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CLINICAL TRIALS |
From the Clinical Research Center, New Orleans, Louisiana (Dr. Noveck) and Pfizer Global Pharmaceuticals, Ann Arbor, Michigan (Dr. Hubbard).
Address for reprints: Richard C. Hubbard, MD, Executive Director, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI 48104.
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ABSTRACT |
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 TOP ABSTRACT MATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Parecoxib sodium • COX-2-specific inhibitor • drug interaction • heparin • UFH • LMWH
Ketorolac (Toradol®) is the only nonspecific NSAID available for parenteral use in the United States, while in other countries, parenteral formulations of naproxen, diclofenac, and ketoprofen are available in addition to ketorolac. Although ketorolac is an effective analgesic,5,6 its use has been associated with upper gastrointestinal (UGI) ulceration and hemorrhage, platelet dysfunction (decreased platelet aggregation, increased bleeding time), surgical bleeding, and acute renal failure.7-11 Significant UGI safety issues have actually led to the withdrawal of ketorolac from several countries and a restriction on the duration of its use (to 5 days) in the United States.7-9,11
Furthermore, a hemostatic interaction has been reported between ketorolac and a commonly used low-molecular weight heparin (LMWH) anticoagulant.12 LMWHs are short chain derivatives of unfractionated heparin (UFH), with higher specificity for thrombin. They have a superior benefit-risk profile as they are associated with a reduced incidence of thrombocytopenia and, according to some studies, a lower risk of bleeding complications than UFH.13-18 Dalteparin sodium is an LMWH used in the prevention of venous thrombosis in a variety of surgical and medical settings19,20 and reportedly has no direct effect on bleeding time in healthy male volunteers.12 However, when dalteparin sodium was coadministered with ketorolac, the bleeding time was significantly prolonged in comparison with ketorolac administered alone.12 This hemostatic interaction further increases the risk of hemorrhagic complications when ketorolac is administered to surgical patients receiving LMWH for thromboprophylaxis.
The anti-inflammatory and analgesic efficacy of NSAIDs is the consequence of COX-2 inhibition.21 However, the platelet inhibitory and UGI adverse effects (especially ulceration and bleeding), which limit the clinical utility of these drugs, are due to nonspecific inhibition of COX-1 as well as COX-2 at full therapeutic dosages.21-24 In addition to being as effective as nonspecific NSAIDs, COX-2-specific inhibitors spare COX-1 at therapeutic concentrations and, therefore, have a superior UGI tolerability and safety profile and no clinically significant effect on platelet function.22,25,26
Parecoxib sodium (parecoxib) is an amide prodrug of the COX-2-specific inhibitor valdecoxib and the first injectable (intravenous [IV] and intramuscular [IM]) formulation of a COX-2-specific inhibitor to be developed.27-30 Following administration, parecoxib is rapidly and fully converted within 10 to 30 minutes to the active COX-2-specific moiety, valdecoxib, in vivo.27-30 Previous studies in healthy subjects showed that single doses of up to 200 mg IV parecoxib are well tolerated and follow predictable pharmacokinetics with a terminal half-life of approximately 10 hours for the active moiety, valdecoxib.28 Peak plasma levels of valdecoxib are achieved approximately 30 minutes after administration of parecoxib IV and within 1 hour after IM administration.28 In clinical trials, parecoxib has demonstrated analgesic efficacy in patients following laparotomy,31 orthopedic (knee) surgery,32 or oral surgery.33 Furthermore, in clinical trials, parecoxib and valdecoxib had no effect on platelet aggregation in healthy elderly and nonelderly volunteers34-36 and were associated with significantly lower incidences of gastroduodenal ulcers than standard doses of the nonspecific NSAIDs ketorolac, diclofenac, and naproxen.37-40 Parecoxib has been approved for the short-term treatment of postoperative pain in the European Union at an initial dose of 40 mg IV/IM.
There is potential for the commonly used anticoagulant UFH, administered to certain surgical patients for thromboprophylaxis and for the treatment of deep vein thrombosis or pulmonary embolism, to be used concurrently with parecoxib. As the nonspecific NSAID ketorolac has been reported to interact with LMWH,12 it is important to determine whether there is any significant hemostatic interaction between UFH and parecoxib that might lead to a raised risk of surgical hemorrhage. The objective of this study was therefore to evaluate the effects of parecoxib and UFH, both alone and when coadministered, on blood coagulation parameters.
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MATERIAL AND METHODS |
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Baseline physical examination and monitoring of vital signs, ECG, clinical laboratory tests, and blood coagulation parameters (aPTT, PT, and platelet counts) were performed in the 24-hour period before administering the first dose of study medication.
Subjects taking any known drug or substance that could affect hematological function or confound the study's results (e.g., aspirin or aspirin/salicylate combination products, ticlopidine, NSAIDs, dipyridamole, or protamine sulfate) within 14 days prior to receiving the first dose of study medication were excluded from participation. In addition, subjects were excluded if they had a history of bruising or bleeding disorders or a known hypersensitivity to COX-2-specific inhibitors, nonspecific NSAIDs, or heparin (UFH or LMWH); chronic disease; or any laboratory abnormality contraindicating study participation.
This study was conducted at the Clinical Research Center (147 S. Liberty St., New Orleans, LA 70112), in accordance with good clinical practice and the Decalration of Helsinki, and was approved by the site institutional review board.
Study Design
This open-label, single-center, two-treatment period pharmacodynamic study was designed to evaluate the hemostatic effects of coadministration of UFH and parecoxib in healthy adults. Participants were confined to the unit for the duration of the study. They were instructed to have a low-fat breakfast and lunch prior to reporting to the unit, and standard low-fat meals were served throughout the course of the study. Participants did not eat from midnight before days 1, 3, 5, and 6 until 4 hours after dose of study medication on those days.
On day 1 of treatment period I, subjects received an initial bolus injection of UFH (4000 U) immediately followed by a minimum 36-hour infusion, starting at a dose of 10 to 14 U/kg and adjusted to achieve a target aPTT of 1.5 to 3.0 times the baseline value.
Blood samples for aPTT and PT were collected within 30 minutes of, as well as 6, 8, 12, 16, 18, 20, 24, 36, and 42 hours after, the start of UFH administration. Samples for platelet counts were collected within 30 minutes prior to, as well as at 1, 3, and 24 hours after the start of, the UFH infusion. Samples for both platelet count and aPTT/PT were then collected 24 hours after completion of the UFH infusion.
After a 2-day washout, subjects with the most stable aPTT proceeded to treatment period II when they received parecoxib 40 mg bid IV for 6 days. Single doses of parecoxib 40 mg IV have been demonstrated in several clinical trials to provide optimum postoperative analgesia.31-33 On day 5, subjects received a 4000-U bolus injection of UFH followed by a 36-hour infusion at the same stable rate as determined during treatment period I. Samples for aPTT, PT, and platelet count were collected within 30 minutes before, as well as 1 and 3 hours after, the start of the parecoxib infusion on day 1 of treatment period II. On day 5, samples were collected prior to the morning dose of parecoxib (aPTT, PT, and platelet counts) and 6, 8, 12, 16, 18, 20, 24, 36, and 42 hours after the start of the UFH infusion (aPTT and PT only). Samples for both platelet count and aPTT/PT were also collected 12 to 24 hours after completion of the UFH infusion.
Subjects remained in the unit for observation until 24 hours after completion of the UFH infusion. Physical examinations, measurement of vital signs, and clinical laboratory tests were repeated 12 to 24 hours after the UFH infusion. Subjects without signs or symptoms of bleeding complication or events were then discharged from the unit once their aPTT, PT, and platelet counts were within the normal range.
Pharmacodynamic Assessments
Pharmacodynamic assessments comprised measurements of the blood coagulation parameters aPTT (clotting time after addition of negatively charged phospholipids and a particulate substance [e.g., kaolin] to plasma), PT (clotting time after addition of thromboplastin to plasma), and platelet count. The primary measure of hematological function used in this study was aPTT, as UFH is not known to influence PT.
Safety Assessments
Clinical safety was assessed by the incidence of treatment-emergent adverse events, results of physical examination, and changes in vital signs and clinical laboratory values from baseline.
Statistical Analyses
Sample Size
A minimum sample size of 16 subjects was considered sufficient to detect a mean difference of 15.0 seconds in aPTT between the coadministration of parecoxib and UFH (days 5-6 of treatment period II and posttreatment) and UFH alone (days 1-3 of treatment period I) with at least 90% power. The power was estimated assuming a standard deviation (SD) for aPTT of 3.84 seconds.
Pharmacodynamic Assessments
All subjects randomized to treatment were included in these analyses. Mean aPTT values for all randomized subjects were plotted against time (± SD), and differences between treatment groups were evaluated by analysis of variance (ANOVA) adjusted for subject and treatment. Mean PT and platelet count values (± SD) were also calculated.
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RESULTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacodynamics
Activated Partial Thromboplastin Time (aPTT)
There were no significant differences in mean aPTT values when UFH was administered alone (treatment period I) or concomitantly with parecoxib 40 mg bid (treatment period II) at each time point during study drug administration (Figure 1; p 
0.76) and for up to 24 hours posttreatment. Mean aPTT values (± standard error) 6 hours after commencing UFH infusion were approximately threefold higher than predose values whether parecoxib was coadministered (79.2 ± 7.6 sec vs. 26.0 ± 0.5 sec) or not (75.5 ± 9.4 sec vs. 26.7 ± 0.5 sec). Similarly, mean aPTT values were approximately 2- to 2.5-fold higher than predose values at 8 to 36 hours after the start of study drug infusion when UFH was administered alone (67.7 ± 9.3 to 50.9 ± 3.5 sec vs. 26.7 ± 0.5 sec) or in combination with parecoxib (61.2 ± 4.3 to 47.7 ± 2.0 sec vs. 26.0 ± 0.5 sec; Figure 1).
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By 12 to 24 hours after the end of the study drug infusion, mean aPTT was similar to predose values in subjects receiving UFH alone (treatment period I: 25.6 sec vs. 26.7 sec predose) or in combination with parecoxib 40 mg bid (treatment period II: 26.2 sec vs. 26.0 sec predose).
Prothrombin Time (PT)
In treatment period I, similar mean PT values (± SD) were observed in subjects prior to UFH infusion (12.3 ± 0.6 sec) and 24 hours after UFH infusion (11.9 ± 0.6 sec). In treatment period II, administration of parecoxib had no effect on the mean PT (12.3 ± 0.5 sec at 1 h or 12.5 ± 0.5 sec at 3 h postdose), which remained similar to predose levels (12.2 ± 0.5 sec). The mean PT 24 hours after coadministration of parecoxib with UFH (12.0 ± 0.7 sec) was also similar to predose levels (12.02 ± 0.6 sec). Furthermore, the mean PT values following coadministration of parecoxib with UFH in treatment period II were similar to those following UFH infusion in treatment period I.
Platelet Counts
Likewise, the mean platelet count (103/µL ± SD) was similar prior to (231.2 ± 53.0) and following (229.0 ± 59.4) UFH infusion in treatment period I. Mean platelet counts were also similar in subjects prior to (212.5 ± 68.2) and up to 3 hours after (218.3 ± 73.3) the start of parecoxib infusion in treatment period II. Coadministering parecoxib with UFH also had no effect on the platelet count, with similar means observed prior to (228.6 ± 64.1) and 12 to 24 hours after infusion (220.5 ± 45.9). The mean platelet count 12 to 24 hours after coadministration of parecoxib with UFH was also similar to the mean count 24 hours after UFH infusion in treatment period I.
Adverse Events
The overall incidence of adverse events in subjects was similar following treatment with UFH (10%, n = 2; treatment period I) or parecoxib 40 mg bid (11.1%, n =2; treatment period II) and when parecoxib 40 mg bid was coadministered with UFH (n = 3; treatment period II; Table II). Adverse events were mild to moderate in severity, and none was considered by the investigator to be treatment related. There were no bleeding-related adverse events and no withdrawals due to adverse events in this study.
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No clinically significant changes in physical examination findings, clinical laboratory tests, or vital signs were observed following treatment with UFH, parecoxib, or parecoxib with UFH.
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DISCUSSION |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, there was no evidence of a hemostatic interaction between a full analgesic dosage of parecoxib 40 mg bid and UFH. Parecoxib 40 mg bid IV coadministered with UFH IV had no effect on blood coagulation parameters (mean aPTT, PT, or platelet count) compared with UFH administration alone at any time point.
Bleeding is the major complication of anticoagulant treatment,41 and this risk may be further increased by concomitant administration of parenteral analgesics (e.g., for postoperative pain relief) that have an antiplatelet effect, such as nonspecific NSAIDs.10,23,24 Unlike nonspecific NSAIDs, which inhibit COX-1,21,22 parecoxib, the prodrug of the COX-2-specific inhibitor valdecoxib, is COX-1 sparing at therapeutic dosages (and, therefore, has no clinically significant antiplatelet effect) and is not associated with an increased risk of UGI or surgical bleeding.34,39,40 In contrast to reported findings with the parenteral nonspecific NSAID ketorolac, when concomitantly administered with LMWH,12 the present study demonstrated that parecoxib also has no hemostatic interaction with UFH. Therefore, unlike ketorolac, parecoxib would not be expected to exacerbate bleeding risk in patients recovering from invasive surgery, particularly those receiving thromboprophylactic UFH, which, according to some studies, is associated with a higher risk of bleeding complications than LMWH.13-18
In conclusion, a full analgesic dosage of parecoxib 40 mg bid IV can be coadministered with UFH without affecting coagulation parameters and, unlike nonspecific NSAIDs, can be appropriately administered to patients receiving thromboprophylaxis and recovering from invasive surgical procedures with a high risk of bleeding. Since it is also the only injectable prodrug of a COX-2-specific inhibitor available, parecoxib is an excellent parenteral nonnarcotic analgesic choice when maintenance of hemostasis is a concern in surgical patients.
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FOOTNOTES |
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This study was sponsored by Pfizer Global Research and Development.
Submitted for publication November 26, 2003; Revised version accepted February 8, 2004.
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REFERENCES |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONREFERENCES |
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