Bivalirudin
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| Image:Bivalirudin.png | |
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Bivalirudin
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| Systematic (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 |
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| Identifiers | |
| CAS number | 128270-60-0 |
| ATC code | ? |
| PubChem | ? |
| Chemical data | |
| Formula | C98H138N24O33 |
| Mol. weight | 2180.3 |
| Pharmacokinetic data | |
| Bioavailability | 100 % (i.v. application only) |
| Metabolism | degraded through proteinases |
| Half life | ~25 minutes |
| Excretion | ? |
| Therapeutic considerations | |
| Licence data | |
| Pregnancy cat. |
B |
| Legal status |
Rx-only. Not a controlled substance. |
| Routes | i.v.-injection/infusion only |
Bivalirudin (Angiomax™) is a drug that belongs to the anticoagulant class and acts as a direct thrombin inhibitor.
Contents |
[edit] 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-bound thrombin. Thrombin is a serine proteinase 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 and hour the mean steady-state-concentration is 12.4 µg/ml. The drug is metabolized by enzymes of the proteinase type (also by thrombin itself) resulting in one inactive main-metabolite. Approximately 20 % are found in the urine as unchanged Bivalirudin. The half-life of Bivalirudin is 25 +- 12 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). 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.
[edit] Existing Drug Forms
In Europe Bivalirudin is sold under the brand name Angiox®, in other countries under Angiomax® (year of obtained license = 2005 in most countries). The drug is intended for parenteral (i.v.) use only. One vial contains 250mg.
Bivalirudin was licensed due to the results of 2 studies (see below under section comparative results).
[edit] 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.
[edit] 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.
[edit] Side 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.
[edit] Possible Interactions
When used with other anticoagulants (heparin, thrombolytics, glycoprotein IIB/IIIA blockers, coumarins, or aspirin), bivalirudin may lead to increased bleeding tendency.
[edit] Dosage Regime
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 and hour for the duration of PCI. Efficiacy of therapy should be measured during infusion by obtaining the above mentioned coagulation parameters. If necessary, the infusion rate may be increased. After withdrawal of Bivalirudin and normalization of all affected coagulation parameters, further 'minimal anticoagulation', for example with Aspirin, may be indicated.
[edit] Comparative Results
In a large comparative 30-days study encompassing 6,010 patients (called REPLACE2 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 REPLACE2 study and the historical data.
[edit] 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.
A serious disadvantage is the high price of bivalirudin. In Germany for example the price for 10 vials Angiox® is € 5,113.58; if one vial is needed for each patient, the cost per patient is approximately € 512. The comparative price for eptifibatide, which is comparable in efficiacy and tolerability, is only € 238.
[edit] References
- AHFS Database online
- 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.eu.int/humandocs/PDFs/EPAR/angiox/H-562-PI-de.pdf (Document of the European Drug Agency, in German)
