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J Am Coll Cardiol, 2003; 41:557-564, doi:10.1016/S0735-1097(02)02868-1
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY: ANTITHROMBOTIC THERAPY

Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects

Troy C. Sarich, PhD*,*, Michael Wolzt, MD{dagger}, Ulf G. Eriksson, PhD{ddagger}, Christer Mattsson, PhD{ddagger}, Alice Schmidt, MD{dagger}, Susanne Elg, MSc{ddagger}, Magnus Andersson, MSc{ddagger}, Maria Wollbratt, MSc{ddagger}, Gunnar Fager, MD, PhD{ddagger} and David Gustafsson, MD, PhD{ddagger}

* AstraZeneca LP, Wilmington, Delaware, USA
{dagger} Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, University of Vienna, Vienna, Austria
{ddagger} AstraZeneca R&D Mölndal, Mölndal, Sweden

Manuscript received April 29, 2002; revised manuscript received October 4, 2002, accepted November 1, 2002.

* Reprint requests and correspondence: Dr. Troy C. Sarich, AstraZeneca LP, DCC2 W1-345, 1800 Concord Pike, Wilmington, Delaware 19850, USA.
troy.sarich{at}astrazeneca.com


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The effects of ximelagatran, an oral direct thrombin inhibitor (DTI), recombinant hirudin (r-hirudin) and enoxaparin on thrombin generation and platelet activation were studied in humans.

BACKGROUND: Recombinant hirudin (parenteral DTI) and enoxaparin (low molecular weight heparin) have been demonstrated to be clinically effective in acute coronary syndromes. Ximelagatran is currently under investigation for the prevention and treatment of thromboembolism. The shed blood model allows for the study of thrombin generation and platelet activation in humans in vivo.

METHODS: This was an open-label, parallel-group study involving 120 healthy male volunteers randomized to receive one of three oral doses of ximelagatran (15, 30 or 60 mg), r-hirudin (intravenous) or enoxaparin (subcutaneous) at doses demonstrated to be clinically effective in acute coronary syndromes, or to serve as a control. Thrombin generation (prothrombin fragment 1+2 [F1+2] and thrombin-antithrombin complex [TAT]) and platelet activation (ß-thromboglobulin [ß-TG]) biomarkers were studied using a shed blood model involving blood collection from skin incisions made using standardized bleeding time devices.

RESULTS: Oral ximelagatran, intravenous r-hirudin and subcutaneous enoxaparin rapidly and significantly (p < 0.05) decreased F1+2, TAT and ß-TG levels in shed blood, indicating inhibition of thrombin generation and platelet activation. Statistically significant concentration (melagatran, the active form of ximelagatran)-response relationships for F1+2 (p = 0.005), TAT (p = 0.005) and ß-TG (p < 0.001) levels, with IC50s of 0.376 (F1+2), 0.163 (TAT) and 0.115 (ß-TG) µmol/l, were detected. Melagatran showed dose-proportional pharmacokinetics with low variability. All drugs were well tolerated.

CONCLUSIONS: Oral administration of the DTI ximelagatran resulted in a rapid inhibition of both thrombin generation and platelet activation in a concentration-dependent manner using a human shed blood model. The inhibition of thrombin generation by 60 mg ximelagatran was comparable to that observed with doses of r-hirudin and enoxaparin demonstrated to be effective for the treatment of acute coronary syndromes.

Abbreviations and Acronyms
  aPTT
  activated partial thromboplastin time
  DTI
  direct thrombin inhibitor
  ESSENCE
  Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events
  F1+2
  prothrombin fragment 1+2
  IV
  intravenous
  LMWH
  low molecular weight heparin
  OASIS
  Organization to Assess Strategies for Ischemic Syndromes
  r-hirudin
  recombinant hirudin
  SC
  subcutaneous
  TAT
  thrombin-antithrombin complex
  ß-TG
  ß-thromboglobulin

Activation of the coagulation cascade by exposure of blood to tissue factor results in a burst of thrombin formation, which can rapidly lead to thrombus growth. Direct thrombin inhibitors (DTIs) block the activity of thrombin and also have been shown to decrease the generation of thrombin via inhibition of thrombin’s positive feedback activation of the coagulation cascade (1–3). In addition to its ability to rapidly catalyze the formation of fibrin, thrombin is a potent activator of platelets. Thrombin generation and platelet activation have previously been studied in humans using an in vivo shed blood model (1,4) that involves incision of the forearm skin with standardized bleeding time devices, resulting in exposure of blood to extravascular tissue factor and rapid activation of both the coagulation cascade and platelets (1,4).

Melagatran, the active form of the oral DTI ximelagatran, is a potent thrombin inhibitor with a Ki for thrombin of 2 nmol/l (5,6). After oral administration, ximelagatran is rapidly absorbed and converted to melagatran, with low interindividual variability in melagatran plasma concentrations (7). Ximelagatran is currently in clinical development for the prevention and treatment of thromboembolic disorders.

In an initial pilot study using the shed blood model, oral ximelagatran (60 mg) and dalteparin (120 IU/kg) were shown to inhibit thrombin generation (7). The present study was performed to expand upon these previous observations. The primary goal of the study was to investigate the pharmacodynamic effects (thrombin generation and platelet activation) of a range of doses of ximelagatran and parenteral doses of recombinant hirudin (r-hirudin) and enoxaparin used in the treatment of acute coronary syndromes. The secondary goals were to investigate the pharmacokinetics of melagatran and the tolerability of oral ximelagatran. Additional investigations into the concentration (melagatran)-response relationships for inhibition of thrombin generation and platelet activation following oral ximelagatran were carried out. The parenteral thrombin inhibitor r-hirudin and the low molecular weight heparin (LMWH) enoxaparin, at the doses used in this study, have been shown to be effective antithrombotic drugs in large clinical studies of acute coronary syndromes, including OASIS-2 (Organization to Assess Strategies for Ischemic Syndromes) (8) and ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) (9).

Prothrombin fragment 1+2 (F1+2) is produced during the final stage of thrombin formation, and thrombin-antithrombin complex (TAT) reflects in vivo thrombin generation processes. Prothrombin fragment 1+2 and TAT were, therefore, used as biomarkers of thrombin generation. Beta-thromboglobulin (ß-TG), an {alpha}-granule protein secreted upon activation of platelets, was used as a biomarker of platelet activation. Although these biomarkers cannot be used for determination of clinical efficacy, understanding the degree of inhibition of thrombin generation and platelet activation may be useful for selecting effective doses of antithrombotic drugs for study in patients with various thromboembolic conditions.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Subjects.   Healthy male subjects age 19 to 40 years, with a body mass index between 19 and 27 kg/m2 and from whom informed consent was obtained before enrollment, were included in this study. The subjects claimed not to have ingested any prescribed medications, "over-the-counter" drugs containing acetylsalicylic acid or nonsteroidal anti-inflammatory drugs from two weeks before study initiation until 48 h postdosing. This study was approved by the University of Vienna Ethics Committee and was performed in compliance with current good clinical practice guidelines and the Declaration of Helsinki.

Study design
This was a randomized, open-label study involving 120 subjects in six parallel groups (20 per group). Each group received one of the following six treatments: a single oral dose of ximelagatran (15, 30 or 60 mg); r-hirudin (Refludan, Hoechst Marion Roussel, Frankfurt, Germany) as a bolus intravenous (IV) injection (0.4 mg/kg), followed by an IV infusion (0.15 mg/kg/h for 2 h plus 0.075 mg/kg/h for 2 h); a single subcutaneous (SC) injection of enoxaparin (100 U/kg; Klexane, Rhône-Poulenc Rorer, Paris, France); or an orally administered control (water). The IV infusion of r-hirudin was given at high dose for only 2 h, followed by 2 h at a 50% lower infusion, in order to study the effects of various concentrations of r-hirudin over time.

All subjects were given a complete health examination (including physical examination, electrocardiogram and laboratory screen) within 14 days of the study day and 2 to 5 days after the study day. The subjects were randomized to a treatment group on the morning of the study day. The subjects were compensated according to accepted local practices and ethics committee approval.

Blood sampling
Shed blood
The shed blood sampling technique was performed as previously described (4,7) with minor modifications. A sphygmomanometer was placed on the upper arm and inflated to 45 mm Hg. A standardized disposable device (Simplate IIR, Organon Technika Corp., Durham, North Carolina) was used to make two incisions on the volar surface of the forearm (each 5-mm long and 1-mm deep) parallel to the antecubital crease. Shed blood was collected predosing and 2, 4 and 10 h postdosing directly from the edge of the incisions, starting immediately after incision and until 4 min after incision, using an automated plastic-tipped pipette. The blood was transferred at approximately 30-s intervals during collection into ice-cooled plastic tubes containing a stop solution consisting of sodium citrate 3.8%, EDTA 100 mmol/l, indomethacin 30 µmol/l, sodium heparin 1,500 U/ml, and aprotinin 1,000 U/ml, to prevent further thrombin generation or platelet activation in the sample tube. After blood collection was complete, the incisions were sealed using butterfly bandages. The shed blood samples were centrifuged at 10,000 x g for 5 min, and the plasma was separated and stored at –70°C until analysis.

Venous blood
Venous blood samples (4.5 ml) for the measurement of F1+2, TAT and ß-TG were collected predosing and 2, 4 and 10 h postdosing into stop solution (described previously) at a 1:9 volume ratio to blood. The samples were centrifuged at 3,000 x g for 10 min, and the plasma was separated and stored at –70°C until analysis.

Venous blood samples (4.5 ml) also were collected into citrated tubes predosing and 1, 2, 3, 4, 6, 8, 10 and 12 h postdosing. A small amount of the citrated whole blood was used to measure the activated partial thromboplastin time (aPTT) in the ximelagatran groups. The remaining whole blood was then centrifuged for 10 min at 1,500 x g, and the plasma separated and stored frozen (–70°C) until determination of either plasma levels of melagatran (ximelagatran groups) or anti-Xa activity (enoxaparin group).

Venous blood samples (3.5 ml) also were collected into tubes containing EDTA predosing and 2, 4, and 10 h postdosing for determination of platelet count for normalization of the ß-TG levels from IU/ml to IU/107 platelets.

Analyses
Prothrombin fragment 1+2, TAT and ß-TG levels were determined in both venous and shed blood samples using ELISA assays (Enzygnost F1+2 and Enzygnost TAT, Behring Diagnostics GmbH, Marburg, Germany; Asserachrom ß-TG, Diagnostica Stago, Asnieres-sur-Seine, France).

Activated partial thromboplastin time was measured using individual TAS-aPTT assay cards and an automated bedside (point of care) Thrombolytic Assessment System (TAS, Pharmanetics Inc., Raleigh, North Carolina) card reader as previously described (7). The TAS-aPTT device generally overestimates conventional laboratory aPTT values.

Citrated plasma samples collected from the subjects who received ximelagatran were analyzed for plasma levels of melagatran using a liquid chromatography-mass spectrometry method (10). Anti-Xa activity was determined using a Coatest Heparin kit (Chromogenix AB, Mölndal, Sweden). For both melagatran (µmol/l) and enoxaparin (anti-Xa activity) the maximum plasma concentration (Cmax) and time to maximum concentration (tmax) were estimated as the highest measured plasma concentration and the time at which that concentration was first measured, respectively. The half-life (t ) was estimated as 0.693/k, where k (elimination rate constant) was estimated by linear regression of the logarithm of plasma concentration versus time in the linear portion of the elimination phase. For melagatran, the area under the curve was calculated using the linear/log trapezoidal rule up to the last measurable plasma concentration and then extrapolated to infinity by addition of the last measurable plasma concentration divided by the elimination rate constant (Clast/k).

Statistics
Prothrombin fragment 1+2, TAT and ß-TG data were normalized by logarithmic transformation for the statistical analyses. Statistical analyses of levels of these biomarkers were performed using a repeated measures analysis of variance with treatment and time as factors in the model. Logarithmically transformed predose values were used as a covariate in the model. Comparisons of between-group effects at all measurement points were made and presented with 95% confidence intervals (CIs). Group differences were considered statistically significant at a level of p < 0.05 (two-tailed) when the 95% CIs of the ratios excluded 1.0. Post hoc comparisons between the different ximelagatran dose groups were performed using unpaired t tests. No corrections have been made for the multiple comparisons performed in this study. Point estimates and variability are expressed as mean ± standard deviation (SD) unless otherwise indicated.

For the analysis of the concentration-effect relationship (F1+2, TAT and ß-TG in shed blood), a repeated measures model adjusting for time since dose, predose levels and interaction between dose and time since dose was used. No interactions between time since dose and dose were detected. An inhibitory concentration-response model was also fit to the data using nonlinear regression and the following equation: , where B0 = baseline response, Cp = plasma concentration, and IC50 = concentration resulting in 50% maximal inhibition.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Effects on thrombin generation and platelet activation biomarkers.   Predose (0 h) shed blood F1+2, TAT and ß-TG levels were comparable between treatment groups (Figs. 1, 2, and 3, respectively). Statistically significant decreases (p < 0.05) in shed blood F1+2, TAT and/or ß-TG levels were observed in all treatment groups at 2, 4 and/or 10 h postdosing compared with the control group (Figs. 1 to 3).



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  		Figure 1 Geometric mean levels (95% confidence intervals) of prothrombin fragment 1+2 (F1+2) in shed blood from healthy male subjects by treatment group predose and 2, 4 and 10 h postdosing. Statistical comparisons between the treatment and control groups have been made at each time point. *p value < 0.05 vs. control.

 


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  		Figure 2 Geometric mean levels (95% confidence intervals) of thrombin-antithrombin complex (TAT) in shed blood from healthy male subjects by treatment group predose and 2, 4 and 10 h postdosing. Statistical comparisons between the treatment and control groups have been made at each time point. *p value < 0.05 vs. control.

 


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  		Figure 3 Geometric mean levels (95% confidence intervals) of ß-thromboglobulin (ß-TG) in shed blood from healthy male subjects by treatment group predose and 2, 4 and 10 h postdosing. Statistical comparisons between the treatment and control groups have been made at each time point. *p value < 0.05 vs. control.

 
Because the effects of both enoxaparin and r-hirudin on shed blood F1+2, TAT and ß-TG levels appeared most comparable to the effects following 60 mg ximelagatran, additional comparisons of these groups with the 60 mg ximelagatran group were made. No important differences on the shed blood biomarkers were found between the 60 mg ximelagatran and r-hirudin groups (Table 1). The reduction in shed blood TAT with 60 mg ximelagatran was significantly greater than with enoxaparin (p < 0.05) at 2, 4 and 10 h postdosing, but the reduction in F1+2 was significantly less than with enoxaparin (p < 0.05) at 4 h postdosing (Table 1). The reduction in shed blood ß-TG levels following 60 mg ximelagatran was significantly greater than those following enoxaparin (p < 0.05) at 2, 4 and 10 h postdosing (Table 1).


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  		Table 1 Ratios (95% CIs) of Shed Blood F1+2, TAT and ß-TG Levels Between Comparator (r-hirudin and Enoxaparin) Treatment Groups and 60 mg Ximelagatran Group

 
Post hoc analyses found the ximelagatran-induced decreases in shed blood F1+2, TAT and ß-TG levels to be concentration (melagatran)-dependent. Statistically significant relationships between concentration of melagatran and the decrease in F1+2 (p = 0.005), TAT (p = 0.005) and ß-TG (p < 0.001) levels relative to predose were detected. A nonlinear fit of the model parameters to the data is shown in Figure 4, and the model parameters are shown in Table 2.



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  		Figure 4 Geometric means (95% confidence intervals) of the ratios of the prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and ß-thromboglobulin (ß-TG) levels in shed blood collected after administration of 15-, 30- and 60-mg oral doses of ximelagatran compared with control (predose and 2, 4 and 10 h postdose) (n = 12 per marker; three doses x four time points). Predose ratios for each dose, when plasma concentrations are zero, are plotted at 0.001 µmol/l on the logarithmic scale.

 

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  		Table 2 Model Parameters Generated by Fitting an Inhibitory Concentration-Response Model by Nonlinear Regression

 
Mean venous plasma F1+2, TAT and ß-TG levels did not change over time, nor did they differ between groups, with only a few exceptions (Table 3). There were no changes in mean platelet count over time (predose to 10 h) in any group (data not shown).


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  		Table 3 Ratios (95% CIs) of Venous F1+2, TAT and ß-TG Plasma Levels Between Treatment Groups and the Control Group (Treatment/Control)

 
Activated partial thromboplastin time
Oral administration of ximelagatran resulted in a dose-dependent prolongation of aPTT (Fig. 5). Regression analysis of transformed data (aPTT-ratio vs. the square root of the plasma concentration of melagatran) produced a correlation coefficient (R2) of 0.81.



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  		Figure 5 Mean (SD) venous blood activated partial thromboplastin time (aPTT; using TAS-aPTT method) values vs. time since oral ximelagatran (15, 30 and 60 mg).

 
Pharmacokinetics
Dose-proportional increases in the Cmax of melagatran (0.12 ± 0.02, 0.25 ± 0.06 and 0.46 ± 0.10 µmol/l) at a consistent tmax (1.9 ± 0.4, 2.0 ± 0.2 and 1.9 ± 0.4 h) were observed following oral administration of the 15-, 30- and 60-mg ximelagatran doses, respectively. The area under the melagatran plasma concentration versus time curves (AUC) for the 15-, 30- and 60-mg dose groups also increased proportionally with dose (0.6 ± 0.1, 1.3 ± 0.3 and 2.5 ± 0.5 µmol · h/l, respectively). The t of melagatran in the ximelagatran 15-, 30- and 60-mg dose groups was independent of dose (2.6 ± 0.3, 2.8 ± 0.3 and 2.8 ± 0.3 h, respectively). The variability (coefficient of variation, CV%) in Cmax, AUC, tmax and t (range of means across doses) was 17% to 24%, 17% to 23%, 10% to 21% and 11% to 12%, respectively. The mean plasma concentrations versus time profiles of melagatran after oral administration of 15, 30 and 60 mg ximelagatran are shown in Figure 6.



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  		Figure 6 Mean (SD) melagatran plasma concentration (µmol/l) vs. time since oral administration of 15-, 30- and 60-mg doses of ximelagatran (n = 20 per group).

 
Administration of enoxaparin (100 U/kg SC) resulted in an anti-Xa activity Cmax of 0.84 ± 0.06 U/ml, a tmax of 3.3 ± 0.7 h and a t of 5.0 ± 1.1 h. The variability (CV%) of Cmax, tmax and t was 7%, 21% and 20%, respectively. Anti-Xa activity in the enoxaparin group predosing and 2, 4, and 10 h postdosing was 0.02 ± 0.02 U/ml, 0.79 ± 0.08 U/ml, 0.83 ± 0.06 U/ml and 0.42 ± 0.07 U/ml, respectively.

Tolerability
Ximelagatran, r-hirudin and enoxaparin were all well tolerated with no laboratory abnormalities, bleeding complications or serious adverse events reported in any of the subjects during the study day.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Effects on thrombin generation and platelet activation.   Our results show that ximelagatran, r-hirudin and enoxaparin inhibit thrombin generation and platelet activation using the shed blood model. The inhibition by ximelagatran was concentration (melagatran)-dependent. In the shed blood model, thrombin generation and platelet activation are initiated immediately after incision of the skin when blood comes into contact with extravascular tissue factor (4,11,12). Inhibition of thrombin generation by DTIs previously has been reported to occur indirectly via inhibition of the positive feedback activation of the coagulation cascade by thrombin (1–3). The exact mechanism may depend largely on inhibition of factor Va formation, because direct inhibition of thrombin decreases conversion of factor V to Va, and factor Va appears to be a rate-limiting step in the formation of the prothrombinase complex and thus in thrombin generation (13).

The doses of r-hirudin and enoxaparin used in this study have been demonstrated to be effective for the treatment of acute coronary syndromes (8,9). However, in order to investigate the effects of r-hirudin at lower blood concentrations in the present study, the infusion rate was halved after 2 h and then stopped after 4 h. Because both r-hirudin and enoxaparin have been shown to be effective in large clinical studies of acute coronary syndromes, understanding their effects on the shed blood biomarkers and comparing these effects to a range of doses of ximelagatran was considered valuable. Ximelagatran 60 mg appeared to most closely match the inhibition of thrombin generation by r-hirudin and enoxaparin. However, the effect of 60 mg ximelagatran on inhibition of platelet activation was similar to that of r-hirudin, but it was significantly better than that of enoxaparin. Overall, these data suggest that doses of ximelagatran up to 60 mg may be required for clinical efficacy in acute coronary syndromes. These results also suggest that, in this model, direct thrombin inhibition by melagatran is superior for the inhibition of platelet activation to the indirect antithrombin-mediated inhibition of thrombin by enoxaparin. Potential mechanistic explanations for the superior effects on platelets observed with ximelagatran include reduced occupancy of platelet thrombin receptors by catalytically active thrombin and/or smaller molecular size, allowing for easier access to clot-bound thrombin (14).

It is interesting to note that 6 h after the stop of the IV infusion of r-hirudin, which has a reported t of ~1.3 h (15), effects on thrombin generation and platelet activation similar to those with 60 mg ximelagatran (t ~3 h) and enoxaparin (t 5 h) were observed. However, a longer terminal t of ~3 h for r-hirudin has been reported, which may explain these observations (16).

Pharmacodynamic and pharmacokinetic effects
Our data suggest that the inhibitory effects of ximelagatran and the LMWHs enoxaparin and dalteparin (7) on thrombin generation are very similar. Excluding the route of administration, ximelagatran and the LMWHs are also similar from a pharmacokinetic point of view. The rapid peak in melagatran plasma concentration following oral administration of ximelagatran is similar to that observed with the LMWHs (tmax 2 to 3 h). This rapid onset of action suggests that treatment of thromboembolism with ximelagatran can be initiated rapidly without concomitant administration of heparin or LMWH, in contrast to the current recommended practice with the oral vitamin K antagonists, such as warfarin (17). This approach is supported by findings of a dose-guiding study with ximelagatran in patients with deep vein thrombosis (18). The elimination half-lives of melagatran and LMWHs are comparable, ranging from 3 to 5 h (7,19–21). In addition, the variability in the pharmacokinetic parameters of melagatran following oral administration of ximelagatran is relatively low (<25%) and comparable to that of parenterally administered enoxaparin. Thus, if the shed blood technique is predictive of an antithrombotic effect in patients, ximelagatran is likely to be effective where LMWHs are effective.

Conclusions
Oral administration of the DTI ximelagatran resulted in a rapid inhibition of both thrombin generation and platelet activation in a concentration-dependent manner using a human shed blood model. The inhibition of thrombin generation by 60 mg ximelagatran was comparable to that observed with doses of r-hirudin and enoxaparin demonstrated to be effective for the treatment of acute coronary syndromes. The inhibition of platelet activation by 60 mg ximelagatran was comparable to that observed with r-hirudin and superior to that observed with enoxaparin. Numerous clinical trials with ximelagatran, including studies in acute coronary syndrome patients, are currently ongoing.


   Acknowledgments
 
The authors thank Ms. Linda Johansson, Ms. Carola Fuchs, Dr. Stig-Lennart Boström and Dr. Aideen Young for their valuable contributions to this manuscript.


   Footnotes
 
This study was sponsored by AstraZeneca. All authors are employees of AstraZeneca, with the exceptions of Drs. Wolzt and Schmidt, who were paid co-investigators.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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