Hadzliana Zainal, Jill Norman, Joseph Standing, Patricia Wilson
UCL Centre for Nephrology, University College London, London
Objectives: Epidermal growth factor receptor (EGFR) upregulation has been implicated in ADPKD. Inhibition of EGFR will downregulate the downstream target activation of cell proliferation, indicated by the reduced expression of phosphorylated ERK expression. The aim of this project is to determine the concentration-effect relationship of the new generation EGFR inhibitor using PK/PD modelling.
Methods: The C57/BL6 Pkd null +/- mice were gavaged IC50 and IC10 doses on day 1 and subsequent daily dose through drinking water for 1, 2, and 4 weeks. Doses were calculated from previous in vitro proliferation assay. Plasma drug levels 1, 2, 4 and 6 hours post-gavage, terminal plasma and kidney drug concentrations were analysed for PK modelling. For the efficacy study, mice were given inhibitors at IC10 in drinking water for 3 months beginning 6- and 9-months. Kidneys were harvested for analysis of ERK expression through western blotting as PD end-point.
Results: The pharmacokinetic was best described by two-compartment distribution models with first order absorption and an adaptation of enzyme turnover model. Estimated typical clearance (CL/F) value was 0.242 L.h-1 and elimination rate constant (Ke) of 2.84h-1 and enzyme production rate (kENZ) of 0.043h-1. The stability of the model and predicted performance were confirmed by bootstrap method and numerical predictive check.
Conclusions: Based on experimental mice data and in vitro parameters, the model provides a useful tool to quantify the estimated antiproliferative effects and to propose an optimal dosing regimen in mice. Subsequently, biomarker of proliferation is used to relate the pharmacodynamics to the pharmacokinetic model for extrapolation into human use.
References:
[1] Wilson S, Amsler K, Hyink D, Li X, Lu W, Zhou J Wilson PD . Inhibition of Her-2 (neu/ErbB2) restores normal function and structure to polycystic kidney disease (PKD) epithelia: Biochim Biophys Acta 2006; 1762:647-655
[2] Zheleznova NN, Wilson PD. Differential ligand-dependent activation of ErbB1 and ErbB2 cell signalling pathways in human and mouse collecting tubule cells: Implication for ADPKD pre-clinical testing. J Am Soc Nephrol 2009; 20:1467A
[3] Smythe W, Khandelwal A, Merle C, Rustomjee R, Gninafon M, Bocar Lo M, Sow OB, Olliaro PL, Lienhardt C, Horton J, Smith P, McIlleron H and Simonsson US (2012) A semimechanistic pharmacokinetic-enzyme turnover model for rifampin autoinduction in adult tuberculosis patients. Antimicrob Agents Chemother 56(4):2091-2098.
Reference: PAGE 24 (2015) Abstr 3531 [www.page-meeting.org/?abstract=3531]
Poster: Drug/Disease modeling - Other topics