Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling

Abstract

Ixazomib is an oral proteasome inhibitor, approved in USA, Canada, Australia and Europe in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We report a population pharmacokinetic model-based analysis for ixazomib that was pivotal in describing the clinical pharmacokinetics of ixazomib, to inform product labelling. Plasma concentration-time data were collected from 755 patients who received oral or intravenous ixazomib in once- or twice-weekly schedules in ten trials, including the global phase III TOURMALINE-MM1 study. Data were analysed using nonlinear mixed-effects modelling (NONMEM software version 7.2, ICON Development Solutions, Hanover, MD, USA). Ixazomib plasma concentrations from intravenous and oral studies were described by a three-compartment model with linear distribution and elimination kinetics, including first-order linear absorption with a lag time describing the oral dose data. Body surface area on the volume of the second peripheral compartment was the only covariate included in the final model. None of the additional covariates tested including body surface area (1.2-2.7 m²), sex, age (23-91 years), race, mild/moderate renal impairment and mild hepatic impairment were found to impact systemic clearance, suggesting that no dose adjustment is required based on these covariates. The geometric mean terminal disposition phase half-life was 9.5 days, steady-state volume of distribution was 543 L and systemic clearance was 1.86 L/h. The absolute bioavailability of an oral dose was estimated to be 58%.

Fig. 1

Geometric mean of dose-normalised ixazomib concentrations observed in: a TOURMALINE-MM1 binned by visit number (open black circles) with individual observations (grey dots) at the actual sampling times. Triangles indicate protocol-specified dose times and numbers indicate the number of PK samples included in each geometric mean calculation. b Cycle 1 in studies with 21-day treatment cycles (TW dosing) binned by protocol-specified sampling time. Triangles indicate protocol-specified dose times. Error bars show 95% CI of the geometric mean. c Cycle 1 in studies with 28-day treatment cycles (W dosing), binned by protocol-specified sampling time. Triangles indicate protocol-specified dose times. Error bars show 95% CI of the geometric mean. CI confidence interval, IV intravenous, PK pharmacokinetic, PO oral, TW twice weekly, W weekly

Fig. 2

Structural model describing the pharmacokinetics of ixazomib. ALAG1 absorption lag time, CL clearance, F absolute bioavailability of an oral ixazomib dose, IV intravenous, KA absorption rate constant, Q ₃ first inter-compartmental clearance, Q ₄ second inter-compartmental clearance, V ₂ central volume of distribution; V ₃ volume of distribution of first peripheral compartment, V ₄ volume of distribution of second peripheral compartment

Fig. 3

Diagnostic plots: a VPC showing data from the first 4 weeks of all studies based on 1000 simulated datasets. Median and 2.5th–97.5th percentile interval of prediction-corrected observed ixazomib concentrations (black and blue dots, respectively) model simulations (95% CI, grey and blue hatched areas). b VPC showing data from TOURMALINE-MM1 based on 1000 simulated datasets. Median and 2.5th–97.5th percentile interval of prediction-corrected observed ixazomib concentrations (black and blue dots, respectively) model simulations (95% CI, grey and blue hatched areas). c Goodness-of-fit of the final model based on data from all studies (left) and data from TOURMALINE-MM1 (right). Black and grey dots show observed data vs. individual and population predictions, respectively. Red dots indicate observed data below the limit of quantification and the solid line is the line of unity. d Individual random effects on V ₄ based on the base model (left) and final model (right) shown vs. body surface area. Solid and dashed lines show a LOESS smooth curve with corresponding 95% CI. BSA body surface area, CI confidence interval, V ₄ volume of distribution of second peripheral compartment, VPC visual predictive check

Fig. 4

Correlations between key continuous covariates and individual predicted exposure in patients receiving oral ixazomib. Red and black dots indicate the median and 5th and 95th percentile of individual covariate values, respectively. Numbers (brackets) show the percent change in AUC_∞ at the 5th and 95th percentile relative to the value at the median, based on the shown linear regression (and 95% CI). ALB serum albumin, AUC area under the concentration–time curve, BILI total bilirubin, BSA body surface area, CrCl creatinine clearance, HCT hematocrit, WGT weight

Fig. 5

Individual predicted exposure stratified by key categorical patient covariates for patients receiving oral ixazomib. Red and black dots indicate the mean exposure in the most prevalent category and in other categories, respectively. Numbers (brackets) in the top of plots show the percent change in AUC_∞ (with 95% CI) in other categories relative to the most prevalent category, while numbers at the bottom show patients in each category. AUC area under the concentration–time curve, CI confidence interval, len/dex lenalidomide/dexamethasone

Fig. 6

Typical concentration–time profile (and 5th–95th percentile interval of individual predicted profiles) during the first two treatment cycles following oral dosing of ixazomib capsules at 4 mg on days 1, 8 and 15 of 28-day treatment cycles, based on a typical patient (body surface area = 1.88 m²)