Modelling of PK/Efficacy/Toxicity in rats to help design a First Human Dose for a cell cycle inhibitor X
Celine Pitou, PharmD1; Inaki Troconiz, PhD2; Sophie Glatt, PhD3
1, Global PK/PD/TS department, Eli Lilly and Company, UK; 2, School of Pharmacy, University of Navarra, Spain; 3, former Lilly employee, currently at UCB Celltech Ltd, UK
Objective: 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: Two mechanistic rat models were built sequentially: the first one describing the efficacy, the second one describing the toxicity. These rat models were generated as follows:
- PK/efficacy model describing the tumour growth rate proportional to both the drug concentration and the number of proliferating tumour cells in both the placebo and the treated groups,
- PK/Tox model describing the neutrophil count over time as a function of the drug concentration. An allometric scaling approach was also applied to predict the human PK parameters. The fully integrated model was then connected to the projected human PK model.
Results: The two fully mechanistic models adequately described the tumour growth and neutrophil data in the rat. A linear relationship between tumour regression and myelosuppression was characterized, allowing to select a targeted efficacious exposure while maintaining myelosuppression to an acceptable level. A similar linear relationship between efficacy and toxicity was assumed in human and the same approach was adopted using an humanised neutrophil model connected to the projected human PK model. The result of the simulations in humans suggested that a dose range of A-E administrated once every 21 days in human was expected to provide efficacy while maintaining neutropenia to a manageable level.
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
