RAT SIMULATION RESULTS HUMAN SIMULATION RESULTS Modelling of PK/Efficacy/Toxicity in rats to help design a FHD for a Cell Cycle Inhibitor X Celine Pitou, PharmD1; Sophie Glatt, PhD3;Inaki Troconiz, PhD2 1, PK/PD/TS dpt, Eli Lilly and Co, UK; 2, School of Pharmacy, University of Navarra, Spain; 3, former Lilly employee, currently at UCB Celltech Ltd, UK OBJECTIVES The primary objective of PK/PD modelling in preparation of the FHD study was to estimate a pharmacologically effective and safe dose range in humans, based on preclinical data. In addition, doses and administration schedules for this compound were optimized in order to minimise the duration of neutropenia. METHODS The PK model was built using both oral and IV rat data from 12 studies over a total dose range of 0.5 to 60mpk dosed QD. The PK/efficacy model was developed using rat HCT116 xenograft data by means of a modified Gompertz model (1) where compound LY is assumed to act as a cytotoxic agent by increasing the rate of cell death. This model was built using IV rat data over a total dose range of 10 to 30mpk dosed weekly. This model is described by several parameters: TS0, tumour size at the start of the experiment; Kgw1, rate constant controlling the cell proliferation with an exponential rate; Kgw2, rate constant controlling the cell proliferation with a linear rate; Kdth, rate constant controlling the cell death; Ktr, first order rate of transition. The PK/Tox model was developed using neutrophil count data obtained in nude rats from 5 pharmacology studies over a total dose range of 9 to 60 dosed QD, Q2D, Q3D or Q7D. The model (2) describes the time course of plasma neutrophil count is assumed to reduce the proliferation rate or induce cell loss, which was modelled as a linear function. A time effect was also added to account for the increase in baseline neutrophil count over time. Allometric Scaling approach was performed to predict human PK parameters using mouse, rat, dog and monkey IV PK data (2 cpt model was assumed for all species). MODELLING RESULTS Allometric Scaling Results: The estimated median and 90% CI for human Cl, V1 and V2 were 8.50L/h (4.61-15.42), 121.55L (35.86-391.76) and 36.61L (19.48-68.41), respectively. Inter-individual variability in humans was assumed to be 30% for CL, V1 and V2. Rat PK data are described adequately with a two cpt model with first order absorption Rat PK/efficacy model was better define with a modified Gompertz model Rat PK/Tox model describes the data with a reasonable uncertainty. A time effect for the baseline was added in the model due to the experimental data as shown below. This was also described and modelled in literature (3). It’s important to note that the rats were immunosuppressed which explain the low Circ0 value. RAT SIMULATION RESULTS In order to correlate the efficacy and the myelosuppression rat models, some simulations were performed at several doses. The figure below represents in function of AUC(0-168h), the fold decrease of tumour volume and the fold decrease of neutrophil count. In this figure, the curve of the toxicity is following the curve of the tumour growth decrease. Based on this, the starting targeted efficacious exposure in rats is 5700ng*h/mL. HUMAN SIMULATION RESULTS Human PK and PD simulations in terms of neutrophil count were generated after adaptation of the rat PD parameters from literature data. It was performed following one or two injections per 21-day cycle for the same total dose per cycle. Compound X given twice per cycle gave a more prolonged nadir compare to a single administration over the cycle. This has been noticed for 5-FU in literature (4). These two sets of simulations suggested that, upon one dose every 21 days, a dose range of A to E should be required to reach efficacy and to have a manageable neutropenia. CONCLUSIONS This modelling study combined both efficacy and toxicity rat data within one fully integrated mechanistic model. This integrated model described the rat data adequately and helped connect efficacy and toxicity outcomes. The model was translated to human to derive an efficacious and safe dose range for the FHD study. References: 1. Simeoni et al, Cancer Res 2004;64:1094-1101, 2. Friberg LE et al, J Clin Oncol 2002;20: 4713-4721. 3. Segura et al, Pharm Res 2004:21:567-572, 4. Friberg LE et al, J Pharmacol Exp Ther 2000;295:734-740 Kprol=(ktr) Drug Effect kCirc(=ktr) Neu MTT Trst 1 ktr feedback=(Circ0/circ)g Prol Trst 2 Trst 3