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DRUG INTERACTIONS

The Effect of Etoricoxib on the Pharmacodynamics and Pharmacokinetics of Warfarin

Jules I. Schwartz, PharmD, MPH, Nancy G. B. Agrawal, PhD, Alan H. Hartford, PhD, Josee Cote, BS, Thomas L. Hunt, MD, PhD, Rene Verbesselt, PhD, Dane R. Eckols, BS and Keith M. Gottesdiener, MD

From Merck Research Laboratories, Rahway, New Jersey, and West Point, Pennsylvania (Dr Schwartz, Dr Agrawal, Dr Hartford, Ms Cote, Dr Gottesdiener); PPD-Inc, Austin, Texas (Dr Hunt, Mr Eckols); and Katholieke Universiteit Leuven, Department of Pharmacology, Campus Gasthuisberg, Leuven, Belgium (Dr Verbesselt).

Address for reprints: Address for correspondence: Jules I. Schwartz, PharmD, MPH, Clinical Pharmacology, Merck Research Laboratories, 126 East Lincoln Avenue, PO Box 2000, RY34-A552, Rahway, NJ 07065-0900; e-mail:jules_schwartz{at}merck.com.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The effects of etoricoxib on pharmacodynamic and pharmacokinetic parameters of warfarin were determined in healthy men and women. Subjects titrated with warfarin to an international normalized ratio for prothrombin time of 1.4 to 1.7 during a 28-day prestudy period were randomly assigned in crossover fashion to be coadministered etoricoxib (120 mg) or matching placebo over two 21-day continuous periods. On day 21, a 24-hour pharmacokinetic profile of both S(-) and R(+) warfarin, as well as international normalized ratio values, were determined. Etoricoxib increased the international normalized ratio by 13% (90% confidence interval: 8%, 19%; P ≤ .001). Etoricoxib had no effect on the pharmacokinetics of S(-) warfarin but led to a modest increase in the AUC24 h (~10%) of R(+) warfarin. This increase in the international normalized ratio is not likely to be clinically important in most patients; however, the international normalized ratio of patients coadministered oral anticoagulants and etoricoxib should be closely monitored, particularly during initiation of therapy.

Key Words: Drug interaction • warfarin • etoricoxib • steady state

The pharmacokinetics and/or pharmacodynamics of warfarin, an enantiomeric drug with a narrow therapeutic index, are known to be altered by many drug-drug interactions. A new therapeutic agent might either alter the pharmacokinetics of either or both enantiomers of warfarin and/or alter the hypoprothrombinemic response to warfarin to a clinically important extent.1 The result of such interactions may be either a reduction or increase in the anticoagulant effectiveness of warfarin with either loss of the desired anticoagulation or the increased risk of bleeding. Thus, an understanding of interactions of a new drug such as etoricoxib with warfarin will provide clinically useful efficacy and safety information.

Etoricoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), is highly effective for the management of the symptoms of osteoarthritis, rheumatoid arthritis, acute gouty arthritis, and acute pain.2-6

Etoricoxib has plasma protein binding of about 92% and is extensively metabolized, with only about 1% being excreted in urine as parent drug. CYP3A4 plays a major role in the metabolism of etoricoxib (~60%), and other CYP isoenzymes—CYP2C9, CYP2C19, CYP2D6—each account for only a minor fraction (≤10%) of etoricoxib's metabolic profile.7 The pharmacokinetic profile is linear across clinically relevant dosages from 30 to 120 mg/d and even to 240 mg/d. In vitro studies support that etoricoxib does not induce CYP isoenzymes, and it is a very weak inhibitor of CYP isoenzymes at concentrations well above those achieved at steady state with clinically relevant doses.8-10

Warfarin is very highly protein bound and is generally administered as a racemic mixture of R and S enantiomers, in which S(-) warfarin is reported to have 5 to 6 times greater anticoagulant potency than R(+) warfarin but a shorter plasma half-life (approximately 32 hours vs 43 hours, respectively).11 The primary metabolic pathway for S(-) warfarin is by the CYP2C9 isoenzyme; the metabolism of R(+) warfarin is more complex.12

Etoricoxib, unlike many nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), does not affect bleeding time or platelet aggregation.10 This property, along with less likelihood to damage the gastrointestinal mucosa because of the reduced affect on gastrointestinal (GI) tract prostaglandin synthesis, could be beneficial to patients treated with warfarin by reducing the propensity for bleeding complications.10,13-16

The present report examines the pharmacokinetics and pharmacodynamics of warfarin at steady state during coadministration with etoricoxib 120 mg daily. Because analgesic and anti-inflammatory agents are frequently used in the same population of patients who are candidates for warfarin therapy, a very narrow therapeutic agent, it was considered necessary to provide information on any possible interaction when etoricoxib and warfarin are coadministered. The dose of etoricoxib was chosen to maximize the effect, if any, on the pharmacokinetics and pharmacodynamics of warfarin. This dosage is within the range of dosages demonstrated to be linear with regards to AUC (30-240 mg/d).9 It is also the highest anticipated clinical dose of etoricoxib worldwide, although it is recommended only for short-term use in the management of acute pain. The effects of warfarin on the pharmacokinetics of etoricoxib were not examined because etoricoxib has a relatively wide therapeutic index relative to warfarin, and warfarin was assessed to possess an extremely low risk of adversely influencing the pharmacokinetics or pharmacodynamics of etoricoxib.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
The subject population eligible for this study were healthy, nonsmoking men and women, between the ages of 18 and 45 years, who were determined to be in good health by physical examination, vital signs, electrocardiography, and routine laboratory safety testing for hematology, chemistry, and urinalysis before, during, and after the trial. Subjects did not take any other drugs for 14 days before and throughout the trial. Subjects who had family members with or a personal history of any blood dyscrasias or who were assessed to have a large dietary intake of green leafy vegetables were excluded. All subjects were informed of the purpose, nature, and possible risks of the trials before giving written informed consent. Research Consultants' Review Committee, serving as the institutional review board for the clinical research site, PPD-Development Inc (Austin, Tex), approved the study (Protocol 037, February 2000 to June 2000). The occurrence of adverse events was assessed at each visit to the clinic throughout the trial.

Study Design
Eighteen subjects received warfarin alone during an open run-in period of up to 28 days. During the first 4 days of the run-in, all subjects took 5 mg warfarin. Starting on day 5, the investigator titrated warfarin until a steady-state international normalized ratio (INR) of 1.4 to 1.7 was achieved for 4 consecutive days. Subjects who achieved a stable INR by day 28 were randomized into the 2-period crossover phase of the study. The dose at which the INR was stable was used for the remainder of the study. Subjects whose INR did not stabilize discontinued from the study. Warfarin (Coumadin, DuPont Pharma, Wilmington, Del) tablets in strengths of 1, 2, and 2.5 mg were used.

During the 2-period, double-blind, randomized, crossover portion of the study, etoricoxib 120 mg or matching placebo was coadministered daily with the INR stabilizing dose of warfarin for each of the two 21-day treatment periods. There was no washout interval between the final dose of the first treatment period and the first dose of the second treatment period. During each 21-day etoricoxib/placebo period, the INR was determined every odd-numbered day and day 20. On day 21 of each period, citrated blood samples were collected for 24 hours for assessment of INR (predose and 4, 8, 12, 16, and 24 hours postdose), and heparinized blood samples were collected for assessment of the steady-state pharmacokinetics of S(-) and R(+) warfarin (predose and 1, 2, 4, 6, 8, 10, 12, 14, and 24 hours postdose). The study design is illustrated in Figure 1.


Figure 1
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  		Figure 1. Study design. INR, international normalized ratio.

 
Coagulation Analysis
The single lot of thromboplastin (Ortho brain thromboplastin) used to measure prothrombin time throughout the study was calibrated against the international standard by the manufacturer, Ortho Diagnostic Systems Inc (Raritan, NJ). Results are reported as the INR derived from [prothrombin time ratio sample/reference]ISI, where ISI was the International Sensitivity Index for the lot of thromboplastin used in this study.1

Analysis of Plasma S(-) and R(+) Warfarin
The S(-) and R(+) warfarin enantiomers were analyzed by a modification of the high-performance liquid chromatography (HPLC) method of Banfield and Rowland.17 Following purification with diethyl ether in an alkaline medium, warfarin was extracted after acidification with a mixture of hexane and diethyl ether. The diastereoisomeric esters of warfarin and the internal standard, p-chlorowarfarin, were formed with carbobenzyloxy-L-proline, separated on a normal-phase silica column and measured using UV detection at 310 nm. The assay was linear over the range of 0.04 to 4 µg/mL for each enantiomer. The lower limit of quantification was 0.04 µg/mL for each enantiomer, with an intraday coefficient of variation (CV%) less than 10%. Interday precision (CV%) for the S(-) and R(+) enantiomers was 15.0% and 5.8% at 0.10 µg/mL and 8.3% and 8.1% at 2.5 µg/mL, respectively. Etoricoxib did not interfere with the measurement of the warfarin enantiomers in plasma.

Pharmacokinetic and Pharmacodynamic Analysis
The area under the plasma concentration-time curve from time 0 to 24 hours (AUC24 h) at steady state was calculated for R(+) and S(-) warfarin using the linear trapezoidal method. The maximum plasma concentration (Cmax) and its time of occurrence (tmax) were determined by inspection of the concentration-time data.

The 24-hour average INR (Average24 h INR) on day 21 was taken to be the average value of the day 21 determinations—that is, the average of the INR values obtained at predose (time 0) and 4, 8, 12, 16, and 24 hours postdose (Figure 2).


Figure 2
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  		Figure 2. The geometric mean (± SE) prothrombin time international normalized ratio (INR) values on day 21 of chronic warfarin treatment plus etoricoxib 120 mg or placebo.

 
Statistical Analysis
The Average24 h INR and AUC24 h of the R(+) and S(-) enantiomers of warfarin were the primary endpoints of the study. The primary hypothesis of this study was that these parameters would not exhibit a meaningful difference (predefined as a 25% change) between etoricoxib and placebo treatments. The evaluation of changes in the Cmax of the R(+) and S(-) enantiomers of warfarin using the prespecified criterion was a secondary endpoint for the study.

The pharmacodynamic (Average24 h INR) and pharmacokinetic parameters (AUC24 h, Cmax, and tmax) were analyzed using an analysis of variance (ANOVA) model appropriate for a 2-period crossover design with terms for sequence, subject within sequence, period, and treatment. Average24 h INR, AUC24 h, and Cmax were log-transformed prior to analysis. The analysis of tmax was performed on the ranks of the tmax values. Least squares means (from the ANOVA model) are reported because the number of subjects was not balanced between the 2 sequences. The magnitude of the difference in the parameters was assessed by 90% confidence intervals for the geometric least squares mean ratio (warfarin + etoricoxib/warfarin + placebo) based on the ANOVA model using the t distribution. These 90% confidence intervals for the day 21 Average24 h INR as well as for AUC24 h for the R and S enantiomers of warfarin were compared against the prespecified clinically meaningful bounds of 0.80 and 1.25. To satisfy the coprimary hypotheses, these 3 confidence intervals must all have fallen within 0.80 and 1.25 for it to be concluded that the concomitant administration of etoricoxib (120 mg) had no clinically important effect on the pharmacodynamics and pharmacokinetics of warfarin. This confidence interval is that defined by the Food and Drug Administration (FDA) for drugs such as warfarin that have a narrow therapeutic index. The normality assumption for the pharmacodynamic and pharmacokinetic variables of the above ANOVA models was tested using the Shapiro-Wilk statistic and was generally satisfied.

Subjects who completed the study per protocol were included in the statistical analyses. The study planned to enroll up to 20 subjects so that at least 12 subjects would complete both periods of the study. Based on prior experience with the variability of warfarin in a similar population and study design, a sample size of 12 subjects would provide 98% power for meeting the 3 primary hypotheses if there was no effect of etoricoxib on warfarin pharmacokinetics or pharmacodynamics.18 All statistical tests were performed at the commonly accepted significance level of .050 (2-tailed).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Eighteen subjects entered the titration phase of the study, and 18 were randomized (12 men, 6 women) into the study. The mean (range) age, weight, and height of the subjects were 32 years (19-44 years), 75.8 kg (62-90 kg), and 174.3 cm (162.6-185.4 cm), respectively. Four (1 man and 3 women) of the 18 subjects discontinued from the trial. Two subjects discontinued because of clinical adverse experiences: 1 discontinued on day 18 of period 2 (warfarin + etoricoxib treatment) because of a rash (bullous erythema multiforme) on the arms; another discontinued on day 7 of period 2 (warfarin + placebo treatment) because of a fractured ankle. One subject discontinued on day 7 of period 2 (warfarin + etoricoxib treatment) because the hematocrit had been steadily decreasing from 37.8% on day 1 of the run-in period (baseline), through the placebo period, to 29.9% at discontinuance. Although the hemoccult blood test result was positive on the day of discontinuance, it had been negative previously and was negative the following day. Although bleeding cannot be ruled out, this subject potentially did not replace red blood cells sufficiently to compensate for repeated blood sampling. Another subject discontinued on day 9 of period 2 (warfarin + etoricoxib treatment) for an increased INR. Although changes in INR similar in magnitude were noted while this subject was on warfarin plus placebo (period 1), the criterion for discontinuation (2 successive days with the INR >2.3) was not formally attained during that first treatment period. None of these subjects had period 2 warfarin samples collected; therefore, only the remaining 14 subjects were included in the pharmacokinetic and pharmacodynamic analyses.

Seven subjects collectively reported 10 adverse experiences that were considered possibly drug related by the investigator: 1 during the run-in period, 3 during warfarin + placebo treatment (hypermenorrhea, fatigue, and rhinorrhea), and 6 during warfarin + etoricoxib treatment (rash [bullous erytherma multiforme], oral mucosal ulcer, fluid retention, 2 taste disturbances, and headache).


Figure 3
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  		Figure 3. The individual (n = 14) average international normalized ratio (INR) values over 24 hours measured on day 21 of concomitantly administered warfarin plus placebo and warfarin plus etoricoxib 120 mg. The plus signs indicate the geometric mean value among subjects during each treatment.

 
Warfarin Pharmacodynamics
On average, 20 days (range, 10-28 days) of warfarin treatment in the run-in period were required before 4 consecutive days during which the INR was stable (remaining between 1.4 and 1.7). At the completion of the run-in period, the mean INR was 1.56 (range, 1.42-1.66), and the mean warfarin dose was 4.1 mg (range, 2-7.5 mg).

The INR values were slightly but consistently greater during etoricoxib treatment as compared with those values during placebo treatment. Geometric mean INR measured over 24 hours on day 21 for etoricoxib and placebo treatments is shown in Figure 2. The Average24 h INR geometric mean ratio (GMR) (90% confidence interval [CI]) for etoricoxib versus placebo treatments on day 21 was 1.13 (1.08, 1.19) (Table I). This 90% CI result fell within the prespecified bounds (80%-125%); therefore, based on the prespecified hypothesis, it can be concluded that there was no clinically important interaction between etoricoxib and warfarin in this study. The individual mean changes in INR between warfarin + placebo and warfarin + etoricoxib are shown in Figure 3.


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  		Table I Comparison of Prothrombin Time INR Values in Healthy Subjects (n = 14) Receiving Multiple Doses of Etoricoxib/Placebo Following Administration of Warfarina

 

Mean trough INRs on days 19, 20, 21, and 22 were 1.49, 1.50, 1.48, and 1.49 for warfarin + etoricoxib and 1.38, 1.36, 1.33, and 1.32 for warfarin + placebo treatment period, respectively. The INR for warfarin + etoricoxib was generally stable over time; the INR for subjects on warfarin + placebo trended lower over time. This difference in the INR cannot be explained by any procedural issues within the study.

Warfarin Pharmacokinetics
Following the warfarin dose on day 21, the mean concentration-time profiles for S(-) and R(+) warfarin for both treatments are given in Figure 4A,B, respectively. There was no between-treatment difference for S(-) warfarin for AUC24 h during treatment with etoricoxib as compared to placebo treatment.


Figure 4
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  		Figure 4. The mean (A) S(-) warfarin and (B) R(+) warfarin plasma concentrations on day 21 of chronic warfarin treatment plus etoricoxib 120 mg or placebo. (Normalized to a 4-mg dose of warfarin.)

 
The R(+) warfarin plasma AUC24 h was slightly but significantly increased when coadministered with etoricoxib (Table II). The S(-) and R(+) warfarin AUC24 h GMRs (90% CI) for warfarin + placebo/warfarin + etoricoxib were 1.00 (0.97, 1.04) and 1.10 (1.06, 1.15), respectively. The primary hypotheses were met because the 90% CI fell within the prespecified bounds (80%-125%) for both enantiomers. The S(-) and R(+) warfarin Cmax GMRs (90% CI) for warfarin + placebo/warfarin + etoricoxib were 1.05 (1.00, 1.11) and 1.14 (1.07, 1.20), respectively. The secondary hypothesis was therefore met because the 90% CI for Cmax fell within the prespecified bounds (80%-125%) for both enantiomers. The median tmax values for S(-) warfarin and R(+) warfarin were 1.0 hour, except for R(+) warfarin during placebo treatment, in which the maximum was 2 hours (P > .200), as seen in Table II.


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  		Table II Pharmacokinetic Parameters of Warfarin Following Administration of Daily Doses of Warfarina and 120 mg Etoricoxib/Placebo to Healthy Volunteers (n = 14)

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Through the use of steady-state administration of warfarin to healthy volunteers, we examined the influence of concurrent etoricoxib treatment on warfarin pharmacokinetics and pharmacodynamics using the highest anticipated clinical dosage of etoricoxib, 120 mg/d. Single-dose interaction studies are useful as screening studies but are more difficult to translate into clinical recommendations. Steadystate studies, although significantly more difficult to conduct, have the advantage of being comparable to clinical regimens.

The study met all 3 primary hypotheses, using strict bioequivalence-type bounds appropriate for narrow therapeutic drugs. Despite this, there were small but statistically significant increases in the INR and R(+) warfarin plasma concentration that were consistently observed in both sequences of drug administration. An average steady-state INR increase of approximately 13% during chronic coadministration of warfarin with once-daily 120 mg etoricoxib may be considered modest and the clinical significance uncertain. However, for narrow therapeutic drugs, mean changes may not fully help to assess risks. For this study, the range of day 21 Average24 h INR ratios (warfarin + etoricoxib/warfarin + placebo) was 1.01 to 1.49 (Figure 3). This suggests that some patients may exhibit larger, more clinically relevant changes.

Etoricoxib did not significantly affect plasma S(-) warfarin pharmacokinetics, but it did induce approximately a 10% increase in plasma R(+) warfarin AUC24 h and Cmax. The magnitude of the increase in R(+) warfarin exposure with etoricoxib is not consistent with the 13% increase in the warfarin anticoagulant effect as R(+) warfarin is recognized to be 4- to 6-fold less potent as an anticoagulant than S(-) warfarin.11 This is especially of interest due to the findings of a similarly designed study where rofecoxib,* 25 mg daily, was associated with a 40% increase in R(+) warfarin concentration, no effect on S(-) warfarin concentration, but a smaller (8%) increase in INR.18 Although the change in R(+) warfarin does not explain the pharmacodynamics of etoricoxib + warfarin, the small ~10% increase in the R(+) warfarin AUC24 h may have made a small contribution. In like manner to the small increase in the R(+) warfarin AUC24 h, the increase in the peak concentration of the enantiomer may have made a small contribution to the increased INR during etoricoxib treatment. Two published studies demonstrate that small but variable changes in the pharmacokinetics of R(+) warfarin concentrations may be associated with changes in the anticoagulant effect but with unpredictable results.19-21

There is no evidence that etoricoxib has any effect on the enzymes responsible for the metabolism of S(-) or R(+) warfarin enantiomers.22 In the in vitro human liver microsomal enzyme experiments at etoricoxib concentrations up to 100 µM, no significant inhibition of CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 was observed (IC50 > 100 µM).22 The metabolic pathways suspected to be responsible for the biotransformation of R(+) warfarin include CYP3A4 (10-hydroxywarfarin), CYP1A2 (6- and 8-hydroxywarfarin), and CYP2C19 (8-hydroxywarfarin).23,24 The reduction of the acetonyl side chain of warfarin by NADPH-dependent carbonyl reductases in the endoplasmic reticulum and cytosol to yield diastereomeric alcohols is also reported to have a notable role.23,24 In contrast, S(-) warfarin is oxidized primarily to S-7-hydroxywarfarin and, to a limited amount, to S-6-hydroxywarfarin, predominately by CYP2C9. A minimal amount of S(-) warfarin is metabolized to S,S-warfarin-alcohol.23,25 Genotyping for CYP2C9 was not conducted on the subjects. Therefore, there is no clear mechanism by which etoricoxib affects R(+) warfarin pharmacokinetics.

The most commonly reported adverse experiences during this trial among the 18 subjects that were thought to be possibly associated with either treatment were headache, taste alteration, and an oral lesion. There were no instances of clinically significant bleeding, hypertension, or cardiovascular adverse events. The clinical adverse experiences were mild to moderate and transient, and all subjects experiencing adverse events recovered fully. The concomitant administration of etoricoxib and warfarin was well tolerated.

Two subjects were excluded from the final endpoint analyses, 1 with decreased hematocrit and a second due to increased INR. These exclusions were dictated by the protocol, and the events could not be associated with a specific treatment.

In conclusion, coadministration of etoricoxib, at a dosage of 120 mg once daily, with warfarin is associated with a small (~10%) increased plasma concentration of R(+) warfarin while leaving the pharmacokinetics of the more potent S(-) warfarin enantiomer unaffected. There is a small mean increase in the prothrombin INR of approximately 13%. For most clinical indications where anticoagulant therapy with warfarin is indicated, the warfarin dose is titrated, with the goal of attaining an INR value between 2.0 and 3.0; therefore, the small mean change observed is unlikely to be clinically important in most patients. However, given the variability that may be observed in the broader population of users, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly during the first week when therapy with etoricoxib is initiated or the dose of etoricoxib is changed.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
We thank Drs William V. Taggart and Bret J. Musser of Merck Research Laboratories for scholarly support in the preparation of the article.

Financial disclosure: This study was supported by a grant from Merck Research Laboratories. Jules I. Schwartz, Nancy G. B. Agrawal, Alan H. Hartford, Josee Cote, and Keith M. Gottesdiener are employees of Merck Research Laboratories and own stock and/or hold stock options in the company. Rene Verbesselt, Dane R. Eckols, and Thomas L. Hunt have received grant support for the conduct of various phases of the study.

DOI: 10.1177/0091270007299758

* On September 30, 2004, Merck & Co Inc announced the voluntary worldwide withdrawl of rofecoxib from the market. Back


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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