Bernardo Miguel-Lillo (1,7), Belén Valenzuela (2,3), José Esteban Peris-Ribera (4), Jorge L. Iglesias (5), Vicente Alfaro (5), Arturo Soto-Matos (1,5), Juan José Pérez-Ruixo (6).
(1) Clinical Pharmacology, Pharma Mar, Colmenar Viejo, Madrid, Spain. (2) Platform of Oncology, Hospital Quirón Torrevieja. Torrevieja, Alicante, Spain. (3) Cathedra of Multidisciplinary Oncology. UCAM Catholic University of San Antonio, Murcia, Spain. (4) Pharmacy and Pharmaceutical Technology Department, Valencia University, Valencia, Spain. (5) Clinical Development, Pharma Mar, Colmenar Viejo, Madrid, Spain. (6) Model Based Drug Development, Janssen Research & Developments, Beerse, Belgium. (7) SGS Exprimo NV, Mechelen, Belgium.
Objectives: Reversible transient elevation of alanine aminotransferase (ALT) is observed after intravenous (iv) administration of kahalalide F (KF) in cancer patients. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model to describe the transient elevation of ALT following different KF dosing schedules.
Methods: A precursor-dependent indirect pharmacodynamic response model (1) was used to characterize the ALT time course (data from 250 patients) using NONMEM (2) , where the transfer process of ALT from hepatocytes to plasma was stimulated by plasma KF concentrations. Potential effect of patient´s covariates was analyzed. Model evaluation was performed using visual predictive check and non-parametric bootstrap. Simulations were conducted to explore the role of dosing schedule on the incidence of severe ALT.
Results: The model differentiated between patients with (14%) and without (86%) ALT elevation. Baseline and terminal half-life for serum ALT were estimated to be 0.517 xULN and 45.5 h, respectively. Evaluated covariates did not significantly explain pharmacodynamic variability, but liver metastasis was associated with a 24% decrease in baseline serum ALT. The model evaluation evidenced an accurate prediction of the incidence of ALT grade 2 and >3. Simulations showed that time course of ALT depends on dose and dosing schedule, but not on the infusion duration.
Conclusions: The time course of ALT after KF iv infusion was adequately characterized by the model developed. According to simulations, the dosing schedule selected for phase II studies (650 µg/m² iv 1 h weekly) will not increase substantially the risk of severe ALT increase in cancer patients.
References:
[1] Fetterly GJ, Owen JS, Stuyckens K, Passarell JA, Zannikos P, Soto-Matos A, Izquierdo MA, Perez-Ruixo JJ Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment. Cancer chemotherapy and pharmacology. 2008;62(1):135-147.
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 25 (2016) Abstr 5711 [www.page-meeting.org/?abstract=5711]
Poster: Drug/Disease modeling - Oncology