E. Dahmane (1) (2), K. Zaman (3), L. Perey (4), A. Bodmer (5), S. Leyvraz (3), C.B. Eap (6) (1), M. Galmiche (3), L. Decosterd (2) (7), T. Buclin (2), M. Guidi (1) (2), C. Csajka (1) (2)
(1) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; (2) Division of Clinical Pharmacology, Department of Laboratories, University Hospital Lausanne; Lausanne, Switzerland; (3) Breast Center, Multidisciplinary Center for Oncology (CePO), University Hospital Lausanne; Lausanne, Switzerland; (4) Medical Oncology, Hospital of Morges; (5) Breast Center, University Hospital Geneva, Geneva, Switzerland; (6) Center for Psychiatric Neurosciences, University Hospital Lausanne; Lausanne, Switzerland; (7) Innovation and Development Unit, Department of Laboratories, University Hospital Lausanne; Lausanne, Switzerland.
Objectives: Tamoxifen (Tam) is a pro-drug metabolized to endoxifen and other active metabolites through cytochromes (CYP) 2D6 and 3A4 pathways. Patients with null or reduced CYP2D6 activity display lower endoxifen concentrations and might thus experience lower benefit from their treatment [1]. High variability in Tam and its metabolites levels has been reported and partially attributed to genetic polymorphism in CYP2D6. The aim of this analysis was to characterize the population pharmacokinetics of Tam and its major metabolites, to quantify the inter- and intra-individual variability and to explore the influence of genetic and non-genetic factors on their disposition. Model-based simulations will be performed to derive dose optimization strategies.
Methods: Patients under Tam 20mg/day were genotyped and phenotyped for CYP2D6 and CYP3A4/5. Plasma levels of Tam, N-desmethylTam (NDTam), 4OHTam and endoxifen were measured at baseline (20mg/day), then at 30, 90 and 120 days after a dose escalation to 20 mg twice daily [2]. A stepwise procedure with sequential addition of metabolites was used to find the full structural model that best fitted the observed data (NONMEM®). Owing to identifiability problem, the volume of distribution of Tam and its metabolites were assumed to be equal.
Results: A total of 457 samples were collected from 97 patients. The full model consisted in a 4-compartment model with first-order absorption and elimination and linear conversion to the three metabolites. Average Tam oral apparent clearance (CL/F Tam) was 5.8 L/h (CV 32%), apparent volume of distribution 1113 L with an absorption constant rate (k12) fixed to 0.7 h-1. Estimated apparent Tam to NDTam (k23), Tam to 4OHTam (k24) and NDTam to Endoxifen (k35) metabolic constant rates were 0.008 (13%), 8.5×10-5 (29%) and 6.3×10-4 h-1 (59%), respectively. NDTam, 4OHTam and endoxifen apparent clearances were 5.6 L/h, 7.8 L/h and 19 L/h (conditional on Tam bioavailability and equal volumes of distribution).
Conclusions: Metabolic formation rates were subject to an important variability, in particular regarding endoxifen. The influences of genetic polymorphisms, as well as other factors such as CYP-interfering comedications, compliance, demographics and clinical characteristics were tested on the kinetic parameters in order to identify relevant sources of variability.
References:
[1] Madlensky L, et al. Clin Pharmacol Ther. 2011 May;89(5):718-25.
[2] Dahmane E, et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Dec 15;878(32):3402-14.
Reference: PAGE 22 () Abstr 2910 [www.page-meeting.org/?abstract=2910]
Poster: Oncology