• Neeraj Gupta, Yuan Zhao, Ai-Min Hui, Dixie-Lee Esseltine, and Karthik Venkatakrishnan.
• Clinical Pharmacology, Takeda Pharmaceuticals International Co, Cambridge, MA, USA.
• Br J Clin Pharmacol. 2015 May 1; 79 (5): 789-800.

AimsThis 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.MethodsData 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.ResultsIxazomib 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.ConclusionsThis 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.© 2014 The British Pharmacological Society.

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