Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis.
OBJECTIVE
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.
Clinical Pharmacology, Takeda Pharmaceuticals International Co, Cambridge, MA, USA.
Neeraj
N
Gupta
Yuan
Y
Zhao
Ai-Min
AM
Hui
Dixie-Lee
DL
Esseltine
Karthik
K
Venkatakrishnan
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001830:Body Surface Area; D001896:Boron Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D017321:Clinical Trials, Phase I as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007275:Injections, Intravenous; D008223:Lymphoma / Q000097:blood / Q000188:drug therapy; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
D000970:Antineoplastic Agents; D001896:Boron Compounds; D011480:Protease Inhibitors; C548400:ixazomib; D005998:Glycine
ixazomib; population PK; proteasome inhibitor; renal insufficiency