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Switching from body surface area‐based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis
Author(s) -
Gupta Neeraj,
Zhao Yuan,
Hui AiMin,
Esseltine DixieLee,
Venkatakrishnan Karthik
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12542
Subject(s) - ixazomib , dosing , pharmacokinetics , body surface area , population , pharmacology , medicine , nonmem , volume of distribution , proteasome inhibitor , carfilzomib , multiple myeloma , environmental health
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 ( K a 0.5 h −1 ), with dose‐ and time‐independent pharmacokinetics. Estimated absolute bioavailability and clearance were 60% and 2 l h −1 , respectively. Although a small effect of BSA (range 1.3–2.6 m 2 ) was observed on the peripheral volume of distribution ( V 4 ), 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 AUC s (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.