Effects of Strong CYP3A Inhibition and Induction on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor: Results of Drug‐Drug Interaction Studies in Patients With Advanced Solid Tumors or Lymphoma and a Physiologically Based Pharmacokinetic Analysis

Abstract

At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty‐eight patients were enrolled across the 3 drug‐drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least‐squares mean area under the plasma concentration‐time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91‐1.31) and was 1.11 (0.86‐1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration‐time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least‐squares mean ratio of 0.26 [90%CI 0.18‐0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least‐squares mean ratio of 0.46 [90%CI 0.29‐0.73]) in the presence of rifampin. The clinical drug‐drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P‐glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib.

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

“…This contrasted with the essentially nil effect of the CYP3A inhibitor itraconazole. Similar findings of discordance between CYP3A inhibition and induction have been reported for several drugs, including ixazomib, 17 tivozanib, 18 and vandetanib 19 ; this contrast has 1 of 2 possible main explanations. First, the induction of CYP3A-mediated metabolism by rifampin might cause a significant increase in clearance of avadomide, although the contribution of CYP3A to avadomide clearance is small at baseline.…”

“…This seems to apply to ixazomib, whose PK was well reconciled by a physiologically based PK model incorporating a minor contribution of CYP3A to overall clearance, strong induction of CYP3A4, and moderate induction of intestinal P-gp. 17 Safety assessment indicated that avadomide, administered as a single oral dose of 3 mg alone or coadministered with itraconazole, fluvoxamine, or rifampin, was well tolerated by the healthy subjects in this study. No new observed or suspected risks were suggested by the study results.…”

“…Indeed, the observed avadomide effects could also result from a combination of both processes. This seems to apply to ixazomib, whose PK was well reconciled by a physiologically based PK model incorporating a minor contribution of CYP3A to overall clearance, strong induction of CYP3A4, and moderate induction of intestinal P‐gp …”

The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib

“…This pleiotropic effect may be contributing to the overall osimertinib metabolism and decreasing exposure. A similar effect has been observed for other agents (tivozanib, ixazomib) where there is no effect with CYP3A inhibitor co-administration, but a clinically meaningful effect when co-administered with rifampicin, which is suggestive of induction of upstream nuclear hormone receptor pathways and multiple enzymes [40][41][42].…”

Ixazomib in the treatment of relapsed multiple myeloma

“…Основным механизмом клиренса иксазомиба является метаболизм ферментами цитохрома P450 (CYP3A -42%) и некоторыми другими дополнительными путями [14]. Иксазомиб (Нинларо) коммерчески доступен в форме капсул по 2,3; 3 и 4 мг для орального применения.…”