Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling.

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Gupta N, Diderichsen PM, Hanley MJ, Berg D, van de Velde H, Harvey RD, Venkatakrishnan K

Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling.

Clin Pharmacokinet. 2017 Nov;56(11):1355-1368. doi: 10.1007/s40262-017-0526-4.

PubMed ID

28290121 [ View in PubMed

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Abstract

Ixazomib is an oral proteasome inhibitor, approved in USA, Canada, Australia and Europe in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We report a population pharmacokinetic model-based analysis for ixazomib that was pivotal in describing the clinical pharmacokinetics of ixazomib, to inform product labelling. Plasma concentration-time data were collected from 755 patients who received oral or intravenous ixazomib in once- or twice-weekly schedules in ten trials, including the global phase III TOURMALINE-MM1 study. Data were analysed using nonlinear mixed-effects modelling (NONMEM software version 7.2, ICON Development Solutions, Hanover, MD, USA). Ixazomib plasma concentrations from intravenous and oral studies were described by a three-compartment model with linear distribution and elimination kinetics, including first-order linear absorption with a lag time describing the oral dose data. Body surface area on the volume of the second peripheral compartment was the only covariate included in the final model. None of the additional covariates tested including body surface area (1.2-2.7 m(2)), sex, age (23-91 years), race, mild/moderate renal impairment and mild hepatic impairment were found to impact systemic clearance, suggesting that no dose adjustment is required based on these covariates. The geometric mean terminal disposition phase half-life was 9.5 days, steady-state volume of distribution was 543 L and systemic clearance was 1.86 L/h. The absolute bioavailability of an oral dose was estimated to be 58%.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Ixazomib	Cytochrome P450 1A2	Protein	Humans	Unknown	Substrate	Details