Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction Between Clopidogrel and Dasabuvir

Abstract

Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-β-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl-β-D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5-1.9-fold for C_max and 1.9-2.8-fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant.

Figure 1

PBPK simulations of the pharmacokinetic profiles of dasabuvir following a single intravenous dose (a,b) or oral dose (c,d) in healthy volunteers. Lines represent simulation results and symbols represent observed data (mean and standard deviation). Pharmacokinetic profiles are shown in linear (a,c) or log‐linear scales (b,d).

Figure 2

PBPK simulations of the pharmacokinetic profiles of clopidogrel (a) and its acyl‐β‐D glucuronide metabolite (b) following a single 300 mg loading dose on day 1 followed by 75 mg q.d. maintenance doses. Simulated trial design in Simcyp: custom dosing of 300 mg loading dose on day 1 at 8:00 am followed by 75 mg q.d. on days 2 and 3. Observed data were digitized from the Tornio et al. publication.8 Population representative was used for these simulations in Simcyp v. 14.1. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Parameter sensitivity analysis of clopidogrel acyl‐β‐D‐glucuronide hepatic uptake factor and its impact on pioglitazone AUC ratio. Gray bar corresponds to the observed AUC ratio of pioglitazone when coadministered with clopidogrel (Kim et al.).10 Simcyp virtual trial design: clopidogrel 300 mg was administered on day 1 at 8:00 am followed by 75 mg q.d. on days 2 and 3 at the same time. Pioglitazone 15 mg was administered on day 1 at 9:00 am. A population representative was used for the sensitivity analysis in Simcyp v14.1. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Automated parameter sensitivity analysis demonstrating the impact of hepatic uptake factor and OATP1B1 Ki of clopidogrel acyl‐β‐D‐glucuronide on repaglinide predicted C_max and AUC ratios. Simulated trial design in Simcyp: clopidogrel was administered as a single 300 mg dose at 8:00 am followed by a single 0.25 mg dose of repaglinide at 9:00 am. Population representative was used for these simulations in Simcyp v. 14.1. Key model parameters of repaglinide: model file from the Simcyp substrate library was used with modification of CYP2C8 f_m from 0.64 to 0.89 based on Tornio et al. Key model parameters of clopidogrel acyl‐β‐D glucuronide: hepatic uptake factor ranged from 1–20‐fold. OATP1B1 Ki ranged from 0.1–10 μM.

Figure 5

Predicted C_max and AUC ratios of dasabuvir (with ritonavir) following coadministration with clopidogrel using PBPK modeling. Simulations using the final dasabuvir PBPK model to demonstrate the impact of active uptake factor into hepatocytes on dasabuvir C_max (a) and AUC (b) ratios. Final model parameters: clopidogrel acyl‐β‐D glucuronide hepatic uptake factor range 1–20‐fold and CYP2C8 inactivation parameters as published in Tornio et al. Trial simulation in Simcyp: dasabuvir dose was 250 mg b.i.d. starting at 9 am for 5 days and a single 250 mg dose on day 6; ritonavir dose was 100 mg q.d. for 6 days at the same time as dasabuvir; clopidogrel dose was 300 mg on day 1 followed by 75 mg q.d. for 5 days starting at 8 am every day. Simulation results were based on 10 virtual trials of 10 subjects each to account for population variability. Results are shown as geometric mean and 95% confidence intervals (CI).

Figure 6

Illustration of the effects of clopidogrel and its acyl‐β‐D glucuronide on dasabuvir CYP2C8 and CYP3A4 mediated intrinsic clearance in the presence of coadministered ritonavir at steady state, using PBPK modeling. Trial simulation in Simcyp: dasabuvir 250 mg b.i.d. was coadministered with ritonavir 100 mg q.d. for 14 days, clopidogrel 300 mg loading dose was coadministered on day 14 followed by 75 mg q.d. maintenance doses for 7 days. RTV: indicates start of ritonavir coadministration; CLOP: indicates start of clopidogrel coadministration.