Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis

Abstract

Aims: This population pharmacokinetic analysis of the investigational oral proteasome inhibitor ixazomib assessed the feasibility of switching from body surface area (BSA)-based to fixed dosing, and the impact of baseline covariates on ixazomib pharmacokinetics.

Methods: Data were pooled from 226 adult patients with multiple myeloma, lymphoma or solid tumours in four phase 1 studies, in which ixazomib dosing (oral/intravenous, once/twice weekly) was based on BSA. Population pharmacokinetic modelling was undertaken using nonmem version 7.2.

Results: Ixazomib pharmacokinetics were well described by a three compartment model with first order absorption and linear elimination. Ixazomib was absorbed rapidly (Ka 0.5 h(-1)), with dose- and time-independent pharmacokinetics. Estimated absolute bioavailability and clearance were 60% and 2l h(-1), respectively. Although a small effect of BSA (range 1.3-2.6 m(2)) was observed on the peripheral volume of distribution (V4), reducing the corresponding inter-individual variability by 12.9%, there was no relationship between BSA and ixazomib clearance (the parameter that dictates total systemic exposure following fixed dosing). Consistently, based on simulations (n = 1000), median AUCs (including interquartile range) were similar after BSA-based (2.23 mg m(-2)) and fixed (4 mg) oral dosing with no trend in simulated AUC vs. BSA for fixed dosing (P = 0.42). No other covariates, including creatinine clearance (22-213.7 ml min(-1)) and age (23-86 years), influenced ixazomib pharmacokinetics.

Conclusions: This analysis supports a switch from BSA-based to fixed dosing, without dose modification for mild/moderate renal impairment or age, in future adult studies of ixazomib, simplifying dosing guidance and clinical development.

Keywords: ixazomib; population PK; proteasome inhibitor; renal insufficiency.

Figure 1

Mean plasma concentration–time profiles following single dose administration of (A) intravenous ixazomib, , 0.125 mg m⁻² (n = 1); , 0.25 mg m⁻² (n = 7); , 0.5 mg m⁻² (n = 10); , 1.4 mg m⁻² (n = 4); , 1.76 mg m⁻² (n = 1); , 2.34 mg m⁻² (n = 1); , 3.11 mg m⁻² (n = 5) and (B) oral ixazomib (weekly dosing regimens), , 0.24 mg m⁻² (n = 1); , 0.48 mg m⁻² (n = 1); , 0.80 mg m⁻² (n = 2); , 1.20 mg m⁻² (n = 1); , 1.68 mg m⁻² (n = 3); , 2.23 mg m⁻² (n = 2); , 2.97 mg m⁻² (n = 24); , 3.95 mg m⁻² (n = 4)

Figure 2

Final model goodness-of-fit plots: (A) log-transformed observed vs. log-transformed population-predicted ixazomib plasma concentration (PRED), (B) log transformed observed vs. log transformed individual predictions of ixazomib plasma concentration (IPRED), (C) conditional weighted residuals (CWRES) vs. PRED and (D) CWRES vs. time after first dose of ixazomib. In A and B, the green line is a line with a slope of 1. In C and D, it is a line with a slope of 0. The blue line in all four panels represents the LOWESS (locally weighted scatterplot smoothing) line. The plots in A and B demonstrate a lack of bias in the model and that the model is appropriate for the population and each individual. The plots in panels C and D indicate a lack of bias in the structural and residual error models

Figure 3

Relationship between inter-individual variability (IIV) in clearance (CL) and (A) body surface area (BSA), (B) patient age, (C) creatinine clearance (CL_cr), (D) ixazomib dose, (E) patient gender and (F) patient race (n = 226). A–D are scatter plots of IIV in CL vs. the covariate. The symbols indicate observed values and the solid blue line represents the LOWESS (locally weighted scatterplot smoothing) line. E and F are box plots of the distribution of IIV in CL by the covariate.The black line within the box is at the median, the box is bounded by the 25th and 75th percentiles of the distribution and the whiskers represent 1.5 times the interquartile range. There was no apparent relationship between ixazomib CL and any of the covariates tested

Figure 4

Dose-normalized ixazomib concentration over time and model-simulated median and 90% prediction interval following (A) intravenous and (B) oral dosing. Observed data (open circles) are from various doses tested in the dose escalation studies and scaled to a dose of 4 mg. Simulations were done for ixazomib 4 mg. Visual predictive checks showed that the model was able to characterize both intravenous and oral data. , median; , high; , low; ○, observations (doses >1 mg)

Figure 5

Simulated area under the plasma concentration–time curve (AUC) for ixazomib (A) after body surface area (BSA)-based (2.23 mg m⁻²) and fixed (4 mg) dosing (n = 1000) and (B) vs. BSA for fixed dosing. Both simulations in A showed no significant difference in AUC between fixed dosing and BSA-based dosing of ixazomib. The symbols in B indicate simulated values and the solid grey line represents the linear regression line