Physiologically Based Pharmacokinetic Models for Prediction of Complex CYP2C8 and OATP1B1 (SLCO1B1) Drug-Drug-Gene Interactions: A Modeling Network of Gemfibrozil, Repaglinide, Pioglitazone, Rifampicin, Clarithromycin and Itraconazole

Abstract

Background: Drug-drug interactions (DDIs) and drug-gene interactions (DGIs) pose a serious health risk that can be avoided by dose adaptation. These interactions are investigated in strictly controlled setups, quantifying the effect of one perpetrator drug or polymorphism at a time, but in real life patients frequently take more than two medications and are very heterogenous regarding their genetic background.

Objectives: The first objective of this study was to provide whole-body physiologically based pharmacokinetic (PBPK) models of important cytochrome P450 (CYP) 2C8 perpetrator and victim drugs, built and evaluated for DDI and DGI studies. The second objective was to apply these models to describe complex interactions with more than two interacting partners.

Methods: PBPK models of the CYP2C8 and organic-anion-transporting polypeptide (OATP) 1B1 perpetrator drug gemfibrozil (parent-metabolite model) and the CYP2C8 victim drugs repaglinide (also an OATP1B1 substrate) and pioglitazone were developed using a total of 103 clinical studies. For evaluation, these models were applied to predict 34 different DDI studies, establishing a CYP2C8 and OATP1B1 PBPK DDI modeling network.

Results: The newly developed models show a good performance, accurately describing plasma concentration-time profiles, area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) values, DDI studies as well as DGI studies. All 34 of the modeled DDI AUC ratios (AUC during DDI/AUC control) and DDI C_max ratios (C_max during DDI/C_max control) are within twofold of the observed values.

Conclusions: Whole-body PBPK models of gemfibrozil, repaglinide, and pioglitazone have been built and qualified for DDI and DGI prediction. PBPK modeling is applicable to investigate complex interactions between multiple drugs and genetic polymorphisms.

Fig. 1

The developed drug–drug interaction (DDI) network with gemfibrozil and gemfibrozil 1-O-β-glucuronide as cytochrome P450 (CYP) 2C8 and organic-anion-transporting polypeptide (OATP) 1B1, itraconazole as CYP3A4, OATP1B1, and OATP1B3, rifampicin as CYP2C8, CYP3A4, OATP1B1, and OATP1B3, and clarithromycin as CYP3A4, OATP1B1, and OATP1B3 perpetrator drugs (upper part); and repaglinide as CYP2C8, CYP3A4, OATP1B1, and OATP1B3 and pioglitazone as CYP2C8 victim drugs (lower part). Physiologically based pharmacokinetic models of itraconazole, rifampicin and clarithromycin were adopted from Hanke et al. [9]. Metabolism and transport are illustrated as black arrows. Solid red lines indicate reversible inhibition processes, dashed bold red lines indicate mechanism-based inactivation. Dashed violet lines indicate interaction processes by rifampicin consisting of inhibition as well as induction processes. The postulated physicochemical interactions are shown as dotted black lines

Fig. 2

Gemfibrozil (a, b), gemfibrozil 1-O-β-glucuronide (gemfi-glu) (a, b), repaglinide (c–f), and pioglitazone (g–i) plasma concentration–time profiles. Observed data are shown as triangles ± standard deviation [–37]. Population simulation arithmetic means or geometric means (a) are shown as black (gemfibrozil), red (gemfibrozil 1-O-β-glucuronide), green (repaglinide), or blue (pioglitazone) lines. The shaded areas represent the respective 68% population prediction intervals. Detailed information about dosing regimens and study populations is given in Electronic Supplementary Material (ESM) Tables S3.3.1, S3.4.1, and S3.5.1. Predicted and observed area under the plasma concentration–time curve (AUC) and maximum plasma concentration (C_max) values are compared in ESM Tables S3.3.4, S3.4.4, and S3.5.4. b.i.d. twice daily, conc concentration, CYP cytochrome P450, po oral, q.d. once daily, s.d. single dose, SLCO solute carrier organic anion transporter family member, t.i.d. three times daily

Fig. 3

Pioglitazone plasma concentration–time profiles during the gemfibrozil–pioglitazone (a), itraconazole–pioglitazone (b), gemfibrozil–itraconazole–pioglitazone (c), and rifampicin–pioglitazone (d) drug–drug interaction (DDI). Observed data are shown as triangles ± standard deviation (dark blue: control, light blue: with perpetrator drug) [19, 38]. Pioglitazone population simulation arithmetic means are shown as lines (dark blue: control, light blue: with perpetrator drug), the dashed line (c) shows the prediction of the gemfibrozil–itraconazole–pioglitazone without pioglitazone solubility adjustment. The shaded areas represent the respective 68% population prediction intervals. Detailed information about dosing regimens and study populations is given in Electronic Supplementary Material (ESM) Tables S4.3.1, S4.5.1, S4.7.1, and S4.9.1. Predicted and observed DDI area under the plasma concentration–time curve (AUC) ratios and DDI maximum plasma concentration (C_max) ratios are compared in ESM Tables S4.3.2, S4.5.2, S4.7.2, and S4.9.2. b.i.d. twice daily, conc concentration, po oral, q.d. once daily, s.d. single dose

Fig. 4

Repaglinide plasma concentration–time profiles during the gemfibrozil–repaglinide (a), itraconazole–repaglinide (b), gemfibrozil–itraconazole–repaglinide (c), rifampicin–repaglinide (d), and clarithromycin–repaglinide (e) drug–drug interaction (DDI). Observed data are shown as triangles, crosses, or stars ± standard deviation (dark green: control, light green: with perpetrator drug) [20, 31, 39, 40]. Repaglinide population simulation arithmetic means are shown as lines (dark green: control, light green: with perpetrator drug). The shaded areas represent the respective 68% population prediction intervals. Detailed information about dosing regimens and study populations is given in Electronic Supplementary Material (ESM) Tables S4.2.1, S4.4.1, S4.6.1, S4.8.1, and S4.10.1. Predicted and observed DDI area under the plasma concentration–time curve (AUC) ratios and DDI maximum plasma concentration (C_max) ratios are compared in ESM Tables S4.2.2, S4.4.2, S4.6.2, S4.8.2, and S4.10.2. b.i.d. twice daily, conc concentration, po oral, q.d. once daily, s.d. single dose

Fig. 5

Correlation of predicted and observed drug–drug interaction (DDI) area under the plasma concentration–time curve (AUC) ratios and DDI maximum plasma concentration (C_max) ratios of all studies. The upper panel illustrates DDI AUC ratios (a) and DDI C_max ratios (b) of the gemfibrozil–repaglinide, itraconazole–repaglinide, gemfibrozil–itraconazole–repaglinide, rifampicin–repaglinide, or clarithromycin–repaglinide DDIs. The lower panel illustrates DDI AUC ratios (c) and DDI C_max ratios (d) of the gemfibrozil–pioglitazone, itraconazole–pioglitazone, gemfibrozil–itraconazole–pioglitazone, or rifampicin–pioglitazone DDIs. The colors represent different perpetrator drugs and the symbols the victim drugs repaglinide (dots) and pioglitazone (triangles). The straight black line marks the line of identity. Light grey lines indicate 0.8- to 1.25-fold and dark grey lines indicate 0.5- to 2-fold acceptance limits. The curved black lines show the prediction success limits suggested by Guest et al. [41]. Detailed information about dosing regimens and study populations is given in Electronic Supplementary Material (ESM) Tables S4.2.1, S4.3.1, S4.4.1, S4.5.1, S4.6.1, S4.7.1, S4.8.1, S4.9.1, and S4.10.1. The plotted DDI AUC ratios and C_max ratios are listed in ESM Tables S4.2.2, S4.3.2, S4.4.2, S4.5.2, S4.6.2, S4.7.2, S4.8.2, S4.9.2, and S4.10.2

Fig. 6

Dose adjustments developed with the physiologically based pharmacokinetic models for repaglinide (upper panel) and pioglitazone (lower panel). Predicted plasma concentration–time profiles are shown for European male CYP2C8 and SLCO1B1 wild-type individuals (red lines) as well as for CYP2C8*3/*3 or SLCO1B1 521CC individuals (repaglinide: green lines, pioglitazone: blue lines) before or during perpetrator drug coadministration. The left-hand plots show predicted plasma concentrations without dose adjustment; the right-hand plots show predicted plasma concentrations with dose adjustment. conc concentration, CYP cytochrome P450, n.a. not applicable, SLCO solute carrier organic anion transporter family member