Analysis of the Repaglinide Concentration Increase Produced by Gemfibrozil and Itraconazole Based on the Inhibition of the Hepatic Uptake Transporter and Metabolic Enzymes

Abstract

The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic uptake transporter and metabolic enzymes involved in repaglinide disposition. Firstly, the plasma concentration profiles of inhibitors (itraconazole, gemfibrozil, and gemfibrozil glucuronide) were reproduced by a PBPK model to obtain their pharmacokinetic parameters. The plasma concentration profiles of repaglinide were then analyzed by a PBPK model, together with those of the inhibitors, assuming a competitive inhibition of CYP3A4 by itraconazole, mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide, and inhibition of organic anion transporting polypeptide (OATP) 1B1 by gemfibrozil and its glucuronide. The plasma concentration profiles of repaglinide were well reproduced by the PBPK model based on the above assumptions, and the optimized values for the inhibition constants (0.0676 nM for itraconazole against CYP3A4; 14.2 mM for gemfibrozil against OATP1B1; and 5.48 mM for gemfibrozil glucuronide against OATP1B1) and the fraction of repaglinide metabolized by CYP2C8 (0.801) were consistent with the reported values. The validity of the obtained parameters was further confirmed by sensitivity analyses and by reproducing the repaglinide concentration increase produced by concomitant gemfibrozil administration at various timings/doses. The present findings suggested that the reported concentration increase of repaglinide, suggestive of synergistic effects of the coadministered inhibitors, can be quantitatively explained by the simultaneous inhibition of the multiple clearance pathways of repaglinide.

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

“…Gemfibrozil was not included in this clinical study. However, the mechanism of gemfibrozil-mediated DDI and clinical DDI data with cerivastatin have already found that gemfibrozil increased the plasma concentration of cerivastatin with the inhibition of CYP2C8 and OATP1B1 by gemfibrozil glucuronide (Backman et al, 2002;Shitara et al, 2004;Kudo et al, 2013). By contrast, to our knowledge, no pharmacokinetics-related DDI between clopidogrel and cerivastatin has been reported, therefore we compared the predicted DDI of cerivastatin by clopidogrel with that of gemfibrozil.…”

“…In vitro f m,CYP2C8 of pitavastatin, pioglitazone, and cerivastatin were reported to be 0.0, 0.68, and 0.61, respectively (Fujino et al, 2003;Shitara et al, 2004;Jaakkola et al, 2006). By contrast, f m,CYP2C8 for repaglinide are various: 0.41-0.71 from in vitro experiments (Kajosaari et al, 2005a;Säll et al, 2012) and 0.80-0.89 from in vivo data with modeling (Honkalammi et al, 2011b(Honkalammi et al, , 2012Kudo et al, 2013). We used in vitro f m,CYP2C8 for the prediction to apply a unified method for all the substrates.…”

“…Recently, epidemiologic research using the FDA Adverse Event Reporting System found that the use of clopidogrel or gemfibrozil was highly associated with rhabdomyolysis caused by cerivastatin (Floyd et al, 2012). In the case of gemfibrozil, it was already reported that gemfibrozil greatly increased the plasma concentration of cerivastatin, because gemfibrozil 1-O-b-glucuronide inhibited CYP2C8-mediated metabolism irreversibly and the organic anion-transporting polypeptide (OATP) 1B1-mediated hepatic uptake of cerivastatin (Backman et al, 2002;Shitara et al, 2004;Kudo et al, 2013). However, there is no clinical evidence for the pharmacokinetic interaction of clopidogrel with cerivastatin, and a study of any drug-drug interaction (DDI) between clopidogrel and cerivastatin is problematic because cerivastatin is not available as a drug for clinical study.…”

Investigation of the Impact of Substrate Selection on In Vitro Organic Anion Transporting Polypeptide 1B1 Inhibition Profiles for the Prediction of Drug-Drug Interactions

“…The static model that assumes a constant inhibitor concentration is suitable in the early stage of drug development because of its simplicity (Yoshida et al, 2012), while allowing for false-positive prediction. The dynamic model allows more accurate prediction by taking the time-course of the inhibitor concentration into account (Imamura et al, 2011;Kudo et al, 2013). In both models, the inhibition constant (K i ) is an essential parameter to evaluate the clinical relevance of the DDIs, so its accurate estimation for the target transporter is a key step to achieve their purposes.…”

Drug Metabolites as Cytochrome P450 Inhibitors: A Retrospective Analysis and Proposed Algorithm for Evaluation of the Pharmacokinetic Interaction Potential of Metabolites in Drug Discovery and Development

“…The study of cytochrome P450 DDIs has advanced such that in vivo DDI can be quantitatively predicted from in vitro data using physiologically-based pharmacokinetic (PBPK) modeling (Chenel et al, 2008;Fenneteau et al, 2010;Perdaems et al, 2010;Jones et al, 2012). Although there are a few examples in which metabolite contributions to DDIs have been retrospectively simulated using PBPK models (Rowland Yeo et al, 2010;Kudo et al, 2013;Varma et al, 2013), our understanding of and capabilities to predict DDIs from in vitro data have been mostly restricted to cases where the parent drug is the perpetrator. The potential for a drug metabolite(s) to be the perpetrator(s) responsible for DDI has been highlighted in recent publications (Isoherranen et al, 2009;Yu and Tweedie, 2013).…”