Kathryn Ball (1), Sylvain Fouliard (1), Yannick Parmentier (2), François Bouzom (2), Marylore Chenel (1)
(1) Clinical Pharmacokinetics and Pharmacometrics Department, Institut de Recherches Internationales Servier, Suresnes, France, (2) Nonclinical Pharmacokinetics and Biopharmaceutical Research Department, Technologie Servier, Orleans, France
Objectives: The once-separate disciplines of population pharmacokinetic (Pop PK) modelling and physiologically based pharmacokinetic modelling (PBPK) are becoming more and more frequently entwined. A population semi-physiological PK model for a Servier compound (S1) was built in order to (i) simulate renal drug-drug interactions (DDI) prior to a clinical study, and (ii) to estimate the inhibition constant Ki from the clinical data.
Methods: A semi-physiological PK model was built for S1 as a victim of DDI, with a separate compartment to represent renal tubule cells [1]. The kinetic parameter of transporter-mediated active secretion was estimated by fitting the model to Phase I clinical study data (plasma and urine concentrations simultaneously). A PK model for probenecid was constructed to provide the time course of inhibitor concentrations, and the in vitro Ki was used to provide the inhibition potential and simulate the DDI with S1. The data from the subsequent clinical DDI study was then used to estimate the model parameter Ki (resulting in a so-called ‘in vivo Ki’) and compare with the previously used in vitro value.
Results: The extent of DDI predicted using the model and in vitro Ki was a 2-fold increase in plasma AUC of S1 and a 2.5-fold reduction in S1 renal clearance. This was in agreement with the observed interaction ratios (2-fold increase in plasma AUC, 2.5-fold reduction in renal clearance). The ‘in vivo’ Ki (6.9 µM) was estimated with a good precision, and was similar to the in vitro value of 7.5 µM.
Conclusions: A good agreement was obtained between the in vitro (experimentally measured) and in vivo (model-estimated) inhibition parameter, which could give confidence in using this approach to predict renal DDI a priori. Although there are relatively few examples of renal DDI modelling in the literature, the extent of renal transporter-mediated DDI is generally low, so physiologically-structured population PK modelling could be used to replace clinical DDI studies when a negligible interaction is predicted [2].
References:
[1] Boom SPA, Meyer I, Wouterse AC, Russel FGM. A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog. Biopharm Drug Dispos, 1998. 19 : p. 199-208
[2] Shitara Y, Sato H, Sugiyama Y. Evaluation of drug-drug interaction in the hepatobiliary and renal transport of drugs. Annu Rev Pharmacol Toxicol. 2005. 45 : p. 689-723.
Reference: PAGE 24 () Abstr 3419 [www.page-meeting.org/?abstract=3419]
Poster: Drug/Disease modeling - Absorption & PBPK