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.