Model-Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor

Abstract

Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of ixazomib.

Figure 1

MIDD across the development continuum for ixazomib.

Figure 2

(a) Relationship between BSA and ixazomib clearance (numbers represent individual patients enrolled across four different phase I studies). (b) Relationship between ixazomib plasma concentrations and mean change from baseline in QTcF.

Figure 3

(a) Fold change in ixazomib AUC according to baseline covariates (test vs. reference), and (b) PBPK model‐predicted and observed geometric least squares mean AUC ratios for ixazomib with and without various strong CYP3A inhibitors and strong CYP3A inducers.18 For predicted data, error bars represent the 5th and 95th percentile. Panel b reproduced from Gupta, N. et al. J. Clin. Pharmacol. 58, 180–192. doi:10.1002/jcph.988 (2017)18 under the Creative Commons license: https://creativecommons.org/licenses/by-nc/4.0/legalcode

Figure 4

(a) Ixazomib exposure–PFS analysis in the ixazomib‐Rd and placebo‐Rd arms of TOURMALINE‐MM1.21 Kaplan–Meier curves show PFS distributions in the placebo‐Rd arm and in the ixazomib‐Rd (IRd) arm by quartiles of ixazomib exposure. (b–e) Observed incidence and predicted probability of (b) grade ≥2 rash, (c) grade ≥3 thrombocytopenia, (d) grade ≥2 fatigue, and (e) grade ≥2 diarrhea as a function of ixazomib exposure using a logistic regression model.21 Black circles and error bars show the event probabilities plus 95% CI in the placebo‐Rd arm and in the IRd arm within each ixazomib exposure quartile. Reproduced from Gupta, N. et al. Target. Oncol. 12, 643–654. https://doi.org/10.1007/s11523-017-0524-3 (2017)21 under the Creative Commons license: https://creativecommons.org/licenses/by-nc/4.0/legalcode

Figure 5

(a) Analysis of lenalidomide RDI according to ixazomib exposure (AUC_inf) in the ixazomib‐Rd arm of TOURMALINE‐MM1, showing probability of lenalidomide RDI ≥60%.21 Black circles and error bars show the event probabilities plus 95% CI in the ixazomib‐Rd arm within each ixazomib exposure quartile. (b) Schematic illustrating the relationship between ixazomib dose, systemic exposure, and the RDI of lenalidomide in the ixazomib‐Rd regimen.21 Reproduced from Gupta, N. et al. Target. Oncol. 12, 643–654. https://doi.org/10.1007/s11523-017-0524-3 (2017) 21 under the Creative Commons license: https://creativecommons.org/licenses/by-nc/4.0/legalcode

Figure 6

Relationship between ixazomib exposure and TEAEs or clinical benefit rate.20 Reproduced from Gupta, N. et al. Invest. New Drugs 34, 338–346, https://doi.org/10.1007/s10637-016-0346-7 (2016) under the Creative Commons license: https://creativecommons.org/licenses/by-nc/4.0/legalcode

Figure 7

(a) Relationship between ORR and median PFS using data from seven phase III studies. The blue line represents the linear regression line and the gray band represents the 95% CI. (b) An illustrative example of predicting PFS using ORR. The probability of achieving the target product profile (PFS 15 months) is 34% (purple area) and the probability of achieving the minimum detectable PFS is 60% (blue area). Reproduced from Teng, Z. et al. Clin. Transl. Sci. e‐pub ahead of print (2017) 22 under the Creative Commons license: https://creativecommons.org/licenses/by-nc/4.0/legalcode