1.Exposure-safety-efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study.
Gupta N1, Labotka R2, Liu G3, Hui AM2, Venkatakrishnan K4. Invest New Drugs. 2016 Apr 2. [Epub ahead of print]
Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic [grade ≥ 3 vs ≤ 2] or non-hematologic [grade ≥ 2 vs ≤ 1] adverse events [AEs], and clinical benefit [≥stable disease vs progressive disease]) using phase 1 data in relapsed/refractory MM (NCT00963820; N = 44). Results Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p < 0.
2.The Effect of a High-Fat Meal on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor, in Patients with Advanced Solid Tumors or Lymphoma.
Gupta N1, Hanley MJ1, Venkatakrishnan K1, Wang B1, Sharma S2, Bessudo A3, Hui AM1, Nemunaitis J4. J Clin Pharmacol. 2016 Feb 13. doi: 10.1002/jcph.719. [Epub ahead of print]
Ixazomib is the first oral proteasome inhibitor to be investigated in the clinic. This clinical study assessed whether the pharmacokinetics of ixazomib would be altered if administered after a high-calorie, high-fat meal. Using a two-period, two-sequence, cross-over study design, adult patients with advanced solid tumors or lymphoma received a 4 mg oral dose of ixazomib as immediate release capsules on Day 1 without food (fasted, administered following an overnight fast) or with food (fed, following consumption of a high-calorie, high-fat meal), followed by another dose on Day 15 in the alternate food intake condition (fasted to fed, or fed to fasted). Twenty-four patients were enrolled; of these, 15 were included in the pharmacokinetic-evaluable population. Administration of ixazomib after a high-fat meal reduced both the rate and extent of absorption of ixazomib. Under fed conditions, the median time to peak plasma concentration (Tmax) of ixazomib was delayed by approximately 3 hours compared with administration in the fasted state (1.
3.Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC Dependent Cell Death in T-Cell and Hodgkin Lymphoma.
Ravi D1, Beheshti A2, Abermil N3, Passero F1, Sharma J1, Coyle M2, Kritharis A2, Kandela I4, Hlatky L5, Sitkovsky MV6, Mazar AP4, Gartenhaus RB7, Evens AM8. Cancer Res. 2016 Mar 17. pii: canres.2477.2015. [Epub ahead of print]
Proteasome regulated nuclear-factor kappa-B has been shown to be important for cell survival in T-cell lymphoma (TCL) and Hodgkin lymphoma (HL) models. Several new small molecule proteasome inhibitors are under various stages of active preclinical and clinical development. We completed a comprehensive preclinical examination of the efficacy and associated biological effects of a second-generation proteasome inhibitor, ixazomib, in TCL and HL cells and in vivo SCID mouse models. Our results demonstrated that ixazomib induced potent cell death in all cell lines at clinically achievable concentrations. Additionally, it significantly inhibited tumor growth and improved survival in TCL and HL human lymphoma xenograft models. Through global transcriptome analyses, proteasomal inhibition showed conserved overlap in down-regulation of cell cycle, chromatin modification, and DNA repair processes in ixazomib sensitive lymphoma cells. The predicted activity for tumor suppressors and oncogenes, the impact on "hallmarks of cancer", and the analysis of key significant genes from global transcriptome analysis for ixazomib strongly favored tumor inhibition via down-regulation of MYC and CHK1 its target genes.
4.Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment.
Gupta N1, Hanley MJ1, Venkatakrishnan K1, Perez R2, Norris RE3, Nemunaitis J4, Yang H1, Qian MG1, Falchook G5, Labotka R1, Fu S6. Br J Clin Pharmacol. 2016 Apr 28. doi: 10.1111/bcp.12991. [Epub ahead of print]
AIM: To characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. Methods Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4, 2.3 or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h post-dose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles.