Population pharmacokinetics of cabazitaxel in patients with advanced solid tumors.

Abstract

PURPOSE:

To develop a population pharmacokinetic (PK) model for cabazitaxel in patients with advanced solid tumors and examine the influence of demographic and baseline parameters.

METHODS:

One hundred and seventy patients who received cabazitaxel (10-30 mg/m(2), 1-h IV infusion) every 7 or 21 days in five Phase I-III studies were analyzed by non-linear mixed-effect modeling (NONMEM VI). Model evaluation comprised non-parametric bootstrap and visual predictive checks.

RESULTS:

Cabazitaxel PK was best described by a linear three-compartment model with: first-order elimination; interindividual variability on clearance (CL), central volume of distribution (V1), and all intercompartmental rate constants except K21; interoccasion variability in CL and V1; proportional residual error of 27.8%. Cabazitaxel CL was related to body surface area (BSA) and tumor type (breast cancer; finding confounded by study). Typical CL for a non-breast cancer patient with a BSA of 1.84 m(2) was 48.5 L/h, with V1 26.0 L, steady-state volume of distribution 4,870 L and alpha, beta, and gamma half-lives of 4.4 min, 1.6, and 95 h, respectively. Sex, height, weight, age, Caucasian race, renal/hepatic function, and cytochrome P450 inducer use did not significantly further explain the PK of cabazitaxel. Bootstrap and posterior predictive checks confirmed the adequacy of the model.

CONCLUSIONS:

Cabazitaxel PK appears unaffected by most baseline patient factors, and the influence of BSA on CL is addressed in practice by BSA-dependent doses. This analysis suggests consistent cabazitaxel PK and exposure across most solid tumor types, although the potential influence of breast cancer on CL requires further confirmation.

• Authors: Géraldine M Ferron, Yang Dai, Dorothée Semiond
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 71 Issue 3 Pg. 681-92 (Mar 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23299792 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• Taxoids
• cabazitaxel
• Cytochrome P-450 Enzyme System

Topics

• Adult
• Aged
• Aged, 80 and over
• Algorithms
• Antineoplastic Agents, Phytogenic (pharmacokinetics, therapeutic use)
• Bayes Theorem
• Body Surface Area
• Cytochrome P-450 Enzyme System (metabolism)
• Data Interpretation, Statistical
• Drug Resistance, Neoplasm
• Enzyme Induction (physiology)
• Female
• Half-Life
• Humans
• In Situ Hybridization
• Linear Models
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Nonlinear Dynamics
• Racial Groups
• Taxoids (pharmacokinetics, therapeutic use)