A Novel PKPD Model to Describe the Interaction of Drug Response of Combination Therapy: An Application in Preclinical Oncology.
Jackson K (1), Chedid M (2), Evans R (2) Troconiz IF(3)
(1) PKPD Department, Eli Lilly and Company, UK ; (2) Department of Oncology Cell Biology, Eli Lilly and Company, USA; (3) Department of Pharmacy, School of Pharmacy, University of Navarra, Pamplona, Spain.
Objectives: Combination drug therapy clinical trials, especially in the field of oncology, are extremely prevalent. In order to evaluate the potential response of combination therapy, the effects of each drug alone and when co-administered need to be evaluated. In the current analysis, a semi-mechanistic PKPD model has been developed to describe the interaction between a targeted therapy (Drug A) and a cytotoxic agent (Drug B) on tumour growth response using murine xenograft data.
Methods: Efficacy studies were conducted for Drugs A and B alone and in combination. PK and biomarker effect data were also available for the targeted agent (Drug A) but due to constraints in blood volume in mice, no blood was available for PK analysis of Drug B. Analyses were performed using the population approach with NONMEM VI. The following three steps were followed to develop the integrated PKPD model: i) modelling of the time course of tumour inhibition caused by the cytotoxic agent; ii) modelling of the biomarker effects of drug A and iii) modelling of the tumour growth inhibition effects when Drugs A and B were co-administered.
Results: The following three models were developed to describe the interaction of two drugs with differing mechanisms of action: i) a modified version of the Gompertz model as described previously (1) successfully described the tumour growth effects of Drug B. Due to the lack of pharmacokinetic data for Drug B, the K-PD approach (2) (in which a virtual compartment is used to represent the biophase where the concentration is in equilibrium with the observed effect) was used to describe drug input to the model; ii) a two-compartment PK model linked to an indirect inhibition of degradation response PD model was used to describe the time course of the biomarker effects of Drug A and iii) a drug interaction model was developed to describe the effects on tumour growth response where it was assumed that Drug A reduces the efficiency of the tumour cell mechanisms to repair Drug B induced DNA damage, thereby enhancing the effect of the cytotoxic drug.
Conclusions: A novel semi-mechanistic model was developed to describe the interaction between combination therapy with a targeted therapy and a cytotoxic agent on tumour growth response using preclinical xenograft data. This approach was able to differentiate the tumour growth response of each drug given alone and combination.
References:
[1] Simeoni et al. Cancer Research, 2004; 64: 1094-1101.
[2] Jacqmin P et al. J Pharmacokinetics and Pharmacodynamics, 2007;34 (1) : 57-85.