Troy C. Sarich

Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers

The objectives were to investigate whether activation of the extrinsic coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. In a single-blind, randomized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (i.v.) infusion to achieve steady-state melagatran plasma concentrations of approximately 0.5 micromol/L, with a single i.v. bolus of rFVIIa (90 microg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-anti-thrombin complex, fibrinopeptide A, beta-thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin potential, thrombus precursor protein (TpP), and plasmin-alpha(2)-antiplasmin complex concentrations were determined in venous blood. Shed blood volume was measured. Melagatran reduced markers of thrombin generation and platelet activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT, and TpP in venous blood. All other parameters were unaffected. In conclusion, rFVIIa did not reverse the anticoagulant effects of high constant concentrations of melagatran. However, the potential value of higher, continuous or repeated doses of rFVIIa or its use with lower melagatran concentrations has not been excluded.

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

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 (beta-thromboglobulin [beta-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 beta-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 beta-TG (p < 0.001) levels, with IC(50)s of 0.376 (F1+2), 0.163 (TAT) and 0.115 (beta-TG) micromol/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.

No Influence of Obesity on the Pharmacokinetics and Pharmacodynamics of Melagatran, the Active Form of the Oral Direct Thrombin Inhibitor Ximelagatran

BackgroundXimelagatran, an oral direct thrombin inhibitor, is currently in clinical development for the prevention and treatment of thromboembolic disease. Following oral administration, ximelagatran undergoes rapid bioconversion to its active form, melagatran, via two minor intermediates. Obesity, defined as body mass index (BMI) >30 kg/m2, is a recognised risk factor for thrombosis. There is potential for differences in the pharmacokinetics and pharmacodynamics of drugs administered to obese versus non-obese patients, and some drugs may require alternative administration strategies in obese patients.ObjectiveTo investigate the effect of obesity on the pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran.Design and participantsThis was an open-label, single-dose, group-matched study in which obese subjects (BMI 32–39 kg/m2; six male and six female; age 21–40 years) were matched by sex and age (±2 years) with non-obese subjects (BMI 21–26 kg/m2; six male and six female; aged 21–39 years). Each subject received a single oral dose of ximelagatran 24mg. Blood samples for determination of plasma concentrations of melagatran and activated partial thromboplastin times (APTT; a marker of melagatran pharmacodynamics) were collected up to 12 hours after administration.ResultsThere were no statistically significant differences in the pharmacokinetic properties of melagatran between obese and non-obese subjects. Values of area under the melagatran plasma concentration-time curve, maximum plasma concentration (Cmax), time at which Cmax occurred and terminal elimination half-life were approximately 1 µmol · h/L, 0.2 µmol/L, 2 hours and 3 hours in both obese and non-obese subjects, respectively. In addition, there was no statistically significant difference between the obese and non-obese subjects in the amount of ximelagatran, melagatran or the minor intermediates ethyl-melagatran and melagatran hydroxyamidine excreted in urine. When relating the prolongation of APTT ratio to the square root of plasma concentration of melagatran and obesity status (no/yes), no statistically significant interaction between plasma concentration and obesity status was observed. Ximelagatran was well tolerated in both obese and non-obese subjects, and no bleeding events or serious adverse events occurred.ConclusionNo differences in the pharmacokinetics or pharmacodynamics of melagatran were detected between obese and non-obese subjects after oral administration of ximelagatran, suggesting that dose adjustment of ximelagatran in obesity (BMI up to 39 kg/m2) is not necessary.

INFLUENCE OF ERYTHROMYCIN ON THE PHARMACOKINETICS OF XIMELAGATRAN MAY INVOLVE INHIBITION OF P-GLYCOPROTEIN-MEDIATED EXCRETION

A pharmacokinetic interaction between erythromycin and ximelagatran, an oral direct thrombin inhibitor, was demonstrated in this study in healthy volunteers. To investigate possible interaction mechanisms, the effects of erythromycin on active transport mediated by P-glycoprotein (P-gp) in vitro in Caco-2 and P-gp-over-expressing Madin-Darby canine kidney-human multidrug resistance-1 cell preparations and on biliary excretion of melagatran in rats were studied. In healthy volunteers (seven males and nine females; mean age 24 years) receiving a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg t.i.d. on days 2 to 5, and a single dose of ximelagatran 36 mg plus erythromycin 500 mg on day 6, the least-squares mean estimates (90% confidence intervals) for the ratio of ximelagatran with erythromycin to ximelagatran given alone were 1.82 (1.64–2.01) for the area under the concentration-time curve and 1.74 (1.52–2.00) for the maximum plasma concentration of melagatran, the active form of ximelagatran. Neither the slope nor the intercept of the melagatran plasma concentration-effect relationship for activated partial thromboplastin time statistically significantly differed as a function of whether or not erythromycin was administered with ximelagatran. Ximelagatran was well tolerated regardless of whether it was administered with erythromycin. Erythromycin inhibited P-gp-mediated transport of both ximelagatran and melagatran in vitro and decreased the biliary excretion of melagatran in the rat. These results indicate that the mechanism of the pharmacokinetic interaction between oral ximelagatran and erythromycin may involve inhibition of transport proteins, possibly P-gp, resulting in decreased melagatran biliary excretion and increased bioavailability of melagatran.

The Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor, Are Unaffected by a Single Dose of Alcohol

Ximelagatran—a direct thrombin inhibitor rapidly converted to its active form, melagatran, after oral administration—is being developed for the prevention and treatment of thromboembolic disease. The pharmacokinetics, pharmacodynamics, and tolerability/safety of ximelagatran following a single 36‐mg oral dose of ximelagatran ± a single oral dose of alcohol (0.5 and 0.6 g ethanol/kg to women and men, respectively) were assessed in a randomized, open‐label, two‐way crossover study (n = 26). The 90% confidence intervals (CIs) and least squares mean estimates for the ratio of ximelagatran plus alcohol to ximelagatran alone for melagatran AUC (1.04 [90% CI = 1.00–1.08]) and Cmax (1.08 [90% CI = 1.03–1.14]) fell within the bounds demonstrating no interaction. Alcohol did not alter the melagatran‐induced prolongation of the activated partial thromboplastin time or the good tolerability/safety profile of ximelagatran. In conclusion, the pharmacokinetics, pharmacodynamics, and tolerability/safety of oral ximelagatran were not affected by alcohol.

Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis

Summary.  Background: Thrombin plays a major role in thrombus formation through activation of platelets and conversion of fibrinogen to fibrin. Objectives: To investigate the antithrombotic effects of the oral direct thrombin inhibitor (DTI) ximelagatran and the parenteral DTI r‐hirudin in humans. Subjects and methods: Healthy male volunteers randomized into four parallel groups each with 15 subjects received either ximelagatran (20, 40 or 80 mg orally) or r‐hirudin (0.4 mg kg−1 intravenous bolus + infusion of 0.15 mg kg−1 h−1 for 2 h and 0.075 mg kg−1 h−1 for 3 h). Antithrombotic effects were assessed as changes in total thrombus area (TTA) and total fibrin area (TFA) from baseline, using the Badimon perfusion chamber model at baseline and 2 h and 5 h after drug administration. Results: Two hours postdosing, ximelagatran showed antithrombotic effects at both high and low shear rates (TTA% of mean baseline value ± SEM was 76 ± 13% and 71 ± 17% [both P < 0.05] for the 20‐mg dose, 85 ± 11% [P > 0.05] and 62 ± 15% [P < 0.05] for the 40‐mg dose and 60 ± 11% and 26 ± 7% [both P < 0.05] for the 80‐mg dose, respectively). r‐Hirudin also showed a significant antithrombotic effect at high and low shear rates (76 ± 11% [P = 0.05] and 57 ± 17% [P < 0.05] of baseline values, 2 h postdosing, respectively). The inhibitory effects on TFA were similar to those on TTA. Conclusions: The oral DTI ximelagatran shows antithrombotic effects under both high and low shear conditions. The antithrombotic effect of 40–80 mg ximelagatran appeared comparable to that of parenterally administered r‐hirudin, which has been previously demonstrated to be clinically effective in acute coronary syndromes.

No Pharmacokinetic or Pharmacodynamic Interaction Between Digoxin and the Oral Direct Thrombin Inhibitor Ximelagatran in Healthy Volunteers

The interaction potential of digoxin and ximelagatran, an oral direct thrombin inhibitor being developed for the prevention and treatment of thromboembolic disease, was investigated in this randomized, double‐blind, 2‐way crossover study. On 2 separate occasions, healthy female and male volunteers (n = 16) received ximelagatran 36 mg or placebo twice daily for 8 days separated by a 4‐ to 14‐day washout period. All volunteers received a single oral dose of digoxin 0.5 mg on day 4 of both study periods. No interaction between ximelagatran and digoxin was detected in the pharmacokinetic parameters (using a 90% confidence interval [CI] of least squares mean estimate ratios), including melagatran (the active form of ximelagatran) AUCτ and Cmax and digoxin AUCt and Cmax. Digoxin did not alter the melagatran‐induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between digoxin and ximelagatran was observed in this study.

No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran.

In this randomized, 2‐way crossover study, the potential for interaction was investigated between atorvastatin and ximelagatran, an oral direct thrombin inhibitor. Healthy female and male volunteers (n = 16) received atorvastatin 40 mg as a single oral dose and, in a separate study period, ximelagatran 36 mg twice daily for 5 days plus a 40‐mg oral dose of atorvastatin on the morning of day 4. In the 15 subjects completing the study, no pharmacokinetic interaction was detected between atorvastatin and ximelagatran for all parameters investigated, including melagatran (the active form of ximelagatran) area under the plasma concentration versus time curve (AUC) and maximum plasma concentration, atorvastatin acid AUC, and AUC of active 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A (HMG‐CoA) reductase inhibitors. Atorvastatin did not alter the melagatran‐induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between atorvastatin and ximelagatran was observed in this study.

A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor

The oral direct thrombin inhibitor ximelagatran is being developed for the prevention and treatment of thromboembolism. This single‐blind, randomized, placebo‐controlled, parallel‐group study investigated the potential for the interaction of ximelagatran (36 mg every 12 hours for 8 days, measured as its active form melagatran in blood) and amiodarone (single 600‐mg oral dose on day 4) in healthy male subjects (n = 26). For amiodarone + ximelagatran versus amiodarone + placebo, geometric mean ratios (90% confidence intervals for amiodarone AUC0–120 and Cmax were 0.87 (0.69–1.08) and 0.86 (0.66–1.11), respectively. For desethylamiodarone, the principal metabolite of amiodarone, the corresponding ratios were 1.00 (0.89–1.12) for AUC0–120 and 0.92 (0.77–1.09) for Cmax. The geometric mean ratios (90% confidence intervals) for ximelagatran + amiodarone versus ximelagatran were 1.21 (1.17–1.25) for melagatran AUC0–12 and 1.23 (1.18–1.28) for melagatran Cmax. These confidence intervals were within or only slightly outside the interval, suggesting no interaction (0.8–1.25 for the effect of amiodarone on melagatran and 0.7–1.43 for the effect of melagatran on amiodarone or desethylamiodarone). Amiodarone did not affect the concentration‐effect relationship of melagatran on activated partial thromboplastin time. Ximelagatran was well tolerated when coadministered with a single dose of amiodarone. Evaluation of the safety of the combination is needed to confirm that the relatively small pharmacokinetic changes in this study are of no clinical significance.

Effects of the Oral Direct Thrombin Inhibitor Ximelagatran on P-Selectin Expression and Thrombin Generation in Atrial Fibrillation

This study investigated the pharmacodynamic effects of the oral direct thrombin inhibitor ximelagatran on platelet activation and thrombin generation in patients with nonvalvular atrial fibrillation. Using an open, group-matched study design, the effects of ximelagatran (36 mg twice daily for 5 days) were studied in 12 patients with permanent nonvalvular atrial fibrillation and in 12 healthy controls. After ximelagatran for 5 days, elevated platelet P-selectin expression in atrial fibrillation patients was lowered to that during coumarin treatment or in controls but had no effect in control subjects. Using the endogenous thrombin potential as a marker, ximelagatran decreased and delayed thrombin generation in both groups. In conclusion, direct thrombin inhibition with ximelagatran reduced elevated platelet P-selectin expression and inhibited thrombin generation.