Kajs-Marie Schützer

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.

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.

Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crushed tablets or dissolved formulation

SUMMARY Objective: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders. Research design and methods: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20–33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube. Results: The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6μmol-h/l_ (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (Cmax) was 0.3μmol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t1/2) was 2.8 h for all treatments. The time to Cmax (tmax) was 2.2 h for the whole tablet and approximately 0.5 h earlier when the tablet was crushed or dissolved (1.7–1.8 h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported. Conclusion: The present study showed that the pharmacokinetics (AUC and Cmax) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.

Inter- and intraday variability in major electrocardiogram intervals and amplitudes in healthy men and women.

DOTA, C.D., et al.: Inter‐ and Intraday Variability in Major Electrocardiogram Intervals and Amplitudes in Healthy Men and Women. The ECG may vary during the day (intra‐day), and between days (interday), for the same subject. Variability in ECG characteristic measurements between different investigators is well documented and is often large. During days 1–6 of each placebo period of a two‐way crossover Phase I study, digital ECGs were recorded at about 8 and 12 am in 16 healthy volunteers (8 men, 8 women). Two observers independently analyzed leads V2 and V6 using EClysis software. The durations and amplitudes of major ECG waves and the intervals between major electrocardiographic events were analyzed in a mixed model ANOVA, in which subject, observer, time, and day were treated as random factors. The influence of various corrections for heart rate on the variability of QT intervals was investigated. The difference among subjects explained between 44–81% of the total variability in ECG intervals and amplitudes. Overall, inter‐ and intraday variability was not statistically significant for any variable. The individualized exponential correction of the QT interval for heart rate eliminated the QT interval dependence on the RR interval in all subjects. Changes in T wave morphology and shortening of the QT interval from morning to noon were observed in ten subjects. The interobserver variability was close to zero (SD < 0.005 ms) for all variables except the PQ interval (SD 1.4 ms). The various sources of variability in determinations of ECG wave characteristics should be considered in the design of clinical studies. The use of EClysis software for ECG measurements in this study made the results highly observer independent. (PACE 2003; 26[Pt. II]:361–366)

No clinically significant interactions between the oral direct thrombin inhibitor ximelagatran and amiodarone, atorvastatin, or digoxin

The oral direct thrombin inhibitor ximelagatran has shown clinical benefit in patients with atrial fibrillation at risk of stroke. The potential for interaction of ximelagatran with amiodarone, atorvastatin, or digoxin, was assessed in 3 randomized studies in healthy volunteers. Methods: Study 1 was a placebo‐controlled, parallel‐group study (n=26) with ximelagatran (36mg) or placebo BID for 8 days and amiodarone (single 600mg oral dose) on Day 4. Study 2 was a crossover study (n=16) with atorvastatin (single 40mg oral dose) during one treatment period and ximelagatran (36mg BID for 5 days) plus a single dose of atorvastatin (40mg) on Day 4 during the other treatment period. Study 3 was a double‐blind, crossover study (n=16) with ximelagatran (36mg) or placebo BID for 8 days and digoxin (single 0.5mg dose) on Day 4. Results: For melagatran, the active form of ximelagatran, AUC and Cmax geometric mean ratios (90% CI) for combined therapy relative to monotherapy with either drug were within or only slightly outside predefined bounds for no interaction. Similarly, no relevant changes were observed for the AUC and Cmax of amiodarone, atorvastatin, or digoxin. None of the coadministered drugs affected the concentration–effect relationship of melagatran on activated partial thromboplastin time. Conclusions: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when ximelagatran was administered with amiodarone, atorvastatin, or digoxin.

Effect on perfusion chamber thrombus size in patients with atrial fibrillation during anticoagulant treatment with oral direct thrombin inhibitors, AZD0837 or ximelagatran, or with vitamin K antagonists

INTRODUCTION AZD0837 and ximelagatran are oral direct thrombin inhibitors that are rapidly absorbed and bioconverted to their active forms, AR-H067637 and melagatran, respectively. This study investigated the antithrombotic effect of AZD0837, compared to ximelagatran and the vitamin K antagonist (VKA) phenprocoumon (Marcoumar), in a disease model of thrombosis in patients with non-valvular atrial fibrillation (NVAF). METHODS Open, parallel-group studies were performed in NVAF patients treated with VKA, which was stopped aiming for an international normalized ratio (INR) of ≤ 2 before randomization. Study I: 38 patients randomized to AZD0837 (150,250 or 350 mg) or ximelagatran 36 mg twice daily for 10-14 days. Study II: 27 patients randomized to AZD0837 250 mg twice daily or VKA titrated to an INR of 2-3 for 10-14 days. A control group of 20 healthy elderly subjects without NVAF or anticoagulant treatment was also studied. Size of thrombus formed on pig aorta strips was measured after a 5-minute perfusion at low shear rate with blood from the patient/control subject. RESULTS Thrombus formation was inhibited by AZD0837 and ximelagatran. Relative to untreated patients, a 50% reduction of thrombus size was estimated at plasma concentrations of 0.6 and 0.2 μmol/L for AR-H067637 and melagatran, respectively. For patients receiving VKA treatment, the thrombus size was about 15% lower compared with healthy elderly controls. CONCLUSIONS Effects of AZD0837 and ximelagatran on thrombus formation were similar or greater than for VKA therapy and correlated with plasma concentrations of their active forms.

Effect of erythromycin on the pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran and its active form melagatran

Ximelagatran (Exanta™, AstraZeneca), an oral direct thrombin inhibitor for the prevention and treatment of thromboembolic disorders, is rapidly absorbed and bioconverted to its active form melagatran. The metabolism of ximelagatran is independent of CYP450 enzymes and hence it has a low potential for drug interactions. This study evaluated the effect of erythromycin on the pharmacokinetics (PK) and pharmacodynamics (PD) of melagatran. Methods: An open, sequential, single‐centre study in healthy volunteers (n=16; mean age 24 years, range 20–32 years) with ximelagatran 36mg on Day 1, then erythromycin 500mg TID on Days 2–5 followed by ximelagatran 36 mg plus erythromycin on Day 6. Results: For melagatran, AUC and Cmax geometric mean ratios for combined therapy (Day 6) relative to monotherapy (Day 1) were 1.82 (90% CI, 1.64–2.01) and 1.74 (90% CI, 1.52–2.00), respectively, (n=15), falling outside of the predefined bounds for no interaction. Geometric mean ratios for tmax and t1/2 of melagatran were 1.14 and 0.93, respectively. The erythromycin‐associated elevation in plasma melagatran concentrations increased the peak activated partial thromboplastin time (aPTT) prolongation from 41s to 44s. Ximelagatran was well tolerated alone, and in combination with erythromycin. Conclusions: This study showed evidence of a pharmacokinetic interaction between ximelagatran and erythromycin with respect to melagatran PK, which is being investigated, but only a small effect on aPTT.

Combined in vitro-in vivo approach to assess the hepatobiliary disposition of a novel oral thrombin inhibitor.

Two clinical trials and a large set of in vitro transporter experiments were performed to investigate if the hepatobiliary disposition of the direct thrombin inhibitor prodrug AZD0837 is the mechanism for the drug-drug interaction with ketoconazole observed in a previous clinical study. In Study 1, [(3)H]AZD0837 was administered to healthy male volunteers (n = 8) to quantify and identify the metabolites excreted in bile. Bile was sampled directly from the jejunum by duodenal aspiration via an oro-enteric tube. In Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics of AZD0837, the intermediate metabolite (AR-H069927), and the active form (AR-H067637) was investigated (n = 17). Co-administration with ketoconazole elevated the plasma exposure to AZD0837 and the active form approximately 2-fold compared to placebo, which may be explained by inhibited CYP3A4 metabolism and reduced biliary clearance, respectively. High concentrations of the active form was measured in bile with a bile-to-plasma AUC ratio of approximately 75, indicating involvement of transporter-mediated excretion of the compound. AZD0837 and its metabolites were further investigated as substrates of hepatic uptake and efflux transporters in vitro. Studies in MDCK-MDR1 cell monolayers and P-glycoprotein (P-gp) expressing membrane vesicles identified AZD0837, the intermediate, and the active form as substrates of P-gp. The active form was also identified as a substrate of the multidrug and toxin extrusion 1 (MATE1) transporter and the organic cation transporter 1 (OCT1), in HEK cells transfected with the respective transporter. Ketoconazole was shown to inhibit all of these three transporters; in particular, inhibition of P-gp and MATE1 occurred in a clinically relevant concentration range. In conclusion, the hepatobiliary transport pathways of AZD0837 and its metabolites were identified in vitro and in vivo. Inhibition of the canalicular transporters P-gp and MATE1 may lead to enhanced plasma exposure to the active form, which could, at least in part, explain the clinical interaction with ketoconazole.