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DRUG INTERACTIONS |
From Experimental Medicine, AstraZeneca LP, Wilmington, Delaware (Dr. Sarich) and Experimental Medicine, AstraZeneca R&D Mölndal, Sweden (Dr. Schützer, H. Dorani, Dr. Wall, Dr. Kalies, L. Ohlsson, Dr. Eriksson).
Address for reprints: Troy C. Sarich, PhD, Experimental Medicine, AstraZeneca LP, C4C-123, P.O. Box 15437, 1800 Concord Pike, Wilmington, DE 19850.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Atorvastatin • ximelagatran • drug interactions • oral direct thrombin inhibitors • thromboembolic disease
Ximelagatran has been studied in several short- and long-term clinical trials without coagulation monitoring or dosage adjustment. In randomized, controlled studies, ximelagatran therapy was associated with a highly statistically significant reduction in the risk of venous thromboembolic events (2.8%) compared with placebo (12.6%) during 18 months of use for secondary prophylaxis of thromboembolism.7 It was significantly more effective than warfarin and more effective or comparable to the low molecular weight heparins dalteparin and enoxaparin at reducing the frequency of venous thromboembolic events in patients undergoing total hip or knee replacement.8-11 Importantly, ximelagatran was as effective as well-controlled dose-adjusted warfarin in preventing stroke and systemic embolic events in patients with atrial fibrillation.12
The pharmacokinetic and clinical profiles of ximelagatran render it suitable for long-term outpatient use. Because many patients requiring anticoagulant therapy suffer from cardiovascular disease, ximelagatran will potentially be administered concomitantly with other cardiovascular medications such as the statins (i.e., 3-hydroxy-3-methylglutaryl-coenzyme A [HMGCoA] reductase inhibitors), 3 of which were among the 20 most commonly prescribed medications in the United States in 2000.13 As ximelagatran and statins will likely be coadministered in clinical practice, assessment of their possible interaction is warranted. Interaction between ximelagatran and statins via the CYP450 metabolic pathways is not expected on the basis of the observation that ximelagatran and its metabolites are not substrates of and do not inhibit any of the major CYP450 isoenzymes.6 In addition, systemic melagatran is primarily renally excreted, whereas atorvastatin and its metabolites are excreted primarily in the bile.1,2,14 These data suggest a low probability of drug-drug interactions involving ximelagatran. Nevertheless, as the interaction potential between ximelagatran and statins has not been previously studied, the current study was conducted to assess the potential for interaction during coadministration of ximelagatran and atorvastatin, which is metabolized via CYP3A4/5 to 2 active metabolites, 2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin.15
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design and Treatments
This randomized, open-label, 2-way crossover study was conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki at a single center in Sweden. The Swedish Medical Agency and the local Independent Ethics Committee (IEC) in Lund, Sweden, approved the study protocol. The study consisted of a screening visit occurring no more than 14 days before the first administration of study medication, 2 study periods during which study medication was administered in the clinic, and a follow-up visit occurring 2 to 7 days after the last study day. During the screening visit, volunteers' eligibility for the study was determined, physical examinations and standard clinical laboratory tests were performed, and electrocardiograms were obtained. Volunteers meeting eligibility criteria were randomized to receive atorvastatin 40 mg as a single oral dose in the morning during the atorvastatin study period and ximelagatran 36 mg twice daily (every 12 hours) for 5 days plus a 40-mg oral dose of atorvastatin on the morning of day 4 during the atorvastatin + ximelagatran study period. Ximelagatran 36 mg has been tested in phase II and III clinical trials for the prevention and treatment of venous thromboembolism.8,12,16 Atorvastatin, available in doses of 10 to 80 mg, was administered as a single 40 mg dose to achieve therapeutically relevant plasma concentrations.17,18 The second study period ensued after a washout period of at least 7 days. During the atorvastatin study period, participants fasted from 10 PM the day before taking study medication and remained at the investigational site through 24 hours after taking study medication. During the atorvastatin + ximelagatran study period, participants fasted from 10 PM on the day before days 3 and 4 and remained at the investigational site through the 5-day duration of the study period.
Prohibited substances included nicotine-containing products during the predose fasting periods, during the 6 hours after the morning dose of atorvastatin during both study periods, and during the 6 hours after the morning dose of study medication on day 3 of the atorvastatin + ximelagatran study period; alcohol during the 2 days before the screening visit and from 2 days before the first administration of study medication through 2 days after the follow-up visit; and grapefruit or grapefruit juice from 3 days before each study period through the end of the study period. Initiation of new physical training regimens, increases in the intensity of existing regimens, and any physical training from 2 days before each study period through the end of each study period were prohibited for the duration of the study.
Assessments
Pharmacokinetics
Venous blood samples for the determination of atorvastatin acid and active HMG-CoA reductase inhibitors were drawn at predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours after administration of atorvastatin. Venous blood samples for the determination of melagatran were also drawn on days 3 and 4 at predoseand 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours after the morning doses of ximelagatran during the atorvastatin + ximelagatran study period. Plasma concentrations of melagatran were determined using liquid chromatography/mass spectrometry with a limit of quantification (LOQ) of 10 nmol/L for melagatran.19 Plasma concentrations of atorvastatin acid were determined using liquid chromatography/mass spectrometry with an LOQ of 0.100 ng/mL. Plasma concentrations of both melagatran and atorvastatin acid were determined at Cephac Europe SA (Saint Benoît Cedex, France). Active HMG-CoA reductase inhibitors, which represent the total enzymatic inhibitory effect of both the parent compound (atorvastatin acid) and the active metabolites (2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin), were assayed in plasma extracts using an enzyme inhibition assay (the performance of which was not affected by melagatran in an interference assay) with an LOQ of 0.360 ng/mL.20 This analysis was performed by Medical Research Laboratories International, Inc (Highland Heights, Ky).
Pharmacodynamics
Activated partial thromboplastin time (APTT), a coagulation time assay, was determined from plasma samples collected in citrated tubes at predose and 1, 2, 4, 6, and 10 hours postdose on days 3 and 4 of the atorvastatin + ximelagatran study period. The blood samples were analyzed using routine methods at the Laboratory of Clinical Chemistry at Lund University Hospital (Lund, Sweden).
Tolerability and Safety
Adverse events, defined as any untoward medical occurrence developing or worsening after administration of study medication regardless of the suspected cause, were recorded beginning with the first administration of study medication through the follow-up visit. All adverse events that subjects reported spontaneously or in response to an open question or that were revealed to the investigator by observation or clinical assessment were recorded.
Blood and urine samples for coagulation analyses, standard hematology and clinical chemistry tests, and urinalysis were obtained at the screening visit, before the first dose of study medication during each study period, the day after the atorvastatin dose in both study periods, and at the follow-up visit.
Statistics
Pharmacokinetic parameters included melagatran area under the plasma concentration versus time curve during a dosing interval (AUC
; calculated using the loglinear trapezoidal rule up to the 12-hour plasma concentration of melagatran), atorvastatin acid AUC (calculated using the log-linear trapezoidal rule to the last measurable plasma concentration of atorvastatin acid and extrapolated to infinity), HMG-CoA reductase inhibitor AUCt (AUC from time 0 to time t, calculated using the log-linear trapezoidal rule up to the 48-hour plasma concentration of HMG-CoA reductase inhibitors), maximum melagatran and atorvastatin acid plasma concentration (Cmax), time to Cmax (tmax) for melagatran and atorvastatin acid, and elimination half-life (t1/2) for melagatran and atorvastatin acid. Actual sampling times were used to estimate these pharmacokinetic parameters in a noncompartmental analysis performed using WinNonlin professional 1.5 software (Pharsight Corporation, Mountain View, CA). At time points before Cmax, plasma concentrations below LOQ were taken as 0 in the calculations. Furthermore, if more than 1 plasma concentration was below LOQ before Cmax, the last one before the first quantifiable plasma concentration was calculated as LOQ/2.
An analysis of variance (ANOVA) model was adopted with the main effects of subject, period, and treatment included (SAS, version 8.1). Logarithmically transformed values of pharmacokinetic parameters (AUC and Cmax for melagatran, AUC for atorvastatin acid, and AUCt for active HMG-CoA reductase inhibitors) were used in the analyses. Least squares estimates with 95% confidence intervals (CIs) for within treatment and 90% CIs for ratios between treatments are presented. For melagatran pharmacokinetic parameters, no interaction was to be concluded if the 90% CI for the geometric mean treatment ratios fell within the interval of 0.80 to 1.25 for AUC and within the interval of 0.70 to 1.43 for Cmax. For the AUC of atorvastatin acid and the AUCt of active HMG-CoA reductase inhibitors, no interaction was to be concluded if the 90% CI for the geometric mean treatment ratios fell within the interval of 0.70 to 1.43. A sample size of 12 subjects was estimated to provide 90% power to establish lack of a clinically significant change in melagatran AUC when ximelagatran was administered with atorvastatin versus without atorvastatin.
A linear regression model was used to relate the APTT ratio (i.e., prolongation of APTT relative to the predose value) as the dependent variable with the independent variables of atorvastatin intake, the square root of the melagatran plasma concentration, and the interaction between the 2 for the data from the atorvastatin + ximelagatran study period. These effects were estimated by using 95% CIs.
Adverse events and results of clinical laboratory tests were summarized descriptively, but no hypothesis testing was undertaken for these data.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
Melagatran
The mean plasma concentration versus time profile of melagatran after administration of oral ximelagatran alone (on day 3 of the atorvastatin + ximelagatran study period) and oral ximelagatran with atorvastatin (on day 4 of the atorvastatin + ximelagatran study period) is shown in Figure 1. The 90% CIs of the ratios for combined therapy relative to monotherapy for both melagatran AUC and melagatran Cmax fell within the limits considered to reflect no clinically significant interaction between atorvastatin and ximelagatran (Table I). The mean (SD) tmax of melagatran after oral ximelagatran and atorvastatin was 1.9 (0.5) hours, which is comparable to the tmax of 1.7 (0.3) hours when ximelagatran was administered alone. The mean (SD) t1/2 of melagatran after oral ximelagatran and atorvastatin was 3.3 (0.3) hours, which is similar to the t1/2 of 3.2 (0.3) hours when ximelagatran was administered alone.
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Atorvastatin Acid
The mean plasma concentration versus time profile of atorvastatin acid after administration of oral atorvastatin alone (during the atorvastatin study period) and atorvastatin with ximelagatran (on day 4 of the atorvastatin + ximelagatran study period) is shown in Figure 2. The 90% CIs of the ratio for combined therapy relative to monotherapy for atorvastatin acid AUC fell within the limits considered to reflect no clinically significant interaction between atorvastatin and ximelagatran (Table I). Although the number of samples collected early after dosing was limited (0.5, 1.0, and 1.5 hours after dosing), the mean (SD) tmax of atorvastatin acid after oral ximelagatran and atorvastatin was estimated to be 0.6 (0.2) hours, which appeared comparable to the tmax of 0.9 (0.7) hours when atorvastatin was administered alone. The mean (SD) t1/2 of atorvastatin acid after oral ximelagatran and atorvastatin was 8.4 (0.9) hours, which is similar to the t1/2 of 8.9 (1.5) hours when atorvastatin was administered alone.
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HMG-CoA Reductase Inhibitors
The mean plasma concentration versus time profile of active HMG-CoA reductase inhibitors after administration of atorvastatin alone (during the atorvastatin study period) and atorvastatin with ximelagatran (on day 4 of the atorvastatin + ximelagatran study period) is shown in Figure 3. The active HMG-CoA reductase inhibitor concentrations were estimated to be 16% lower after coadministration of ximelagatran and atorvastatin versus atorvastatin alone. However, the 90% CIs of the ratio for combined therapy relative to monotherapy for active HMG-CoA reductase inhibitors AUCt fell within the limits considered to reflect no clinically significant interaction between atorvastatin and ximelagatran (Table I).
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Pharmacodynamics
Melagatran prolonged the APTT in a concentration-dependent, nonlinear manner (Fig. 4). Neither the slope nor the intercept of the melagatran-APTT relationship differed as a function of whether atorvastatin was administered with ximelagatran (Table II).
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Tolerability
No serious adverse events were reported during the study, and no adverse event was specifically attributed to the combination of ximelagatran and atorvastatin. One participant withdrew from the study because of an adverse event (gastroenteritis with vomiting) during the second day of the atorvastatin + ximelagatran study period. No clinically significant laboratory abnormalities were observed.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The statins are predominantly metabolized by hepatic CYP450 enzymes (with the exception of pravastatin) and can interact with medications that are substrates, inducers, or inhibitors of CYP450 enzymes, particularly CYP3A/5, but also CYP2C9 and CYP2D6.14 Ximelagatran and its metabolites are not substrates of and do not inhibit any of the major CYP450 isozymes, and melagatran is primarily renally cleared, with approximately 80% of systemic melagatran excreted unchanged in urine.1,2,6 Therefore, interactions between melagatran and atorvastatin were not expected in this study. A single 40-mg dose of atorvastatin, which is in the upper end of the 10- to 80-mg clinical dose range, was used to produce therapeutically relevant concentrations of atorvastatin acid and active HMG-CoA reductase inhibitors.17,18 The lack of a clinically significant interaction during coadministration of ximelagatran and atorvastatin in the current study suggests that neither drug requires dose adjustment when used in combination. A similar lack of clinically significant interaction was observed between ximelagatran and the CYP450 substrates diclofenac (a CYP2C9 substrate), diazepam (a substrate for CYP2C19 and CYP3A4), nifedipine (a CYP3A4 substrate), and ethanol (a CYP2E1 substrate).6,21
This lack of interaction with atorvastatin differentiates ximelagatran from warfarin, which is metabolized via CYP450 isoenzymes. Coadministration of warfarin and atorvastatin or other statins can alter prothrombin time, increase the risk of bleeding, and necessitate dose adjustment of warfarin.14 Furthermore, a warfarin-statin interaction has been implicated in cases of myopathy as well as rhabdomyolysis, a rare but potentially fatal condition with increased incidence when statins are coadministered with CYP450-metabolized medications.14,22
Ximelagatran administered with or without atorvastatin was well tolerated in this study. No serious adverse events were reported, and no adverse event was specifically attributed to the combination of ximelagatran and atorvastatin. These results corroborate previous findings showing ximelagatran to be well tolerated in healthy volunteers and patients across a range of doses.1,7-12,16
In conclusion, the results of this study demonstrate that the pharmacokinetics, pharmacodynamics, and tolerability of melagatran after administration of the oral DTI ximelagatran were not affected by coadministration of a single dose of atorvastatin. Similarly, the pharmacokinetics and tolerability of atorvastatin were not affected by coadministration of ximelagatran. These data suggest that dose adjustment of ximelagatran and atorvastatin is not necessary for the concomitant use of both medications.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication March 14, 2004; Revised version accepted June 6, 2004.
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REFERENCES |
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1. 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]
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4. Wolzt M, Wollbratt M, Svensson M, Wahlander K, Grind M, Eriksson UG: Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects. Eur J Clin Pharmacol 2003;59: 537-543.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. 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.
6. 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]
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8. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, et al for the EXULT A Study Group: Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349: 1703-1712.
9. 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]
10. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Mouret P, Rosencher N, et al on behalf of the METHRO III Study Group: Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO III study. Thromb Haemost 2003;89: 288-296.[Web of Science][Medline] [Order article via Infotrieve]
11. 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 enoxaparin 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]
12. Olsson SB and 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]
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15. Jacobsen W, Kuhn B, Soldner A, Kirchner G, Sewing K-F, Kollman PA, et al: Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-coa reductase inhibitor atorvastatin. Drug Metab Disp 2000;28: 1369-1378.
16. Huisman MV, on behalf of the THRIVE Treatment Study Investigators: Efficacy and safety of the oral direct thrombin inhibitor ximelagatran for acute deep vein thrombosis with or without pulmonary embolism [abstract OC003]. Paper presented at the XIX Congress of the International Society on Thrombosis and Haemostasis, Birmingham, UK, July 12-18, 2003.
17. Lennernäs H: Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 2003;42: 1141-1160.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Cilla DD Jr, Whitfield LR, Gibson DM, Sedman AJ, Posvar EL: Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Clin Pharmacol Ther 1996;60: 687-695.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. 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.
20. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, et al: Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 1980;77: 3957-3961.
21. Sarich T, Johansson S, Schützer K-M, Wall U, Kessler E, Teng R, et al: The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor, are unaffected by a single dose of alcohol. J Clin Pharmacol 2004;44: 388-393.
22. Omar MA, Wilson JP: An FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother 2002;36: 288-295.[Abstract]
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Day 4 of atorvastatin + ximelagatran study period.
