Dataset Information

Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis.

ABSTRACT:

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.

SUBMITTER: Gupta N

PROVIDER: S-EPMC4415715 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Publications

Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis.

Gupta Neeraj N Zhao Yuan Y Hui Ai-Min AM Esseltine Dixie-Lee DL Venkatakrishnan Karthik K

British journal of clinical pharmacology 20150501 5

<h4>Aims</h4>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.<h4>Methods</h4>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 pharmaco ...[more]

PMID: 25377318

Similar Datasets

Project description:Background:Capecitabine is generally dosed based on body surface area (BSA). This dosing strategy has several limitations; however, evidence for alternative strategies is lacking. Therefore, we analyzed the toxicity and effectiveness of fixed-dose capecitabine and compared this strategy with a BSA-based dose of capecitabine in a large set of patients. Methods:Patients treated with fixed-dose capecitabine between 2003 and 2015 were studied. A comparable group of patients, dosed based on BSA, was chosen as a control cohort. A total of two combined scores were used: capecitabine-specific toxicity (diarrhea, National Cancer Institute Common Toxicity Criteria grade ?3, hand-foot syndrome ?2, or neutropenia ?2), and clinically relevant events due to toxicity, that is, hospital admission, dose reduction, or discontinuation. Per treatment regimen, patients were divided into three BSA groups based on BSA quartiles corrected for sex. Toxicity scores were compared by a Chi-square test between cohorts, and within cohorts using BSA groups. Progression-free survival (PFS) was estimated by the Kaplan-Meier method. Results:A total of 2319 patients were included (fixed dosed, n = 1126 and BSA-based dose, n?=?1193). Overall, four regimens were evaluated: capecitabine-radiotherapy (n = 1178), capecitabine-oxaliplatin (n = 519), capecitabine triplet (n = 181) and capecitabine monotherapy (n = 441). The incidence of capecitabine-specific toxicity and clinically relevant events was comparable between fixed-dose and BSA-dosed patients, while a small difference (7.1%) in absolute dose was found. Both cohorts showed only a higher incidence of both toxicity scores in the lowest BSA group of the capecitabine-radiotherapy group (p < 0.05). Subgroups of the fixed-dose cohort analyzed for PFS, showed no differences between BSA groups. Conclusions:Fixed-dose capecitabine is as comparably well tolerated and effective as BSA-based dosing and could be considered as a reasonable alternative for BSA-based dosing.

Dataset Information

Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis.

Aims

Methods

Results

Conclusions

Publications

Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis.

Similar Datasets

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