A model-based approach to extrapolate drug-drug interactions from rats to humans
C. Piana (1), P. Mazzei (1), G. Smania (1), P. Magni (2), A. Lecci (1), A. Capriati (1), A. Pellacani (1)
(1) Menarini Ricerche S.p.A., Florence (Italy) (2) Department of Electrical, Computer and Biomedical Engineering, University of Pavia (Italy)
Objectives: The first objective of the present analysis is to develop a population pharmacokinetic (PK) model able to quantify in vivo in rat the interaction between azathioprine (AZA), a pro-drug of 6-mercaptopurine (6-MP), and febuxostat (FBX) or allopurinol (ALL). The second objective is to build a modelling and simulation (M&S) framework capable of extrapolating to humans the findings from the preclinical study.
Methods: Non-linear mixed effects modelling was applied to describe 6-MP PK in rats after administration of AZA with and without FBX or ALL. Data below the limit of quantification were handled with the M3 method [1, 2]. The inhibitory effect of FBX/ALL on 6-MP apparent clearance (CL/F) was modelled as a multiplicative constant on the clearance of the single drug administration. For the prediction of human PK, final PK parameters in rats were scaled based on weight by using standard allometric exponents (0.75 for CL/F, 1 for volumes and -0.25 for rate constants). Allometric scaling was also applied to predict 6-MP CL/F in human following the co-administration of AZA with FBX/ALL based on the inhibited CL/F estimated in rats. NONMEM and R were used for PK data analysis and data manipulation, respectively.
Results: The final model was a one compartment model with first order absorption and elimination. Inter-individual variability was estimated for CL/F (21.9%) and absorption rate constant (119.6%). According to the model, 6-MP CL/F in rats is reduced from 11.34 L/h to 3.30 L/h and 2.09 L/h in presence of ALL and FBX, respectively. Internal and external validation satisfactory qualified the model.
The predicted AZA dose reduction in human was of 80% and 70% of the standard dose when co-administered with FBX and ALL, respectively. The model developed was deemed to be fit-for-purpose considering that both ALL Summary of Product Characteristics [3] and AZA Product Information Leaflet [4] recommend a dose reduction of AZA to 25%-30% of the usual dose when co-administered with ALL.
Conclusions: The proposed M&S analysis provided a reliable framework for translating into human species the AZA-FBX interaction observed in rats. Due to feasibility and ethical hurdles in performing a clinical drug-drug interaction study, the possibility to use the current model-based approach to provide AZA treatment recommendations when co-administered with FBX is under discussion with the European Medicine Agency.
References:
[1] Ahn JE, Karlsson MO, Dunne A and Ludden TM, 2008. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn vol. 35: 401–421.
[2] Beal SL, 2001. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn vol. 28: 481–504.
[3] Allopurinol 300mg Tablets. Summary of Product Characteristics. https://www.medicines.org.uk/emc/medicine/25728
[4] Imuran (azathioprine) 50-mg Scored Tablets. Product Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf