In Vitro Predictability of Drug-Drug Interaction Likelihood of P-Glycoprotein-Mediated Efflux of Dabigatran Etexilate Based on [I]₂/IC₅₀ Threshold

Abstract

Dabigatran etexilate, an oral, reversible, competitive, and direct thrombin inhibitor, is an in vitro and in vivo substrate of Pglycoprotein (P-gp). Dabigatran etexilate was proposed as an in vivo probe substrate for intestinal P-gp inhibition in a recent guidance on drug-drug interactions (DDI) from the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). We conducted transcellular transport studies across Caco-2 cell monolayers with dabigatran etexilate in the presence of various P-gp inhibitors to examine how well in vitro IC 50 data, in combination with mathematical equations provided by regulatory guidances, predict DDI likelihood. From a set of potential P-gp inhibitors, clarithromycin, cyclosporin A, itraconazole, ketoconazole, quinidine, and ritonavir inhibited P-gp-mediated transport of dabigatran etexilate over a concentration range that may hypothetically occur in the intestine. IC 50 values of P-gp inhibitors for dabigatran etexilate transport were comparable to those of digoxin, a well established in vitro and in vivo P-gp substrate. However, IC 50 values varied depending whether they were calculated from efflux ratios or permeability coefficients. Prediction of DDI likelihood of P-gp inhibitors using IC 50 values, the hypothetical concentration of P-gp inhibitors, and the cut-off value recommended by both the FDA and EMA were in line with the DDI occurrence in clinical studies with dabigatran etexilate. However, it has to be kept in mind that validity of the cut-off criteria proposed by the FDA and EMA depends on in vitro experimental systems and the IC 50 -calculation methods that are employed, as IC 50 values are substantially influenced by these factors.

Inhibitory Potential of Antifungal Drugs on ATP-Binding Cassette Transporters P-Glycoprotein, MRP1 to MRP5, BCRP, and BSEP

“…Different probe substrates can shift IC 50 s, as previously reported for P-gp (41,42). Therefore, caution should be exercised by translating these results to different transporter-substrate combinations.…”

In vitro and in silico evaluation of P‐glycoprotein inhibition through 99mTc‐methoxyisobutylisonitrile uptake

“…Moreover, IC50 value for prazosin was found to be 4.055 μM, which shows its P-gp inhibition potential. [26] In a study conducted by Kishimoto et al, [24] taking dabigatran etexilate into account as substrate, IC50 value of itraconazole was equal to 0.46 μM. Accordingly, in a study by Volpe et al in 2014, to determine various parameters affecting IC50 for inhibitors of P-gp, IC50 value for itraconazole was shown to be 0.376 μM while digoxin was used as substrate.…”

Effects of Strong CYP3A Inhibition and Induction on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor: Results of Drug‐Drug Interaction Studies in Patients With Advanced Solid Tumors or Lymphoma and a Physiologically Based Pharmacokinetic Analysis

“…The final PBPK model was then used to simulate the effects of ketoconazole, clarithromycin, and rifampin on the PK of ixazomib. The default Sim‐ketoconazole 400‐mg a day model within Simcyp version 15.1 was used with 1 modification: the lowest in vitro P‐gp K i value of 0.42 μM determined in Caco‐2 cells using digoxin (1 μM) as the probe substrate was incorporated . The default SV‐clarithromycin model within Simcyp version 15.1 was used without any modification.…”

“…The default Sim-ketoconazole 400-mg a day model within Simcyp version 15.1 was used with 1 modification: the lowest in vitro P-gp K i value of 0.42 μM determined in Caco-2 cells using digoxin (1 μM) as the probe substrate was incorporated. 14 The default SV-clarithromycin model within Simcyp version 15.1 was used without any modification. The rifampin simulation used induction parameters from a previously reported rifampin model 15 in which an Ind max value of 37.1 and an IndC 50 value of 0.28 μM were used.…”