Alicja Puszkiel (1), Cécile Arellano (1), Christelle Vachoux (1), Alexandre Evrard (2,3), Valérie Le Morvan (4), Jean-Christophe Boyer (2), Jacques Robert (4), Caroline Delmas (1,5), Florence Dalenc (1,5), Marc Debled (4), Laurence Venat-Bouvet (6), William Jacot (3,7), Etienne Suc (8), Isabelle Sillet Bach (9), Thomas Filleron (5), Henri Roché (5), Etienne Chatelut (1,5), Fabienne Thomas (1,5), Melanie White-Koning (1)
(1) Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France (2) Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes-Carémeau, Nîmes, France (3) IRCM, Inserm, Université de Montpellier, ICM, Montpellier, France (4) Institut Bergonié, Bordeaux, France (5) Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse – Oncopole, Toulouse, France (6) CHU Dupuytren, Limoges, France (7) Institut du Cancer de Montpellier, Montpellier, France (8) Clinique Saint Jean du Languedoc, Toulouse, France (9) CH, Brive, France
Objectives: Plasma levels of endoxifen (ENDO), the major active metabolite of tamoxifen (TAM), vary widely among individuals (1) which may explain the high inter-individual variability (IIV) in efficacy and toxicity observed in breast cancer patients (2). The aim of this study was to develop a population pharmacokinetic (PK) model for TAM and six of its metabolites in breast cancer patients and to investigate the impact of genetic polymorphisms and co-medications on TAM metabolism.
Methods: PK data for TAM and six metabolites (N-desmethyl TAM [NDT], 4-hydroxy-TAM [4-OHTAM], 4’-OHTAM, ENDO, Z’-ENDO and N-oxyde TAM [NOX-TAM]) come from a prospective, multicenter, 3-year follow up study of breast cancer patients initiating adjuvant TAM treatment (20 mg/day). Plasma samples were drawn 24 hours post-dose every 6 months over a 3-year period and co-medications at time of PK sampling were recorded. A validated UPLC-MS/MS method (3) was used to measure plasma concentrations of TAM and metabolites. Analysis of CYP2D6, CYP3A4, CYP2C19 and CYP2B6 genetic polymorphisms was performed at study inclusion. Patients were assigned a CYP2D6 phenotype – poor (PM), intermediate (IM), normal (NM) or ultrarapid metaboliser (UM) – based on the presence of functional (*1), reduced function (*9, *10, *17, *41) or non-functional alleles (*4, *6, *7) and the number of gene copies (*5 or gene duplication). PK analysis was performed using non-linear mixed-effects modelling in NONMEM 7.4.1.
Results: The preliminary concentration-time data for TAM and six metabolites included 27 076 concentrations from 917 patients and were analysed simultaneously with a seven-compartment model. Apparent volumes of distribution of the metabolites (V/F/fm) were not identifiable and were fixed to the value of V/F of TAM. The formation of primary or secondary metabolites and their subsequent elimination were described by first-order conversion (k) or elimination (ke) rate constants, respectively. The IIV was included on PK parameters according to an exponential model. The base model was used to perform covariate analysis with significance levels of p<0.05 and p<0.01 in the forward and backward steps, respectively. The estimates of kNDT/ENDO were 81% and 65% lower in CYP2D6 PM and IM patients, respectively, and 47% higher in UM patients, compared to the estimate in NM patients. In addition, kTAM/4-OHTAM was decreased in both CYP2D6 IM and PM patients by 28%. Carriers of CYP3A4*22 allele had significantly lower kTAM/NDT (–21%) and ke,NDT (–19%) whereas patients with CYP2B6*6/*6 genotype had significantly lower kTAM/NOX-TAM (–26%). Use of weak/moderate or potent CYP2D6 inhibitors decreased kNDT/ENDO in CYP2D6 NM and UM patients by 29% and 47%, respectively, whereas they had no effect on kNDT/ENDO in CYP2D6 IM and PM patients. Finally, ke,NDT increased with body weight whereas kTAM/NDT, kTAM/4-OHTAM and kNDT/ENDO decreased with age. The final estimates (%RSE) of the PK parameters were: kTAM/NDT =7.3 x 10-3 h-1 (2%), IIV = 31% (3%), kTAM/4-OHTAM = 6.2 x 10-5 h-1 (20%), IIV = 51% (3%), kTAM/4’-OHTAM = 6.1 x 10-8 h-1 (2%), IIV = 20% (5%), kTAM/NOX-TAM = 2.5 x 10-7 h-1 (2%), IIV = 45% (3%), kNDT/ENDO,CYP2D6 UM = 10.4 x 10-4 h-1 (10%), kNDT/ENDO,CYP2D6 NM = 7.1 x 10-4 h-1 (7%), IIV = 48% (3%), kNDT/ENDO,CYP2D6 IM = 2.5 x 10-4 h-1 (9%), kNDT/ENDO,CYP2D6 PM = 1.3 x 10-4 h-1 (12%), kNDT/Z’-ENDO = 4.1 x 10-7 h-1 (1%), k4-OHTAM/ENDO = 3.4 x 10-3 h-1 (19%), ke,NDT = 3.5 x 10-3 h-1 (4%) IIV = 46% (3%), ke,ENDO = 12 x 10-3 h-1 (6%), ke,4’-OHTAM = 2.0 x 10-6 h-1(fixed), ke,NOX-TAM = 1.8 x 10-6 h-1(fixed), ke,Z’ENDO = 1.1 x 10-5 h-1 (fixed). The visual predictive check showed good agreement between observed and predicted concentrations. According to simulations, at standard dose of 20 mg/day, 11%, 40% and 93% of PM, IM and NM, respectively, reach the target ENDO level. A dose increase to 40 and 80 mg/day in PM patients increased the number of patients reaching the therapeutic threshold to 54% and 94%, respectively. In IM patients, a dose increase to 40 and 60 mg/day would result in reaching ENDO target in 85% and 98% patients, respectively.
Conclusions: A dose increase to 80 and 40 mg/day in CYP2D6 PM and IM patients, respectively, could help to increase the number of patients reaching the target ENDO concentration consistently with previous reports (4). Research with efficacy data is needed to confirm the clinical benefit of CYP2D6 phenotype guided dosing.
References:
[1] Mürdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W, et al. Activity Levels of Tamoxifen Metabolites at the Estrogen Receptor and the Impact of Genetic Polymorphisms of Phase I and II Enzymes on Their Concentration Levels in Plasma. Clin Pharmacol Ther. Wiley-Blackwell; 2011;89:708–17.
[2] Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet. Elsevier; 1998;351:1451–67.
[3] Arellano C, Allal B, Goubaa A, Roché H, Chatelut E. An UPLC–MS/MS method for separation and accurate quantification of tamoxifen and its metabolites isomers. J Pharm Biomed Anal. Elsevier; 2014;100:254–61
[4] Klopp-Schulze L, Joerger M, Wicha SG, ter Heine R, Csajka C, Parra-Guillen ZP, et al. Exploiting Pharmacokinetic Models of Tamoxifen and Endoxifen to Identify Factors Causing Subtherapeutic Concentrations in Breast Cancer Patients. Clin Pharmacokinet. Springer International Publishing; 2018;57:229–42.
Reference: PAGE 28 (2019) Abstr 9171 [www.page-meeting.org/?abstract=9171]
Poster: Drug/Disease Modelling - Oncology