Bivalirudin

drugbox
IUPAC_name = d-Phenylalanyl-l-prolyl-l-arginyl
-l-prolylglycylglycylglycylglycyl-l-asparaginylglycyl
-l-alpha-aspartyl-l-phenylalanyl
-l-alpha-glutamyl-l-alpha-glutamyl-l-isoleucyl
-l-prolyl-l-alpha-glutamyl-l-isoleucyl
-l-prolyl-l-alpha-glutamyl-l-alpha-glutamyl
-l-tyrosyl-l-leucine


CAS_number = 128270-60-0
ATC Code = B1A2
ATC_supplemental =
PubChem =
DrugBank =
C=98 | H=138 | N=24 | O=33
molecular_weight = 2180.3
bioavailability = 100 % (i.v. application only)
protein_bound =
metabolism = degraded through proteinases
elimination_half-life = ~25 minutes
license_EU = Angiox
license_US = Bivalirudin
pregnancy_US = B
pregnancy_category =
legal_status = Rx-only. Not a controlled substance.
routes_of_administration = i.v.-injection/infusion only

Bivalirudin (Angiomax) is a drug that belongs to the anticoagulant class and acts as a direct thrombin inhibitor.

Basic chemical and pharmacological properties

Chemically it constitutes a synthetic congener of the naturally occurring drug hirudin (found in the saliva of the medicinal leech "Hirudo medicinalis").

Both bivalirudin and hirudin directly inhibit thrombin by specifically binding as well to the catalytic site and to the anion-binding exosite of circulating and clot- or thrombus-bound thrombin. Thrombin is a serine protease that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release.

The pharmacological difference between both drugs is that Hirudin is an irreversible inhibitor of thrombin while Bivalirudin is a reversible one. This leads to a relatively small rate of severe bleedings under Bivalirudin compared to standard therapy (see below under section comparative results). When delivered by i.v.-infusion with a rate of 2.5 mg/kg/hr, the mean steady-state-concentration is 12.4 µg/ml. Bivalirudin exhibits linear pharmacokinetics following IV administration to patients undergoing percutaneous coronary intervention. 80% of the drug is proteolytically cleaved, and the remaining 20% is renally metabolized. The half-life of Bivalirudin is 25 minutes.

The clinical onset of action is almost immediate after i.v.-bolus. Bivalirudin prolongs a number of coagulation parameters due to its mode of action. These are the activated clotting time (ACT), the activated partial thromboplastin time (aPPT), the thrombin time (TT), and the prothrombin time (PT,protime). After termination of treatment the coagulation parameters return to normal within 1 to 2 hours indicating a short action of Bivalirudin resulting in a good controllability of therapy.

Existing Drug Forms

In Europe Bivalirudin is sold under the brand name Angiox, and in other countries, including the United States, under Angiomax (the year of obtained license is 2005 in most countries).

The drug is intended for parenteral (i.v.) use only. One vial contains 250mg.

Bivalirudin was initially approved by FDA based on results from 2 studies and subsequently approved for an expanded indication based on 3 additional studies. Bivalirudin was licensed in the EU based on 2 studies (see below under section comparative results).

Indications

Bivalirudin is indicated to reduce the risk of acute ischemic complications, for example death due to myocardial infarction or need for urgent revascularization procedures, in patients with unstable angina pectoris undergoing percutaneous coronary intervention (PCI). If indicated, the therapy may be continued for up to 4 hours after termination of PCI.

Contraindications and Precautions

* The drug must not be given to patients with clinically relevant preexisting bleeding disorders of any origin.
* Allergy to Bivalirudin or other ingredients of the preparation.
* Women planning to become pregnant (Pregnancy Category B) or wishing to start breast-feeding (effects on the newborn not known) should ask their clinician.
* Patients with significantly reduced renal function should receive Bivalirudin in reduced doses.
* Pediatric patients should not be treated, because there is no clinical experience.
* Although most bleeding associated with the use of bivalirudin in angioplasty occurred at the site of the arterial puncture, hemorrhage can occur at any site. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of bivalirudin administration.

ide Effects

The main risk is the occurrence of severe bleedings in 2.4 % of patients in clinical studies. Elderly patients experienced more bleeding episodes than younger patients. Cases of deaths due to severe bleeding attributable to bivalirudin were seen.

Cases of local (skin) or generalized, sometimes severe, anaphylactic allergic reactions (including shock) were observed. Isolated cases of death from anaphylactic reactions were seen. Thrombocytopenia was only infrequently encountered. Unspecific pains and anxiety were frequent but tolerable side-effects.

Possible Interactions

When used with other anticoagulants (heparin, thrombolytics, glycoprotein IIB/IIIA blockers, coumarins, or aspirin), bivalirudin may lead to increased bleeding tendency.

Dosage Regimen

It is recommended to start therapy with an initial i.v.-loading dose (fast injection) of 0.75 mg/kg followed by i.v.-infusion at a rate of 1.75mg/kg per hour for the duration of PCI. Continuation of the infusion for up to 4 hours is optional at the discretion of the treating physician. After 4 hours, an additional IV infusion of bivalirudin may be initiated at a rate of 0.2 mg/kg per hour for up to 20 hours. 2 hours after withdrawal of bivalirudin infusion, sheaths may be removed in most patients.

Comparative Results

In a large comparative 30-days study encompassing 6,010 patients (called REPLACE-2 study) Bivalirudin was compared with a standard therapy of either Abciximab or Eptifibatide plus initial Heparin bolus. The study had a randomized, double-blinded design. Regarding the primary endpoint (death, myocardial infarction, urgent revascularization procedures, severe bleedings) no statistically significant difference between Bivalirudin and standard therapy was noticed (9.2 versus 10.0 %). Regarding ischemic complications (death, myocardial infarction, and urgent revascularization procedures) there was also no statistically significant difference (7.6 vs. 7.1 %). But the risk for severe bleedings was 2.4 % in the Bivalirudin group compared to 4.1 % in the standard therapy-group; a significant difference. In an additional study comparing historical data of Heparin alone (EPISTENT, ESPRIT) with current Bivalirudin results, Bivalirudin gave superior results. Bivalirudin was licensed based on the results of both the REPLACE-2 study and the historical data.

Conclusions

Bivalirudin has the potential to become an important anticoagulant during PCI procedures because of the reduced likelihood of severe bleeding as compared with standard therapy. There is ready reversibility of its action after the end of PCI, together with a relatively low frequency of allergic reactions and thrombocytopenia compared with heparin. It is also unnecessary to give other anticoagulants concomitantly with bivalirudin.

References

* AHFS Database online
* Angiomax (bivalurdin) Prescribing Information. The Medicines Company, Parsippany, NJ December 6, 2005.
* Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. "JAMA". 2003;289:853-863.
* http://www.pharmazeutische-zeitung.de/index.php?id=121&type=0 (in German)
* Arzenimittel-Datenbank (in German)
* http://rx.onconews.org/news/Bivalirudin.html
* http://www.emea.europa.eu/humandocs/PDFs/EPAR/angiox/H-562-PI-de.pdf (Document of the European Drug Agency, in German)