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki.

The study comprised a screening visit, two clinic visits during which medication was administered (Days 1 and 2), and a follow-up visit. During the screening visit, physical examinations and clinical laboratory tests were performed, and the volunteers' eligibility for the study was determined. On Day 1, which occurred within 14 days after the screening visit, volunteers who met eligibility criteria received either a single oral dose of ximelagatran 36 mg or a single oral dose of ximelagatran 36 mg followed immediately by alcohol (women, 1.6 mL/kg body weight; men, 1.9 mL/kg body weight), which was consumed over a 30-minute period as a solution of vodka containing 40% alcohol diluted with 330 mL orange juice. This dose of alcohol is equivalent to 0.5 g ethanol/kg body weight in women and 0.6 g ethanol/kg body weight in men. On Day 2, which was separated from Day 1 by a 2- to 7-day washout period, volunteers were crossed over to the treatment they had not received on Day 1. On both treatment days, ximelagatran was administered with 180 mL of water 2 hours after a standard breakfast that was served after an overnight fast in the clinic.

Alcohol (other than that given with study medication) was not permitted from 2 days prior to the screening visit and prior to each study day (and through completion of the follow-up visit following Day 2). Initiation of new physical training regimens and increases in the intensity of existing regimens were prohibited for the duration of the study.

Assessments
Pharmacokinetics of Melagatran
Venous blood samples (4.5 mL) for the determination of melagatran plasma concentrations were collected predose and up to 12 hours postdose on Days 1 and 2. Blood samples were collected in tubes containing sodium citrate and were centrifuged (1500g, 10 min). The plasma was separated and stored at -20°C until analysis. Plasma concentrations of melagatran were determined with liquid chromatography/mass spectrometry (LC/MS) with a limit of quantification (LOQ) of 10 nmol/L.29 A dilution factor of 1.185 was used to adjust plasma concentrations for the dilution of blood with citrate buffer.

Breath alcohol concentrations were measured with an Alcolmeter (Palmenco AB, Sweden) 1, 2, and 12 hours after dosing on Day 2 among volunteers receiving ximelagatran and alcohol. The measurement range for the Alcolmeter is 0.05 to 4.00 g/kg breath alcohol (grams of alcohol in a kilogram of breath air).

Pharmacodynamics
Activated partial thromboplastin time (APTT), a coagulation time assay, was determined from plasma samples collected predose and 2, 4, 6, and 10 hours postdose on Days 1 and 2. An extra blood sample was collected at 12 hours postdose following administration of ximelagatran and alcohol. The plasma samples were analyzed using routine methods at the Clinical Chemistry Laboratory, University Hospital Lund, Sweden. The blood samples were analyzed with the immediate diagnostic analyzer Thrombolytic Assessment System (TASTM; Pharmanetics, Inc., Raleigh, NC) as previously described.11

Tolerability/Safety
The main measure of tolerability and safety was the occurrence of adverse events, defined as any untoward medical occurrence developing or worsening after administration of study medication regardless of the suspected cause. All adverse events were reported spontaneously by the volunteers or in response to an open question or were revealed by observation or clinical assessment. The collection/recording of adverse events started at the time of first administration of study drug and lasted until the follow-up visit.

Blood and urine samples for standard hematology and clinical chemistry tests and urinalysis were obtained at the screening visit, before the first dose of study medication, after the last dose of study medication, and at the follow-up visit.

Statistics
The area under the melagatran plasma concentration versus time curve (AUC), calculated using the loglinear trapezoidal rule to the last measurable plasma concentration and extrapolated to infinity; maximum plasma concentration (Cmax); time to Cmax (tmax); and elimination half-life (t1/2) were determined. Actual sampling times were used to estimate pharmacokinetic parameters in a noncompartmental analysis performed with WinNonlin professional 1.5 software (Pharsight Corporation, Mountain View, CA). Cmax and AUC were analyzed using standard equivalence techniques following log transformation of the data. Analysis of variance (ANOVA) methods with subject, period, and treatment as factors were used to establish 90% confidence intervals (CIs) for the ratio of the two treatments (i.e., ximelagatran + alcohol/ximelagatran alone). No interaction was to be concluded if the 90% CI for the geometric mean treatment ratios (test/reference) fell within the interval of 0.8 to 1.25 for AUC and within the interval of 0.7 to 1.43 for Cmax. The pharmacokinetic parameters tmax and t1/2 were summarized descriptively.

A sample size of 24 subjects was estimated to provide more than 80% power to establish clinical equivalence in melagatran AUC between groups administered ximelagatran or ximelagatran administered with alcohol.

A repeated-measures covariance analysis (ANCOVA) was used to relate the APTT ratio (prolongation of APTT relative to the predose value) as the dependent variable with the independent variables of alcohol intake, the square root of the melagatran plasma concentration, and the interaction between the two. The effects were estimated by using 95% CIs.

Adverse events, clinical laboratory tests, and breath alcohol concentrations were summarized descriptively.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
A total of 27 volunteers (11 women and 16 men) were randomized, and 26 completed the study. Pharmacokinetic and pharmacodynamic analyses included data from the 26 volunteers who completed the study; tolerability analyses included data from all 27 volunteers randomized to treatment. One volunteer, as discussed below, withdrew from the study before completing it. The volunteers had a median age of 23 years (range: 20-35) and median BMI of 22 kg/m2 (range: 19-27).

Pharmacokinetics
The mean plasma melagatran concentration versus time profile following administration of oral ximelagatran with and without alcohol is shown in Figure 1. The 90% CIs and least squares mean estimates for the ratio of ximelagatran with alcohol to ximelagatran alone were within the predetermined bioequivalence limits of 0.80 to 1.25 for AUC and 0.70 to 1.43 for Cmax (Table I). The mean tmax (± SD) of melagatran following oral ximelagatran and alcohol (2.9 ± 0.54 h) was approximately 30 minutes later than that after ximelagatran alone (2.4 ± 0.55 h). The mean t1/2 (± SD) of melagatran following oral ximelagatran and alcohol (2.8 ± 0.24 h) was similar to that after ximelagatran alone (2.9 ± 0.26 h). The variability, expressed as the coefficient of variation (CV), was 21% to 23%, 23% to 24%, 19% to 23%, and 9% for AUC, Cmax, tmax, and t1/2, respectively (range of CV for the 2 study days).



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  		Figure 1. Mean plasma concentrations of melagatran versus time after oral administration of ximelagatran plus alcohol and ximelagatran alone (n = 26).

 

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  		Table I Melagatran Pharmacokinetic Parameters after Administration of Ximelagatran Plus Alcohol and Ximelagatran Alone

 

Breath Alcohol Concentrations
Breath alcohol measurements obtained on the day of administration of ximelagatran and alcohol confirmed that all volunteers had ingested alcohol. One and 2 hours postdose, median breath alcohol concentrations were 0.47 g/kg (range: 0.34-0.60) and 0.37 g/kg (range: 0.16-0.51), respectively. Breath alcohol concentration was zero at the last measurement 12 hours postdose for all subjects.

Pharmacodynamics
The APTT was prolonged in a concentration-dependent and nonlinear manner by melagatran (Figure 2). Neither the slope nor the intercept of the melagatran-APTT relationship differed as a function of whether or not alcohol was administered with ximelagatran (Table II).



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  		Figure 2. Activated partial thromboplastin time (APTT) prolongations (relative to predose) versus plasma concentration of melagatran after administration of ximelagatran or ximelagatran plus alcohol (n = 26). Regression lines for each treatment are fitted to values of the APTT ratio and the square root of the plasma concentration of melagatran (r2 = 0.62).

 

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  		Table II Parameter Estimates for the Regression Lines Associating the Activated Partial Thromboplastin Time (APTT) Ratio with the Square Root of the Plasma Concentration of Melagatran after Administration of Ximelagatran Plus Alcohol or Ximelagatran Alone

 

Tolerability
No serious adverse events were reported during the study, and no adverse event was specifically attributed to the combination of study medication and alcohol. No adverse bleeding events were observed or reported. One volunteer withdrew from the study because of an adverse event (severe nausea and vomiting accompanied by moderate headache) after treatment with ximelagatran. She recovered from the incident the same day. Five days after this incident, this volunteer again experienced vomiting. No clinically significant laboratory abnormalities were observed in the study.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Despite the potential for adverse consequences, the consumption of alcohol in combination with prescription and nonprescription medications is common.24,28 The results of this study show that acute intake of a moderate amount of alcohol does not affect the pharmacokinetics of melagatran, the active form of ximelagatran, after oral administration of ximelagatran 36 mg. An approximately 30-minute delay in the tmax of melagatran was observed when ximelagatran was administered with alcohol mixed in 330 mL orange juice. This relatively minor delay may be the result of an alcohol-induced delay in gastric emptying.28 An approximately 1-hour delay in tmax, but no change in AUC or Cmax, has been previously observed when ximelagatran is administered with food.14

The pharmacodynamics of melagatran were also unaffected by alcohol, as demonstrated by a lack of effect of alcohol on the melagatran-dependent prolongation of the APTT. The APTT was prolonged by melagatran in a nonlinear manner, as previously reported.7,11,14,22

Ximelagatran was well tolerated in this study regardless of whether it was administered with alcohol. Headache was the most common adverse event observed with both treatments. No serious adverse events or adverse bleeding events were reported. These results corroborate previous findings showing ximelagatran to be well tolerated in healthy volunteers across a range of doses.7,12,13

The results of this study extend those of previous pharmacokinetic and pharmacodynamic investigations of ximelagatran. The pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran were shown to be stable over time in patients during long-term treatment16 and to be unaffected by intrinsic factors such as age, obesity, and ethnicity.14,30,31 Renal function influences the pharmacokinetics of melagatran, as systemic melagatran is eliminated primarily through the kidneys.7,8 The lack of effect of ethanol, a cytochrome P450 2E1 substrate, on melagatran pharmacokinetics is consistent with previous findings that ximelagatran, its intermediates, and melagatran do not interact with the major cytochrome P450 isoenzymes.15 These pharmacokinetic and pharmacodynamic properties are advantageous for a medication intended for long-term outpatient use and differentiate ximelagatran from warfarin, which has a narrow therapeutic window and requires frequent coagulation monitoring and dose adjustment.

In conclusion, the results of this study demonstrate that the pharmacokinetics, pharmacodynamics, and tolerability/safety of melagatran after administration of the oral DTI ximelagatran 36 mg were not affected by concomitant consumption of a single dose of alcohol.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors wish to thank Dr. Lennart Jansson and his team for the conduct of this study and Dr. Jane Saiers for her assistance in preparing the manuscript.


   FOOTNOTES
 
This study was funded by AstraZeneca.

DOI: 10.1177/0091270004263649

Submitted for publication August 8, 2003; Revised version accepted January 23, 2004.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Da Silva MS, Sobel M: Anticoagulants: to bleed or not to bleed, that is the question. Semin Vasc Surg 2002;15: 256-267.[CrossRef][Medline] [Order article via Infotrieve]

2. Pinede L, Duhaut P, Ninet J: Management of oral anticoagulants in the treatment of venous thromboembolism. Eur J Intern Med 2001;12: 75-85.[CrossRef][Medline] [Order article via Infotrieve]

3. Ageno W, Squizzato A, Ambrosini F, Dentali F, Marchesi C, Mera V, et al: Thrombosis prophylaxis in medical patients: a retrospective review of clinical practice patterns. Haematologica 2002;87: 746-750.[Abstract/Free Full Text]

4. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Forcier A, Patwardhan NA: Physician practices in the prevention of venous thromboembolism. Ann Intern Med 1991;115: 591-595.

5. Ginsberg JS: Management of venous thromboembolism. N Engl J Med 1996;335: 1816-1828.[Free Full Text]

6. Wells PS, Holbrook AM, Crowther NR, Hirsch J: Interactions of warfarin with drugs and food. Ann Intern Med 1994;121: 676-683.[Abstract/Free Full Text]

7. Eriksson UG, Bredberg U, Gislén K, Johansson LC, Frison L, Ahnoff M, et al: Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003;59: 35-43.[Web of Science][Medline] [Order article via Infotrieve]

8. Eriksson UG, Bredberg U, Hoffmann KJ, Thuresson A, Gabrielsson M, Ericsson H, et al: Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003;31: 294-305.[Abstract/Free Full Text]

9. Gustaffson D, Antonsson T, Bylund R, Eriksson U, Gyzander E, Nilsson I, et al: Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998;79: 110-118.[Web of Science][Medline] [Order article via Infotrieve]

10. Klement P, Carlsson S, Rak J, Liao P, Vlasin M, Stafford A, et al: The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model. J Thromb Haemost 2003;1: 587-594.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Sarich TC, Eriksson UG, Mattsson C, Wolzt M, Frison L, Fager G, et al: Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects. Thromb Haemost 2002;87: 300-305.[Web of Science][Medline] [Order article via Infotrieve]

12. Sarich TC, Wolzt M, Eriksson UG, Mattsson C, Schmidt A, Elg S, et al: Effects of ximelagatran, an oral direct thrombin inhibitor, rhirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects. J Am Coll Cardiol 2003;41: 557-564.[Abstract/Free Full Text]

13. Sarich TC, Osende JI, Eriksson UG, Fager GB, Eriksson-Lepkowska M, Ohlsson L, et al: Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis. J Thromb Haemost 2003;1: 999-1004.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. Johansson LC, Frison L, Logren U, Fager G, Gustafsson D, Eriksson UG: Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003;42: 381-392.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Bredberg E, Andersson TB, Frison L, Thuresson A, Johansson S, Eriksson-Lepkowska M, et al: Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003;42: 765-777.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

16. Grind M, Hamren B, Baathe S, Wollbratt M, Eriksson UG: Pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation receiving long-term treatment: a population analysis by nonlinear mixed effect modeling [abstract MPI-99]. Clin Pharmacol Ther 2002;71: P31.

17. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P, et al, on behalf of the EXPRESS study group: The direct thrombin inhibitor Melagatran followed by oral ximelagatran compared with enoxparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. J Thromb Haemost 2003;1: 2490-2496.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, et al: Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349: 1703-1712.[Abstract/Free Full Text]

19. Eriksson BI, Bergqvist D, Kalebo P, Dahl OE, Lindbratt S, Bylock A, et al: Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002;360: 1441-1447.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Schulman S, Wåhlander K, Lundström T, Billing Clason S, Eriksson H, for the THRIVE III Investigators: Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349: 1713-1721.[Abstract/Free Full Text]

21. Olsson SB, Executive Steering Committee on behalf of the SPORTIF III Investigators: Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362: 1691-1698.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

22. Wåhlander K, Lapidus L, Olsson CG, Thuresson A, Eriksson UG, Larson G, et al: Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thromb Res 2002;107: 93-99.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

23. Eriksson H, Wåhlander K, Gustafsson D: A randomised, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003;1: 41-47.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

24. Adams WL: Potential for adverse drug-alcohol interactions among retirement community residents. J Am Geriatr Soc 1995;43: 1021-1025.[Web of Science][Medline] [Order article via Infotrieve]

25. Hirsh J, Fuster V, Ansell J, Halperin JL: American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107: 1692-1711.[Free Full Text]

26. Coumadin® (warfarin): product package insert, in: Physicians' Desk Reference. 58th ed. Montvale, NJ: Medical Economics Company, 2004.

27. O'Reilly RA: Lack of effect of fortified wine ingested during fasting and anticoagulant therapy. Arch Intern Med 1981;141(4): 458-459.[Abstract/Free Full Text]

28. Fraser AG: Pharmacokinetic interactions between alcohol and other drugs. Clin Pharmacokinet 1997;33: 79-90.[Web of Science][Medline] [Order article via Infotrieve]

29. Larsson M, Logren U, Ahnoff M, Lindmark B, Abrahamsson P, Svennberg H, et al: Determination of melagatran, a novel direct thrombin inhibitor, in human plasma and urine by liquid chromatography-mass spectrometry. J Chromatogr B Biomed Sci Appl 2002;766: 47-55.[CrossRef]

30. Sarich TC, Teng R, Peters GR, Wollbratt M, Homolka R, Svensson M, et al: No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor, ximelagatran. Clin Pharmacokinet 2003;42: 485-492.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

31. Johansson LC, Andersson M, Fager G, Gustafsson D, Eriksson UG: No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers. Clin Pharmacokinet 2003;42: 475-484.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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 The Annals of PharmacotherapyHome page
W. E Dager, T. G Vondracek, B. A McIntosh, and E. A Nutescu
Ximelagatran: An Oral Direct Thrombin Inhibitor
Ann. Pharmacother., November 1, 2004; 38(11): 1881 - 1897.
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 J Clin PharmacolHome page
T. C. Sarich, K.-M. Schutzer, H. Dorani, U. Wall, I. Kalies, L. Ohlsson, and U. G. Eriksson
No Pharmacokinetic or Pharmacodynamic Interaction Between Atorvastatin and the Oral Direct Thrombin Inhibitor Ximelagatran
J. Clin. Pharmacol., August 1, 2004; 44(8): 928 - 934.
[Abstract] [Full Text] [PDF]

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 J Clin PharmacolHome page
T. C. Sarich, K.-M. Schutzer, M. Wollbratt, U. Wall, E. Kessler, and U. G. Eriksson
No Pharmacokinetic or Pharmacodynamic Interaction Between Digoxin and the Oral Direct Thrombin Inhibitor Ximelagatran in Healthy Volunteers
J. Clin. Pharmacol., August 1, 2004; 44(8): 935 - 941.
[Abstract] [Full Text] [PDF]

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 J CARDIOVASC PHARMACOL THERHome page
W. E. Dager
Ximelagatran: A New Antithrombotic Option in Atrial Fibrillation
Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2004; 9(3): 151 - 162.
[Abstract] [PDF]

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