Sensitivity analysis of P-glycoprotein Ki values in dynamic DDI predictions
Eleanor M. Howgate, Sibylle Neuhoff, Karen Rowland-Yeo
Simcyp Limited (a Certara company), Sheffield, UK
Objectives: The advantages of using PBPK models for prediction of transporter-mediated DDIs have been recognised [1]; although at present the observed degree of interaction is often under-predicted. One of the potential issues is the large variability in measured IC50 values [2]. The importance of using sensitivity analysis for key experimentally determined parameters has been highlighted in recent draft guidance for PBPK modelling [3,4]. The objective of this work was to investigate the fold range of intestinal P-gp Ki values required to recover digoxin DDIs with known inhibitors.
Methods: Published clinical studies involving inhibition of intestinal P-gp, using oral digoxin as the victim compound, were identified using the University of Washington drug interaction database [5]. In vitro P-gp inhibition data (IC50) for perpetrator compounds, measured in Caco-2 cells with digoxin as the probe substrate, were collated from the literature. IC50 values determined using the efflux ratio (ER) of digoxin were favoured; if only net secretory flux (NSF) or unidirectional flux (UF) approaches had been used the data was corrected to representative ER values (ER values are on average 3-fold lower than NSF or UF [2]). DDI simulations were performed (Simcyp Simulator V15.1) using the clinical study designs and Ki values calculated using the Cheng-Prusoff equation [6]. Sensitivity analyses for Ki were used to determine the values required to recover the observed in vivo Cmax ratios.
Results: Healthy volunteer DDI studies with orally administered digoxin as the victim compound were identified for Clarithromycin, Itraconazole, Ritonavir and Verapamil. A range of IC50 values were identified for each compound, typically using the ER or NSF methods. Simulations using Ki values calculated from the lowest IC50 (ER method) were unable to recover the in vivo Cmax ratios. The results of the sensitivity analyses revealed that Ki values of <0.1 µM were required for all four compounds. The difference between the ‘fitted’ and in vitro Ki values (ER method) ranged from 4.1-fold to 654-fold, with a mean of 94-fold.
Conclusions: In vitro P-gp inhibition data required an average fold decrease of 94-fold to recover the in vivo interactions with digoxin. Potential reasons may relate to the (pre-)incubation conditions, inhibitor binding in the assay and inhibitory metabolites.
References:
[1] Zamek-Gliszczynski MJ et al., ITC Recommendations for Transporter Kinetic Parameter Estimation and Translational Modeling of Transport-Mediated PK and DDIs in Humans. Clin Pharmacol Ther (2013) 94(1): 64-79
[2] Bentz J et al., Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria. Drug Metab Dispos (2013) 41(7):1347-66
[3] European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on the qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation. (2016)
[4] U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Physiologically Based Pharmacokinetic Analyses —Format and Content. (2016)
[5] https://didb.druginteractioninfo.org, accessed September 2016
[6] Cheng, Y.-Ch. and Prusoff, W. H. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction Biochem. Pharmacol. (1973) 22:3099-3108