Bortezomib

Bortezomib (BAN, INN and USAN; marketed as Velcade by Takeda Oncology; Chemobort by Cytogen and Bortecad by Cadila Healthcare) is an anti-cancer drug and the first therapeutic proteasome inhibitor to be used in humans. Proteasomes are cellular complexes that break down proteins. In some cancers, the proteins that normally kill cancer cells are broken down too quickly. Bortezomib interrupts this process and lets those proteins kill the cancer cells. It is approved in the U.S. and Europe for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease. Bortezomib (BAN, INN and USAN; marketed as Velcade by Takeda Oncology; Chemobort by Cytogen and Bortecad by Cadila Healthcare) is an anti-cancer drug and the first therapeutic proteasome inhibitor to be used in humans. Proteasomes are cellular complexes that break down proteins. In some cancers, the proteins that normally kill cancer cells are broken down too quickly. Bortezomib interrupts this process and lets those proteins kill the cancer cells. It is approved in the U.S. and Europe for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease. Bortezomib was originally synthesized in 1995 at Myogenics. The drug (PS-341) was tested in a small Phase I clinical trial on patients with multiple myeloma. It was brought to further clinical trials by Millennium Pharmaceuticals in October 1999. In May 2003, seven years after the initial synthesis, bortezomib (marketed as Velcade by Millennium Pharmaceuticals Inc.) was approved in the United States by the Food and Drug Administration (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial. Bortezomib is approved for initial treatment of patients with multiple myeloma by the U.S. FDA in 2008. Later in August 2014, this Administration approved Velcade for the retreatment of adult patients with multiple myeloma who had previously responded to Velcade therapy and relapsed at least six months following completion of prior treatment. The drug is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid. The boron atom in bortezomib binds the catalytic site of the 26S proteasome with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitylated proteins, and also rids the cell of abnormal or misfolded proteins. Clinical and preclinical data support a role for the proteasome in maintaining the immortal phenotype of myeloma cells, and cell-culture and xenograft data support a similar function in solid tumor cancers. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, thereby triggering programmed cell death in neoplastic cells. Recently, it was found that bortezomib caused a rapid and dramatic change in the levels of intracellular peptides that are produced by the proteasome. Some intracellular peptides have been shown to be biologically active, and so the effect of bortezomib on the levels of intracellular peptides may contribute to the biological and/or side effects of the drug. After subcutaneous administration, peak plasma levels are ~25-50 nM and this peak is sustained for 1-2 hrs. After intravenous injection, peak plasma levels are ~500 nM but only for ~5 minutes, after which the levels rapidly drop as the drug distributes to tissues (volume of distribution is ~500 L). Both routes provide equal drug exposures and generally comparable therapeutic efficacy. Elimination half life is 9–15 hours and the drug is primarily cleared by hepatic metabolism. The pharmacodynamics of bortezomib are determined by quantifying proteasome inhibition in peripheral blood mononuclear cells taken from patients receiving the drug. In the UK, NICE initially recommended against Velcade in October 2006 due to its cost of about £18,000 per patient, and because studies reviewed by NICE reported that it could only extend the life expectancy by an average of six months over standard treatment. However, the company later proposed a performance-linked cost reduction for multiple myeloma, and this was accepted.