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DRUG INTERACTIONS |
From ALZA Corp, Mountain View, California (Dr Modi, Dr Kell, Ms Simon) and MDS Pharma Services, New Orleans, Louisiana (Dr Vargas).
Address for reprints: Nishit B. Modi, PhD, ALZA Corp, Department of Clinical Pharmacology, 1900 Charleston Road, PO Box 7210, Mountain View, CA 94039-7210.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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840 to 890 ng/mL and 680 to 730 ng/mL, respectively, and was similar in the absence and presence of pentosan polysulfate sodium. The half-life for R- and S-warfarin was 52 to 56 hours and 36 to 40 hours, respectively. Prothrombin time, partial thromboplastin time, and the international normalized ratio for warfarin + placebo and warfarin + pentosan polysulfate sodium were comparable. The AUCINR indicated no treatment effect (P = .772); however, there was a period effect. Analysis of variance for the treatments by period indicated no treatment effect (P > .1). Adverse events were mild and included headache, epistaxis, and rash. Most adverse events were unrelated to treatment and were seen during warfarin titration. Pentosan polysulfate sodium did not affect warfarin pharmacokinetics or pharmacodynamics.
Key Words: Pharmacokinetics • pharmacodynamics • warfarin • pentosan polysulfate sodium
Injectable PPS has been investigated for prophylactic treatment of thromboembolic disease complications.4-6 Several in vitro and in vivo studies with PPS have shown marked inhibition of factor Xa activity at microgram concentrations.7
Several studies have been conducted to evaluate the pharmacokinetics of PPS in humans. Fellström and colleagues8 measured the plasma and urine concentrations of pentosan polysulfate following intravenous (IV) and oral administration in a group of 8 healthy subjects using a radioassay. Following IV administration of 40 mg of PPS, plasma clearance was 49.9 ± 6.6 mL/min, of which renal clearance constituted 4.2 ± 1.2 mL/min. Only 8% of the IV dose was recovered in the urine, suggesting that there is extensive metabolism. Following daily oral dosing of 400 mg, steady-state trough plasma concentrations were low (20-50 ng/mL), and bioavailability was 0.5% to 1%.
Faaij et al9 studied the pharmacodynamic effect of PPS following IV (50 mg) and oral (1500 mg) administration. Intravenous PPS significantly increased activated partial thromboplastin time (aPTT) and antiactivated factor X (anti-Xa) activity compared with placebo. Oral PPS did not significantly influence any of the pharmacodynamic parameters. The lack of a pharmacodynamic effect following oral administration was attributed to the negligible oral availability of PPS.
Warfarin is an anticoagulant that acts by inhibiting vitamin K–dependent coagulation factors, which include factors II, VII, IX, and X, and the anticoagulant proteins C and S. Warfarin is a racemic mixture of R- and S-enantiomers. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans10 but generally has a more rapid clearance.11 Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, as well as pulmonary embolism; for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement; and to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
The dosage and administration of warfarin must be individualized for each patient according to the particular patient's international normalized ratio (INR) response to the drug. Multiple drugs have been reported to interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms, and some drugs may interact by several mechanisms.12,13
Patients who are on PPS may also receive concurrent warfarin therapy. The objective of the current study was to investigate the effect of PPS on the pharmacokinetics and pharmacodynamics of warfarin. A secondary objective was to assess the safety and tolerability of PPS coadministered with warfarin.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Subjects underwent a screening evaluation within 30 days of the first-dose administration. This consisted of a medical history, including current medical condition, physical examination, standard 12-lead electrocardiogram (ECG), vital signs, and urinalysis. Laboratory tests included urine pregnancy test for women of childbearing potential, complete blood cell count and blood chemistry, and a drug screen before the first dose during each treatment period. Eligible subjects were normotensive (sitting systolic blood pressure between 90 and 140 mmHg and diastolic blood pressure between 50 and 90 mmHg), nonsmoking healthy men and women (18-45 years) who weighed at least 50 kg and were within 20% of ideal weight for height and body build according to the Metropolitan Life Insurance tables. Subjects underwent a physical examination and review of medical history to ensure healthy status. Subjects who had a platelet count less than 150 x 109/L or had an abnormal PTT, who had or were planning to have surgery within 4 weeks or a dental procedure within 1 week of participation in the study, who had donated blood within 4 weeks or plasma within 7 days of the study, who had received an investigational agent within the previous month, who had a known history of venous thromboembolic disorder, or who had a known allergy or hypersensitivity to PPS, heparin, protamine sulfate, warfarin, or related compounds were excluded. Additional exclusion criteria included use of other medications, with the exception of birth control medications, sex hormone replacement, and acetaminophen (if medically necessary at a dose less than 2 g/d). In addition, women who were pregnant or breastfeeding were excluded.
Study Design
The study comprised an initial open-label warfarin titration/stabilization phase followed by a randomized, double-blind, 2-group, 2-way crossover interaction phase. During the double-blind phase, 1 group of 15 subjects received warfarin + placebo followed by warfarin + PPS. The alternative group of 15 subjects received treatments in the opposite order. Subjects arrived at the study center the evening before the start of the warfarin titration phase and were housed in the clinical unit throughout the warfarin titration and double-blind interaction phase. The dose of warfarin (Coumadin, Bristol-Myers Squibb, Princeton, NJ) was administered each day before measurement of the INR and was titrated and stabilized individually in each subject in the initial titration/stabilization phase. The dose was monitored periodically to maintain INR values between 1.4 and 1.8 for at least 3 consecutive days before the subject could enter the double-blind interaction phase. Subjects with 3 INR measurements greater than 2.5 were to be discontinued from the study. The range of INR between 1.4 and 1.8 was chosen to avoid any unnecessary risks of bleeding in the participants yet be able to study the effects of adding PPS to a stable dose of warfarin. To minimize the risk of hemorrhage, subjects stayed in the clinical unit for the duration of the study and were closely monitored. Once the INR was within the target range, each subject remained on that dosage of warfarin through both 7-day treatment periods (1 daily dose given in the morning). Subjects received either PPS or placebo in a crossover fashion during the interaction phase of the study in addition to their fixed dose of warfarin. Pentosan polysulfate sodium 100 mg (Elmiron, Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ) or matching placebo was given every 8 hours (nominally at 0800, 1600, and 0000) for 7 days in each of the 2 treatment periods in a crossover fashion. Each dose of PPS or placebo was given 1 hour before or 2 hours after a meal with approximately 8 oz (240 mL) of water. During the study, vitamin K intake was carefully controlled, and subjects received standardized meals that contained known quantities of vitamin K.
Blood samples (7 mL) were collected in heparin-containing Vacutainer tubes for up to 24 hours after warfarin dosing on the day before the subject entered the interaction phase and on the last day of each PPS and placebo interaction treatment. Samples were centrifuged at approximately 2500 rpm for 10 to 15 minutes immediately after collection. Plasma was removed and divided into 2 aliquots, placed separately into polypropylene vials, and stored frozen at –20°C.
Plasma samples for analysis of R- and S-warfarin during the stabilization and interaction phases were obtained at 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the warfarin dose.
Clinical Evaluations
Laboratory and clinical tests were conducted at screening and before discharge from the study. These tests included a physical examination, ECG, blood chemistry, complete blood count, and urinalysis. Vital signs (systolic and diastolic blood pressure, heart rate, and respiration) were measured at scheduled times during the study. Adverse events were obtained at scheduled assessments and when volunteered by the subjects.
Analysis of R- and S-Warfarin
Heparinized plasma samples were analyzed for R- and S-warfarin using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Internal standards (R,S)-warfarin-d6 in citric acid were added to each plasma sample. The samples were centrifuged and injected onto an LC/MS/MS system. The LC/MS/MS system consisted of Shimadzu pumps, a Series 200 autosampler (PerkinElmer Corp, Norwalk, CT), and a PE SCIEX API 365 mass spectrometer (PE SCIEX, Concord, Ontario). The samples were cleaned on a semipermeable surface (SPS)-Ph (2.1 x 100 mm, 5 µm) trapping column (Regis Technologies, Inc, Morton Grove, Ill), and the 2 enantiomers were then separated chromatographically with a mobile phase that consisted of 70:30 methanol/0.05% acetic acid in water, using a chiral column ((R, R) Whelk-O1 2.1 x 100 mm, 5 µm, Regis Technologies, Inc). Negative ions were monitored in the selected reaction monitoring (SRM) mode. R- and S-warfarin had a retention time of 1.2 and 0.67 minutes, respectively, and the transitions were monitored at m/z = 307.2 
m/z = 161.0. Calibration curves were linear in the range of 10 to 2500 ng/mL. The interday precision (percent coefficient of variation [%CV]) for spiked quality control samples was less than 10%, and the interday bias was less than ±4% for both R- and S-warfarin. Stability of the samples was established at –20°C, under ambient conditions and following 3 freeze-thaw cycles.
Pharmacodynamic Assessments
The degree of anticoagulation was determined as the prothrombin time (PT), PTT, and INR measured daily during each treatment period. Prothrombin time values were measured periodically during the titration phase and daily during the interaction phase. International normalized ratio values were derived from the prothrombin times ratio sample divided by the reference International Sensitivity Index (ISI).14,15 As in the warfarin titration/stabilization phase, subjects with 3 INR measurements greater than 2.5 were to be discontinued from the study.
The null hypothesis that PPS does not affect INR was tested by analysis of variance (ANOVA). The area under the INR-time curve (AUCINR) values for days 4 to 7 and days 11 to 14 in the interaction phase were estimated. The AUCINR values for the warfarin + PPS and warfarin + placebo treatments were compared in subjects who completed both treatments using an ANOVA. The ANOVA model included the factors sequence, subject within sequence, period, and treatment. All tests were 2-sided at an 
= 0.05 level of significance.16
Based on an assumption of a 20% intraindividual coefficient of variation in the INR values, a sample size of 20 subjects would provide a power of at least 80% to allow demonstration of whether the difference in the INR values exceeded 25% between the warfarin + placebo and warfarin + PPS treatments.
Pharmacokinetic Analyses
Maximum plasma concentration (Cmax) and time to maximum plasma concentration (tmax) of R- and S-warfarin were observed values. Area under the curve from 0 to 24 hours (AUC0–24) and t1/2 were obtained using standard methods.17 Logarithmically transformed area under the curve (AUC) and Cmax values of R- and S-warfarin for subjects who completed both treatment periods were analyzed using standard equivalence techniques. Analysis of variance methods with sequence, subject within sequence, period, and treatment as factors were used to calculate least squares means and 90% confidence intervals (CIs) for the treatment ratios (warfarin + PPS/warfarin alone) between treatments. No effect of PPS on warfarin pharmacokinetics was concluded if the 90% CI fell within 80% to 125% for AUC and Cmax.16 Statistical analyses were conducted using SAS with data for each isomer analyzed separately.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacokinetics
The plasma concentration-time profiles for R- and S-warfarin following warfarin alone, warfarin with placebo, and warfarin with PPS are shown in Figure 1. Summary pharmacokinetics for R- and S-warfarin are presented in Tables I and II, respectively. Mean plasma concentrations of R- and S-warfarin were comparable for the 3 treatments. Peak concentrations for R- and S-warfarin were noted approximately 0.7 to 1.3 hours after dosing. R-warfarin concentrations were higher than S-warfarin concentrations. The estimated AUC0-24 values for R- and S-warfarin were comparable for the 3 treatments. There was greater variability in the estimated t1/2 values because sampling was possible only for 24 hours; however, the mean t1/2 values were comparable for all 3 treatments. There was no statistically significant difference in the warfarin + placebo and warfarin + PPS groups, as determined by ANOVA comparing R- and S-warfarin pharmacokinetics of the 2 groups. All the 90% confidence intervals for the ratio of the means fell within 80% to 125% (Table III).
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The warfarin dose titration/stabilization resulted in mean INR values at the start of the interaction phase that were in the target range of 1.4 to 2.5. The INR values stayed in the target range during the study, and there was no difference in the pharmacodynamic effects between the warfarin + placebo and warfarin + PPS groups, as evidenced by the overlapping standard errors (Figure 2). There was no statistical difference in the AUC value for the INR between the 2 treatment groups (P >.1).
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Safety
There were no serious adverse events (AEs) or other significant AEs in this study. The frequency of AEs for each treatment and commonly reported side effects are presented in Table V. The most frequently reported AEs (seen in 2 or more subjects with at least 1 treatment) were headache, epistaxis, and rash, and most were considered unrelated to study medication. Adverse events were all mild except 1 report of moderate headache. Three subjects had mild elevations in liver enzymes, and 1 subject had a significant but transient increase of a liver transaminase. One subject discontinued the study during the warfarin titration phase because of severe tooth pain and abscess judged to be unrelated to study medication.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The pharmacokinetic profiles of R- and S-warfarin when warfarin was given alone and during the warfarin + placebo treatment were comparable to data in healthy subjects reported in the literature.19,20 There was no difference in any of the pharmacokinetic indices of R- or S-warfarin when given alone or in combination with PPS, and the 90% confidence interval fell within accepted boundaries of 80% to 125%, indicating the absence of clinically significant differences between the treatment groups. These concentration results indicate that PPS does not have a pharmacokinetic interaction with R- or S-warfarin.
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The dose of PPS selected in the present study was the currently approved dosing regimen. The dose of warfarin was individually titrated to provide a clinically relevant prolongation in the INR. Statistical analyses of the pharmacodynamic effects demonstrated an absence of an interaction between warfarin and PPS based on an overall ANOVA; however, a period effect was noted. To address this potential confounding effect, pharmacodynamic data for the 2 periods were evaluated using separate ANOVAs for each period. Although this reduced the power, no statistical difference was noted between the warfarin + PPS and warfarin + placebo treatments in either period, and the 90% confidence interval included 100% (Table III).
Warfarin induces the depletion of vitamin K–dependent coagulation factors. The anticoagulant effect of warfarin can be affected by concomitant administration of drugs or food.21 The anticoagulant effect of warfarin has considerable inter- and intraindividual variation in dose requirements.14 Multiple factors affect warfarin dose, including vitamin K intake.22,23 The INR is a standard measurement of oral anticoagulation.24 In the present study, the warfarin dose was titrated individually for each subject to ensure pharmacologically relevant anticoagulation before the subject entered the double-blind interaction phase.
Faaij and colleagues9 evaluated the oral availability of oral pentosan polysulfate sodium in 18 healthy male subjects with normal coagulation. In their study, subjects received 1500 mg of oral pentosan polysulfate sodium or 50 mg IV. Intravenous pentosan polysulfate significantly increased aPTT and anti-Xa activity compared with placebo. In contrast, oral PPS did not significantly influence any of the parameters compared with placebo. These investigators estimated that the oral bioavailability of PPS was too low to increase anticoagulant activity compared with IV injection. Interestingly, subcutaneous dosing of the synthetic pentasaccharide fondaparinux sodium has also been shown not to affect the pharmacokinetics and pharmacodynamics of oral warfarin.25
In vitro studies with sodium and calcium pentosan polysulfate indicate that concentrations of 5 mcg/mL in rat plasma are necessary to produce a statistically significant increase in aPTT (49.3 and 48.6 seconds for sodium and calcium pentosan polysulfate, respectively), whereas concentrations of 5 mcg/mL did not increase aPTT.26 In the study by Giedrojc! and colleagues,26 the authors also noted that in an ex vivo rat model of anticoagulant effects, sodium and calcium pentosan polysulfate concentrations of 1 mg/mL did not increase the aPTT 2 hours following subcutaneous injection, whereas concentrations of 10 mg/mL did.
Similarly, in an animal model of thrombosis, Giedrojc! and colleagues27 have shown that IV PPS and pentosan polysulfate calcium had antithrombotic activity that lasted 8 to 12 hours. In contrast, following oral administration, no antithrombotic activity was noted with the sodium salt, whereas the calcium salt demonstrated some activity.
Taken together, these results indicate that oral PPS does not have anticoagulant activity following oral administration, nor does it affect warfarin pharmacokinetics. Previous studies have shown that PPS has a low oral bioavailability and that anticoagulant activity is notable only following injection.9 Thus, it is not surprising that the pharmacodynamics of warfarin are not affected upon coadministration of oral warfarin and pentosan polysulfate sodium.
There was no difference in the AE profile between the warfarin + placebo and warfarin + PPS treatments. Adverse effects were generally mild or moderate in severity. There was only 1 AE characterized as severe (tooth abscess), which occurred during the warfarin titration/stabilization period in a single subject who was discontinued from the study. The study protocol required that subjects should be monitored regularly and should be withdrawn if there were 3 readings where the INR was >2.5 or if, in the opinion of the investigator, they would be at increased risk if they continued. As a consequence, 1 subject was discontinued during the warfarin + placebo treatment.
In conclusion, the present study found that therapeutic doses of PPS have no effect on the pharmacokinetics of R- and S-warfarin or on pharmacodynamic effect as measured by PT, PTT, and INR. Therefore, it seems unnecessary to make changes in the PPS or warfarin dosing regimen when the 2 agents are co-prescribed. We also noted that warfarin + PPS was well tolerated, and there was no difference in the AE profile between the warfarin + placebo and warfarin + PPS treatments. However, careful monitoring should be undertaken when initiating concomitant therapy, and intermittent monitoring during chronic therapy would be merited.
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REFERENCES |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
