Population pharmacokinetics of cabazitaxel in patients with advanced solid tumors

• Published in: Cancer chemotherapy and pharmacology Vol. 71; no. 3; pp. 681 - 692
• Main Authors: Ferron, Géraldine M., Dai, Yang, Semiond, Dorothée
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2013; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Algorithms; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - therapeutic use; Bayes Theorem; Biological and medical sciences; Body Surface Area; Cancer Research; Continental Population Groups; 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; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - metabolism; Nonlinear Dynamics; Oncology; Original; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Taxoids - pharmacokinetics; Taxoids - therapeutic use; Tumors; Advanced solid tumors; Urogenital cancer; Population pharmacokinetics; Chemotherapy; Taxane; Cabazitaxel; Antineoplastic agent; Human; Solid tumor; Urinary system disease; Genitourinary cancer; Malignant tumor; Genital diseases; Treatment; Taxane derivatives; Advanced stage; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-2058-9

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.