Bortezomib: a novel chemotherapeutic agent for hematologic malignancies.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage and administration, place in therapy, and cost of bortezomib in the treatment of multiple myeloma and mantle cell lymphoma are reviewed. SUMMARY: Bortezomib is a modified dipeptidyl boronic acid that disrupts essential intracellular pathways by inhibiting proteasomes. The drug is metabolized by cytochrome P-450 isoenzymes 3A4, 2C19, and 1A2 to four inactive metabolites. Bortezomib was initially developed for the treatment of multiple myeloma based on the findings of early in vitro studies of patients with multiple myeloma who received at least one prior course of treatment; the drug received approval for the treatment of mantle cell lymphoma based on a single, noncomparative, Phase II study of previously treated patients. Significant toxicities have been reported with the use of bortezomib, including peripheral neuropathy, neutropenia, and thrombocytopenia. The dosage of bortezomib recommended by the manufacturer is 1.3 mg/m(2) per dose administered as an i.v. bolus injection twice weekly on days 1, 4, 8, and 11 of a three-week cycle. It is not necessary to adjust the dosage of bortezomib in patients with renal impairment. Bortezomib is being investigated as a treatment for several other malignant conditions. The current wholesale price of bortezomib is $1,322.40 for a single-use vial containing 3.5 mg of bortezomib lyophilized powder, with one course of treatment costing approximately $27,500 in drug cost alone. CONCLUSION: Bortezomib, an antineoplastic agent that reversibly inhibits the 26S proteasome, offers an important treatment option for patients with multiple myeloma or mantle cell lymphoma.

A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer.

PURPOSE: This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination of bortezomib and doxorubicin in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-six patients were treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both in a 21-day cycle. Dosing ranged from 1.0 mg/m(2) of bortezomib with 15 mg/m(2) of doxorubicin to 1.5 mg/m(2) of bortezomib with 20 mg/m(2) of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates. RESULTS: The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m(2) bortezomib, 20 mg/m(2) doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m(2) bortezomib, 15 mg/m(2) doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was observed in peripheral blood mononuclear cells of most patients. CONCLUSIONS: Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m(2 )intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m(2) intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease.

Effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors.

PURPOSE: The effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors were examined. SUMMARY: The bioavailability and metabolism of cyclosporine and tacrolimus are primarily controlled by efflux pumps and members of the cytochrome P-450 (CYP) isoenzyme system found in the liver and gastrointestinal tract. The number and severity of adverse effects from these drugs are related to the overall exposure, measured by length of therapy and blood drug concentration. One contributing factor to the inconsistent pharmacokinetics of calcineurin inhibitors may be variable expression of functional CYP3A4, CYP3A5, and P-glycoprotein (PGP) efflux pumps, which may be the result of single-nucleotide polymorphisms found on the genes encoding for CYP3A4, CYP3A5, and PGP. CYP3A5*3 and CYP3A5*6 are the most common polymorphisms of CYP3A5. Using genetic markers to adjust initial doses of cyclosporine or tacrolimus may prove difficult, considering the variety of polymorphism known to affect CYP3A4, CYP3A5, and the multidrug resistance-1 (MDR1) gene (the gene that codes for PGP). Studies have found that carriers of CYP3A5*1 consistently have higher clearance rates of tacrolimus than do CYP3A5*3 homozygotes. The influences of CYP3A5 alleles on cyclosporine metabolism and the MDR1 C3435T polymorphism on tacrolimus metabolism remain controversial. CONCLUSION: For renal transplant recipients receiving tacrolimus as an immunosuppressant, practitioners can expect CYP3A5*1 carriers to have a tacrolimus clearance 25-45% greater than that of CYP3A5*3 homozygotes, with proportional dosing needs to maintain adequate immunosuppression. Since inadequate immunosuppression is linked to graft rejection, evaluation of CYP3A5 polymorphisms may be helpful in determining an appropriate starting dosage, rapidly achieving adequate immunosuppression, and ultimately improving the outcome of renal transplantation.