Summary Basis of Decision for Pradax ™

Pradax (dabigatran etexilate mesilate, a salt form of dabigatran etexilate) is the prodrug of dabigatran, a novel, synthetic, specific, non-peptide thrombin inhibitor. Dabigatran etexilate mesilate (BIBR 1048 MS) is devoid of any antithrombin activity in vitro. However, after oral administration and absorption from the gastrointestinal tract, dabigatran etexilate mesilate is converted by esterases into the active form dabigatran (BIBR 953 ZW).

In the non-clinical studies, oral dosing was done with BIBR 1048 MS while the intravenous (IV) administration used BIBR 953 ZW.

3.2.1 Pharmacodynamics

BIBR 953 ZW has been shown to be a potent and specific inhibitor of thrombin, demonstrating anti-coagulant and anti-thrombotic activity both in vitro and in vivo. BIBR 953 ZW inhibited purified human thrombin in vitro with an inhibitory constant of 4.5 nM. Its selectivity was apparent through the 700-fold or larger concentrations required to inhibit other serine proteases involved in coagulation.

Anticoagulant Activity

In vitro, BIBR 953 ZW potently prolonged the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and prothrombin time (PT) in rat, rabbit, and Rhesus monkey plasma. Human platelet aggregation was not affected by BIBR 953 ZW unless thrombin was used as the stimulus to induce aggregation.

Anticoagulant activity ex vivo was prolonged in a dose-dependent manner in rats, Rhesus monkeys, and rabbits. Five minutes after administration of BIBR 953 ZW in rats, the aPTT was prolonged by 15- and 45-fold after an IV bolus of 1 and 3 mg/kg, respectively. Oral administration of BIBR 1048 MS in rats, in doses between 10 and 100 mg/kg, resulted in a dose-dependent elevation of the aPTT, with a 13-fold elevation over control that peaked 30 min post dosing with the highest dose. Similar effects were also seen with Rhesus monkeys after IV and oral dosing. After a single oral dose of 5 mg/kg, there was a peak 3-fold prolongation of the aPTT values 2 hours after administration, and prolonged aPTT values could still be measured 8 hrs after dosing. Similarly in rabbits, a dose-dependent effect could be measured ex vivo with aPTT after IV administration of BIBR 953 ZW or after oral administration of BIBR 1048 MS.

Antithrombotic Activity

The ED₅₀ is the dose that is pharmacologically effective for 50% of the population exposed to the drug. BIBR 953 ZW inhibited thrombus formation with an ED₅₀ of 33 µg/kg in rats, and an ED₅₀ of 66 µg/kg in rabbits, after IV administration. Complete inhibition of thrombus formation occurred with the highest IV dose of 0.1 and 0.5 mg/kg in rats and rabbits, respectively. In both species, there was an approximate linear inverse correlation between reduction of clot size and increased aPTT time. Similar results were obtained after oral dosing with BIBR 1048 MS in rats and rabbits. The test results demonstrated that dabigatran is a potent antithrombotic agent with a rapid onset of action.

Bleeding Effects

Potential bleeding side-effects were evaluated in rats. IV doses of BIBR 953 ZW 5-fold higher than the dose that resulted in complete inhibition of thrombus formation induced significant bleeding. These effects also correlated well with the aPTT prolongation, suggesting that monitoring of potential overdosing is possible. The results in this non-clinical model suggest a 5-fold safety margin between maximum antithrombotic effects and bleeding onset.

Secondary Pharmacodynamics

Secondary pharmacodynamic studies investigated effects in cardiovascular, pulmonary, central nervous system (CNS), gastrointestinal, and renal systems. A comprehensive cardiovascular profiling was performed with an assessment of both in vitro and in vivo proarrhythmic risk. The data suggest that the risk for proarrhythmic events is low. Cardiovascular studies in rats and rabbits showed very little effect. The doses given were between 20- and 100-fold greater than those that elicited antithrombotic effect. Respiratory parameters were also measured parallel to cardiovascular function in rabbits. No effect was seen at IV doses up to 10 mg/kg.

There was no effect on locomotor activity in rats and effects on the gastrointestinal tract were minimal.

Renal and liver effects were tested in dogs. After IV or oral administration, there was no effect on metabolites or electrolytes in serum. After IV administration of the highest dose, 3 mg/kg, there was a slight decrease in sodium and chloride excretion and a slight elevation in potassium excretion in urine. These effects with the highest dose were significant over control but were still within normal ranges.

Safety Pharmacology

A core battery of safety studies were conducted according to Good Laboratory Practices (GLP).

CNS testing was performed in rats after a single oral administration of 30, 100 or 300 mg/kg BIBR 1048 MS. No relevant effects on general behavior and physiological state, including body temperature, were reported at the two lower doses. At the highest dose of 300 mg/kg, there was a slight decrease in body temperature 4 and 24 hours after dosing.

Effects on respiration were tested in conscious rats administered with a single oral dose of 30, 100 or 300 mg/kg BIBR 1048 MS, as compared to control. There were only insignificant effects on respiratory rate, tidal volume, and minute volume at all doses tested.

Cardiovascular investigations were conducted as part of the 4-week toxicity study in conscious rats and further ECG investigations were conducted in the 26- and 52-week toxicity studies in Rhesus monkeys. There was no effect on heart rate or blood pressure with oral doses of 30, 100 or 300 mg/kg in conscious rats. There were also no relevant, dose-dependent or consistent effects on heart rate, blood pressure, and on electrocardiogram morphology, including PR-interval, QT-interval, and QS-complex width after oral doses up to 200 mg/kg in Rhesus monkeys.

3.2.2 Pharmacokinetics

Absorption

The oral pharmacokinetics of the prodrug dabigatran etexilate mesilate (BIBR 1048 MS) in various animal species (mouse, rat, rabbit and Rhesus monkey) was characterized in vivo as having low oral absorption. Once absorbed, BIBR 1048 MS was almost completely cleaved during first-pass metabolism to the active moiety, dabigatran (BIBR 953 ZW). In general, the pharmacokinetics of BIBR 953 ZW after oral dosing of BIBR 1048 MS were almost dose-linear at clinically relevant doses with no consistent effect of gender or repeated dosing.

Distribution

Distribution of BIBR 953 ZW in rats was relatively low, and occurred in most tissues except the CNS. The highest concentrations were found in the liver and urinary tract. Plasma protein binding was low in all species with a range of 22-39%. Low drug concentrations were detected in fetal tissues of pregnant dams, relative to those seen in blood and placenta. Thus, the placental barrier was seen to be somewhat effective at limiting maternal-fetal drug transport.

Metabolism

The cleavage of the prodrug BIBR 1048 MS to the active moiety BIBR 953 ZW by esterase-catalysed hydrolysis was the most prevalent metabolic reaction. The involvement of CYP isoenzymes to the metabolism was minimal. Consistent with this finding, there was neither inhibition nor induction of CYP isoenzymes at therapeutic or supratherapeutic drug concentrations.

BIBR 953 ZW was the predominant drug-related compound in plasma, urine, and feces following both oral administration of BIBR 1048 MS and intravenous administration of BIBR 953 ZW. Beside the active intermediates BIBR 1087 SE and BIBR 951 ZW, and the active moiety BIBR 953 ZW, pharmacologically active acyl-glucuronides of BIBR 953 ZW were identified as additional metabolites, especially in Rhesus monkey and man. The acyl-glucuronides of BIBR 953 ZW (present in man) were also generated in significant amounts in the main animal species (rats and Rhesus monkeys) used in the non-clinical studies. All of the acyl-glucuronide metabolites have been adequately qualified in the non-clinical evaluation.

Excretion

Following oral or intraduodenal administration of radiolabelled BIBR 1048 MS, excretion of drug-related radioactivity ranged between 87-93% in the faeces, 2-11% in the urine, and 0.3-8% in the bile of all species investigated. Following IV administration of radiolabelled BIBR 953 ZW, approximately 40-50% of the drug-related radioactivity was excreted in the urine and about 40% in the faeces (including bile) in the rodent species. However, in the Rhesus monkey up to 80% of the radioactivity was excreted in the urine and about 20% in faeces, after IV dosing. In the rodent species, excretion was fast and almost complete (>90%) within 24 hours, and in the rabbit, excretion was within 72 hours. Enterohepatic circulation was negligible.

3.2.3 Toxicology

The toxic potential of BIBR 1048 MS, known as dabigatran etexilate mesilate, which is the orally non-active prodrug of BIBR 953 ZW, has been investigated in an extensive program of non-clinical studies. The program included single-dose toxicity studies, repeat-dose toxicity studies, genotoxicity/mutagenicity in vitro and in vivo assays, reproductive and developmental toxicity studies, well as an immunotoxicity study.

Single-Dose Toxicity

The acute oral toxicity of BIBR 1048 MS after oral administration was low. The approximate lethal dose (ALD) was >2,000 mg/kg in mice and rats, and >600 mg/kg in dogs and Rhesus monkeys.

Repeat-Dose Toxicity

In the repeat-dose toxicity studies, up to 26 weeks in rats and up to 52 weeks in Rhesus monkeys, no adverse effects except for pharmacodynamically-mediated bruising and hemorrhages induced by administration of high doses of BIBR 1048 MS were reported. The findings that reflected exaggerated pharmacological effects or compensatory effects showed recovery after discontinuation of treatment. In all animal species used in the non-clinical program, it was noteworthy that no evidence was obtained of adverse effects on the liver. No early signals of hepatotoxicity were detected in rats or Rhesus monkeys.

Genotoxicity and Mutagenicity

In a battery of in vitro and in vivo studies (including the Ames Bacterial Reversion assay, the mouse lymphoma mutation assays, and the bone marrow micronucleus assays), BIBR 1048 MS and BIBR 953 ZW did not provide evidence of genotoxic/mutagenic potential.

Carcinogenicity

Carcinogenic studies were not provided. This exclusion is justified as the recommended treatment regime does not extend beyond 6 months in duration.

Reproductive and Developmental Toxicity

In the embryo-fetal development and fertility/early developmental toxicity studies in rats, maternal and (early) embryo-fetal toxicity occurred only at the high dose of 200 mg/kg BIBR 1048 MS. Fertility, and the ability to mate and reproduce were not affected by exposure to BIBR 1048 MS at potentially relevant exposures.

The embryo-fetal development toxicity study in rabbits also indicated maternal effects only at the high dose of 200 mg/kg. No teratogenic effects were noted.

In the pre- and post-natal development study in rats, maternal toxicity was observed at 70 mg/kg BIBR 1048 MS due to bleeding episodes into the genital tract during parturition. No drug-related effects on the post-natal development of the offspring were noted, as shown by normal body weight development, normal survival after birth, and normal physical post-natal development.

Local Tolerance

BIBR 1048 MS and BIBR 953 ZW did not provide evidence of local intolerance in the studies provided.

Immunotoxicity

In the immunotoxicological assessment of a 13-week dose study in rats, a slight reduction of splenic lymphocytes was reported which did not appear to be clearly dose-related, in female rats that received 100 and 300 mg/kg BIBR 1048 MS. Male rats did not show similar changes of lymphocyte counts. There was also no histopathological correlate in the spleen of the affected animals. Therefore, this change was not considered to be drug-related. In the other toxicity studies, there was also no presence of histopathological changes in the bone marrow or the lymphatic organs (thymus, spleen, lymph nodes). The lack of these changes provide evidence of the absence of a drug-related effect of BIBR 1048 MS on the immune system.

3.2.4 Conclusion

Dabigatran (BIBR 953 ZW) is a potent and specific inhibitor of thrombin, demonstrating anti-coagulant and anti-thrombotic activity both in vitro and in vivo. In vivo, it has a relatively wide safety window between anti-thrombotic efficacy and bleeding side effects.

Both the orally administered prodrug, dabigatran etexilate mesilate (BIBR 1048 MS), and its principal active metabolite, BIBR 953 ZW, were generally well tolerated. Few adverse effects were observed in the non-clinical safety studies in mice, rats, guinea pigs, rabbits, dogs, and Rhesus monkeys, except at exceedingly high doses of the administered drug. In general, these effects were directly or indirectly associated with the anticoagulant properties of BIBR 953 ZW, namely an enhanced propensity for bleeding events or relevant compensatory effects at high dose levels, and thus correspondingly, high plasma concentrations of drug.

Based on the non-clinical data, Pradax appears to be a drug with a favourable risk profile, given its evident anticoagulant properties, with good potential for clinical benefit in the treatment and prevention of thrombotic diseases.