Litaty C. Mbatchi (1,2,3) Matthieu Gassiot (1,3), Philippe Pourquier (3), Michel Audran (4), Guilhem Roubaud (5), Alexandre Evrard (1,2,3),and Nadine Houede (3)
(1) Laboratoire de biochimie, Centre Hospitalier Universitaire (CHU) of Nîmes, Hôpital Carémeau, Nîmes, France ; (2) Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France (3) IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, INSERM, U1194 France ; (4) Laboratoire de Biophysique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France (5) Service d'oncologie médicale, Institut Bergonié Bordeaux
Objectives: To develop a PK model of temsirolimus and its active metabolite sirolimus, and to correlate the exposure with the antitumoral response and with pharmacogenetics markers.
Methods: In a multicentric phase II study, 16 bladder cancer patients received once weekly infusion of temsirolimus at the dose of 25mg. Whole blood sample were collected at 0 hours (predose) and at 0.5, 1, 2, 6, 24, 74, 96, and 168 hours after the start of the infusion during the first week. A HPLC-MS/MS method was validated in order to quantify temsirolimus and sirolimus its active metabolite. Plasma concentrations were fitted to a pharmacokinetic model using non-linear mixed-effects modelling implemented in NONMEM V7.2.0 [1]. Area Under Curve (AUC) of each molecule were calculated by using the individuals estimation of clearance (AUC=DOSE/clearance) and we also calculated the total AUC of the active coumpounds (AUCTEMSIROLIMUS + AUCSIROLIMUS). Associations between pharmacokinetic parameters and efficacy or polymorphisms in genes that control the metabolisms of our compounds (CYP3A4, CYP3A5, ABCB1 and NR1I2) were assessed.
Results: A 3-compartment model with zero-order infusion was shown to most adequately describe the concentrations of temsirolimus. For sirolimus, the active metabolite, a 2-compartment model with first-order input was found as the most adequate.
Conclusion: This model could help to optimize the dosing of temsirolimus for bladder patient and also in. for metastatic renal cancer, which is the main indication of temsirolimus.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] https://www.pharmgkb.org/
Reference: PAGE 25 (2016) Abstr 5838 [www.page-meeting.org/?abstract=5838]
Poster: Drug/Disease modeling - Oncology