ABSTRACT:Bortezomib (Velcade, PS-341), a dipeptidyl boronic acid, is a firstin-class proteasome inhibitor approved in 2003 for the treatment of multiple myeloma. In a preclinical toxicology study, bortezomibtreated rats resulted in liver enlargement (35%). Ex vivo analyses of the liver samples showed an 18% decrease in cytochrome P450 (P450) content, a 60% increase in palmitoyl coenzyme A ␤-oxidation activity, and a 41 and 23% decrease in CYP3A protein expression and activity, respectively. Furthermore, liver samples of bortezomib-treated rats had little change in CYP2B and CYP4A protein levels and activities. To address the likelihood of clinical drug-drug interactions, the P450 inhibition potential of bortezomib and its major deboronated metabolites M1 and M2 and their dealkylated metabolites M3 and M4 was evaluated in human liver microsomes for the major P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4/5. Bortezomib, M1, and M2 were found to be mild inhibitors of CYP2C19 (IC 50 ϳ 18.0, 10.0, and 13.2 M, respectively), and M1 was also a mild inhibitor of CYP2C9 (IC 50 ϳ 11.5 M). However, bortezomib, M1, M2, M3, and M4 did not inhibit other P450s (IC 50 values > 30 M). There also was no time-dependent inhibition of CYP3A4/5 by bortezomib or its major metabolites. Based on these results, no major P450-mediated clinical drug-drug interactions are anticipated for bortezomib or its major metabolites. To our knowledge, this is the first report on P450-mediated drug-drug interaction potential of proteasome inhibitors or boronic acid containing therapeutics.The approval of bortezomib (Velcade, PS-341) by the U.S. Food and Drug Administration for treatment of multiple myeloma made it the first drug in a new class of medicines called proteasome inhibitors. The proteasome is an enzyme complex found in the nucleus and cytoplasm of all cells in the body. It degrades intracellular proteins, such as IB and p53, through the ubiquitin proteasome pathway (Ciechanover, 1994) and regulates cell growth, apoptosis, and cell adhesion. In tumor cells, the blockage of degradation of IB by proteasome inhibitors makes the inflammatory nuclear factor B remain in an inactive form, thus enhancing tumor cell apoptosis (Palombella et al., 1998;Berenson et al., 2001;Garg and Aggarwal, 2002). In addition, proteasome inhibitors block the degradation of the tumor suppressor protein p53. When cells undergo radiation or chemotherapy, the p53 expressed in normal cells allows the arrest of cell proliferation and permits the repair of damaged DNA. In contrast, tumor cells express mutated forms of p53, which hinders cell cycle arrest and the ability to repair damaged DNA (Kuerbitz et al.,1992). Thus proteasome inhibitors help normal cells to recover from DNA damage while allowing tumor cells to undergo apoptosis (Adams, 2001;Chauhan et al., 2005).Bortezomib, a dipeptidyl boronic acid ( Fig. 1; Wu et al., 2000), is a potent, selective, and reversible inhibitor of the proteasome in mammalian cells (Adams, 2001;Richardson et al., 2003;Chauhan et al., 2005). Bo...

SummaryThis two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material.Trial ID: ClinicalTrials.gov # NCT01953783.

No abstract