2017 - Budapest - Hungary

PAGE 2017: Benefit-Risk assessment
Neeraj Gupta

Model-Informed Drug Development (MIDD) for ixazomib, an oral proteasome inhibitor

Neeraj Gupta (1), Michael J. Hanley (1), Paul M Diderichsen (2), Huyuan Yang (1), Yeamin Huh (3), Alice Ke (4), Zhaoyang Teng (1), Richard Labotka (1), Deborah Berg (1), Chirag Patel (1), Guohui Liu (1), Helgi van de Velde (1), and Karthik Venkatakrishnan (1)

(1) Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. (2) Quantitative Solutions, Breda, The Netherlands (3) Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA (4) Certara USA, Inc., Princeton, NJ, USA

Objectives: Ixazomib is approved in the US, EU, Canada, Australia, Venezuela, Israel, Singapore, and Switzerland, in combination with lenalidomide-dexamethasone (Rd), for the treatment of patients with multiple myeloma (MM) who have received at least 1 prior therapy. MIDD was used across the ixazomib development continuum, including population (pop) PK analysis, concentration (conc)-QTc analysis, exposure-response (ER) analysis, physiologically-based pharmacokinetic (PBPK) modeling, and model-based meta-analysis (MBMA), to make drug development decisions and facilitate regulatory review.

Methods: PK and clinical data from multiple studies, including the phase 3 TOURMALINE-MM1 (T-MM1) study[1], contributed to MIDD analyses. Pop PK analyses were performed using NLME modeling in NONMEM v7.2. ER relationships were examined using logistic regression analysis in SAS v9.2. The conc-QTc relationship was assessed using linear mixed-effects models in R v3.0.1. A PBPK model was developed using SimCYP v15. A MBMA framework was developed using R to predict progression-free survival (PFS) from overall response rate (ORR) in relapsed/refractory (RR)MM.

Results: A pop PK analysis (N=137) supported the switch from body surface area-based to fixed dosing in early clinical development[2], simplifying dosing and capsule strength manufacture. A conc-QTc analysis of data from 4 phase 1 studies (N=245) showed no effect of ixazomib on the QTc interval[3], obviating the need for a dedicated QTc study. Pop PK analysis of phase 1-3 data (N=755) confirmed that no dose adjustment is necessary for ixazomib on the basis of age (23-91 years), sex, BSA, or race, or for mild-moderate renal impairment (CrCl ≥30 mL/min) or mild hepatic impairment[4]. A PBPK model enabled an integrated understanding of the victim drug-drug interaction profile for ixazomib. ER analyses on data (N=347) from T-MM1 quantitatively supported the benefit-risk and regulatory review of the 4 mg starting dose[5]. Separate ER analyses supported the dose titration approach in phase 3 maintenance trials[6] and a planned phase 2/3 study in RRMM. A MBMA predicted a PFS of 20 months based on an ORR of 78% for ixazomib-Rd[7], consistent with results of T-MM1[1]. This MBMA framework can be used to inform future decision-making and the strategy for new combinations in lifecycle management.

Conclusions: MIDD played a pivotal role in the development of ixazomib, impacting internal decisions, regulatory review, and product labeling.

[1] Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016;374(17):1621-34.
[2] Gupta N, Zhao Y, Hui AM, et al. Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis. Br J Clin Pharmacol 2015;79(5):789-800.
[3] Gupta N, Huh Y, Hutmacher MM, et al. Integrated nonclinical and clinical risk assessment of the investigational proteasome inhibitor ixazomib on the QTc interval in cancer patients. Cancer Chemother Pharmacol 2015;76(3):507-16.
[4] Gupta N, Diderichsen PM, Hanley MJ, et al. Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling. Clin Pharmacokinet 2017;manuscript in press.
[5] NINLARO (ixazomib) Clinical Pharmacology NDA Review. US FDA CDER. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208462Orig1s000ClinPharmR.pdf
[6] Gupta N, Labotka R, Liu G, et al. 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. Invest New Drugs. 2016;34(3):338-46.
[7] Gupta N, Teng Z, Labotka R, et al. Model-based meta-analysis (MBMA) for relapsed/refractory multiple myeloma (RRMM): Application of a quantitative drug-independent framework for efficient decisions in oncology drug development. J Pharmacokinet Pharmacodyn 2016;43(suppl):S110 (abstract W-55). Poster presentation the American Conference on Pharmacometrics, October 23–26 2016, Bellevue, Washington, USA.

Reference: PAGE 26 (2017) Abstr 7307 [www.page-meeting.org/?abstract=7307]
Oral: Benefit-Risk assessment
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