784P - Pharmacokinetic (PK) activity of cabazitaxel (Cbz) in patients (pts) with renal impairment (RI)

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Pharmacology
Prostate Cancer
Cancer in Special Situations
Presenter Analía Azaro
Citation Annals of Oncology (2014) 25 (suppl_4): iv255-iv279. 10.1093/annonc/mdu336
Authors A. Azaro1, J. Rodon2, J. Machiels3, S. Rottey4, S. Damian5, R. Baird6, A. Nieuweboer7, P. Clot8, C. Wack9, L. Shen10, D. Bobilev11, M. de Jonge12
  • 1Molecular Therapeutics Research Unit, Department Of Medical Oncology, Vall d`Hebron University Hospital Institut d'Oncologia, 08035 - Barcelona/ES
  • 2Department Of Medical Oncology, Vall d`Hebron University Hospital Institut d'Oncologia, 08035 - Barcelona/ES
  • 3Medical Oncology, Cliniques Universitaires Saint-Luc, 1200 - Brussels/BE
  • 4Medical Oncology, University Hospital Ghent, 9000 - Ghent/BE
  • 5Department Of Medical Oncology, Fondazione IRCCS National Cancer Institute of Milan, Milan/IT
  • 6Department Of Oncology, University Of Cambridge, Early Phase Clinical Trials Team, Cambridge/GB
  • 7Medical Oncology, Erasmus University Medical Center, Rotterdam/NL
  • 8Clinical And Exploratory Pharmacology, Sanofi, Chilly Mazarin/FR
  • 9Dsar, Drug Disposition, Sanofi, Chilly Mazarin/FR
  • 10Biostatistics, Sanofi, Bridgewater/US
  • 11Oncology Development, Sanofi, Cambridge/US
  • 12Cancer Institute, Erasmus University Medical Center, Rotterdam/NL

Abstract

Aim

Limited data are available on Cbz PK in pts with RI (14 with moderate RI, 1 with severe RI [Ferron, Cancer Chemother Pharmacol 2013]). This open-label, multicentre study assessed Cbz PK in pts with advanced solid tumours and normal or impaired renal function.

Methods

Pts enrolled into cohorts A (normal control, creatinine clearance [CrCL] >80 ml/min/1.73 m2), B (moderate RI, CrCL 30– < 50 ml/min/1.73 m2) or C (severe RI, CrCL <30 ml/min/1.73 m2) received Cbz 25 mg/m2 Q3W (A and B), or 20 mg/m2, which could be increased to 25 mg/m2 (C). The primary endpoint was Cbz PK (clearance normalised to body surface area [CL/BSA]; area under the curve normalised to dose [AUC/dose]). PK parameters were calculated by non-compartmental analysis and individual modelling using a 3-compartment open model with first-order elimination. Log PK parameters and Cbz unbound fraction (FU) were analysed using linear regression and linear mixed models, respectively. Geometric mean (GM) estimates were determined using log CrCL corresponding to the mean of each cohort's CrCL interval (moderate and severe RI: 40 and 15 ml/min/1.73 m2, respectively). GM ratios (GMRs) were expressed vs control (90 ml/min/1.73 m2).

Results

Pts (n = 25) received a median of 3 Cbz cycles (range 1–20: cohort A, 5 [2–13]; cohort B, 3 [1–15]; cohort C, 5 [1–20]), and 24 were eligible for PK analysis (8/cohort). For moderate and severe RI vs controls, GMR estimates were: CL/BSA 0.95 (90% CI 0.80–1.13) and 0.89 (0.61–1.32); AUC/dose 1.06 (0.88–1.27) and 1.14 (0.76–1.71); FU 0.99 (0.94–1.04) and 0.97 (0.87–1.09), respectively. Estimated slope of linear regression of log parameters vs log CrCL was: CL/BSA 0.06 (90% CI -0.15–0.28); AUC/dose -0.07 (-0.30–0.16); Cbz FU 0.02 (-0.05–0.08). Cbz safety was consistent with previous reports.

Conclusions

RI had no clinically meaningful effect on Cbz PK. Non-significant trends of increasing AUC and decreasing Cbz CL with greater RI were seen.

PK parameter estimates for pts with moderate and severe renal impairment and controls
GM estimate (90% CI)
Control CrCL 90 ml/min/1.73 m2 Moderate renal impairment CrCL 40 ml/min/1.73 m2 Severe renal impairment CrCL 15 ml/min/1.73 m2
CL/BSA, l/h/m2 29.81 (24.18–36.75) 28.34 (24.44–32.86) 26.66 (20.15–35.27)
AUC/dose, ng*h/ml/mg/m2 33.23 (26.65–41.44) 35.21 (30.24–40.99) 37.75 (28.29–50.39)
Cbz FU, % 5.51 (5.08–5.96) 5.44 (5.13–5.76) 5.36 (4.95–5.80)

Disclosure

J. Machiels: has been a member of advisory boards for Boehringer Ingelheim and Novartis and his institution has received research funding from Sanofi; S. Rottey: has attended advisory boards and received research funding from Sanofi; R. Baird: has received research funding from Sanofi; P. Clot and C. Wack: is an employee of Sanofi; L. Shen and D. Bobilev: is an employee and stock holder of Sanofi. All other authors have declared no conflicts of interest.