Semi-Mechanistic Modelling of the Tumour Growth Inhibitory Effects of a New Anti-angiogenic Drug.
Lorea Bueno1, Dinesh P de Alwis2, Colin Miles2, Sophie Glatt2, and Iñaki F. Trocóniz1
1 Department of Pharmacy and Pharmaceutical Technology; School of Pharmacy; University of Navarra; Pamplona 31080; Spain. 2 Global PK/PD and trial simulations, Eli Lilly and Company, Earl Wood, UK
Objectives: To develop a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for a new antiangiogenic drug using human xenografts.
Methods: Experimental. Human xenografts (NCIH460) were implanted subcutaneously onto nude mice. Experiments started 7 to 10 days after tumour implantation. Two types of investigation were carried out: (i) An experiment providing information about the plasma levels of the antiangiogenic drug and the percentage change (inhibition of a biomarker) with respect to baseline of phospho-pKDR in tumour, and (ii) A tumour growth experiment where the kinetics of tumour growth was monitored during 20 to 41 days after the first day of drug administration. In both experiments, either saline or drug (dose range 1.5 to 40 mg/kg) was administered orally as a single dose or in a multiple dosing design.
Data modeling. Plasma levels of the compound, percentage of pKDR in tumour, and tumour size were used to establish a semi-mechanistic, population PK/PD model that was used to predict tumour stabilisation using NONMEM[1].
Results: Pharmacokinetics. Drug disposition was best described using a two compartment model with first order absorption. Plasma clearance was dose-dependent and was described as a function of plasma concentration using the Michaelis-Menten expression.
Biomarker model. An indirect response model was used to relate the predicted plasma concentrations to the observed inhibition of pKDR. The model assumes the existence of factors within the tumour cell responsible for the synthesis and degradation of pKDR. This process is inhibited by the compound under investigation. The model predicted a complete inhibition of pKDR, and a very rapid turnover rate.
Tumour growth model. The mean signal propagation time was estimated at over 20 days. The effect originated by the decrease in pKDR levels demonstrated a non-linear (amplified) inhibition of tumour proliferation. The results show that 75% tumour growth inhibition is associated with a corresponding decrease in pKDR of 50%.
Conclusion: The integrated model provided a useful tool to investigate different experimental scenarios, and provided valuable insights into the mechanisms of signal transduction and tumour growth. From a developmental perspective, these types of models provide a simulation platform to explore the relationship between drug exposure, efficacy, and toxicity in silico.
[1] Bueno, L et al., (2008). European Journal of Cancer 44, 142-150.
