Multi-species translational PK/PD modelling in type 2 diabetes
Nathalie Perdaems (1), Sylvain Fouliard (1), Marylore Chenel (1)
(1) Clinical PK and Pharmacometrics division, Servier, France
Objectives: In preclinical research, pharmacokinetic/pharmacodynamic (PK/PD) modelling is very helpful in the drug development. The PK/PD model developped in mice was used to support the dose-efficacy relationship assessment in other species (diabetic monkeys and patients).
Methods: A PK/PD model was built in mice using data from an efficacy study including oral glucose tolerance test (OGTT) with a reference compound (rosiglitazone) and a S compound, describing the time-course of 3 biomarkers (glucose, insulin and HbA1c). The distinction between drug related parameters and system related parameters allowed a physiological inter-species translation. A population PK model was built in diabetic monkeys. This PK model was used in the transposed PK/PD model, and the system related parameters were transposed from mice to monkeys using allometric scaling. This approach allowed to choose different doses for a PD study in diabetic monkeys. To improve the predictability in translated PK/PD models in type 2 diabetes, the mice PK/PD model was also transposed in patients using the rosiglitazone as proof of concept.
Results: The population PK/PD model developed in mice allowed to well describe plasma concentrations of rosiglitazone and the S compound and the 3 biomarkers (glucose, insulin and HbA1c) with and without treatment. A linear effect for the rosiglitazone and an Emax effect for the S drug were applied to describe the stimulation of the glucose use. All the system and drug related parameters were well estimated (RSE < 30 %), except drug effect and Ke0. The Kin was 0.017 g/h for glucose and 0.558 µg/h for insulin. A dose of 15 mg/kg was predicted as an active dose in diabetic monkeys using the scaled model. Data from literature [1] [2] [3] allowed comparing the PK/PD predictions and the observations. Modifications were necessary to well describe the dynamics of biomarkers in patients (for instance, slower absorption of glucose during OGTT (in addition to the Ka from intestinal compartment at 1.1 h-1, a stomach compartment was added with a Kdiss at 1.6 h-1) and then to well predict the antidiabetic effect in patients.
Conclusions: To propose a modelling strategy for the translational drug development from animal to human, the disease should be well understood and its specificities modelled in each species. Reference compounds are very useful to characterise the disease in each population.
References:
[1] Miyazaki Y, DeFronzo R. Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients Diabetes, Obesity and Metabolism. (2008) 10 : 1204–1211
[2] Vahidi O. Dynamic Modeling of Glucose Metabolism for the Assessment of Type II Diabetes Mellitus. Thesis (2013)
[3] Chapelsky M., Thompson-Culkin K., Miller A, Sack M., Blum R., Freed M. Pharmacokinetics of Rosiglitazone in Patients with Varying Degrees of Renal Insufficiency J Clin Pharmacol (2003) 43:252-259
