Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate

Abstract

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Physiologically‐based pharmacokinetic modeling to evaluate in vitro‐to‐in vivo extrapolation for intestinal P‐glycoprotein inhibition

“…20 Subsequently, the vendor-verified verapamil and norverapamil models from Simcyp (Certara UK Ltd., Simcyp Division, Sheffield, UK) have been applied to the DDI prediction with bosutinib, dabigatran etexilate, and rivaroxaban with or without modifications. [27][28][29][30] Pgp K i values used in these models were 0.10 to 0.16 μM for verapamil and 0.04 to 0.3 μM for norverapamil, whereas PBPK models often utilized the lower end of the reported in vitro K i values as the worst-case scenario. Overall, in these reports, only one Pgp substrate was used for the model verification and/or application, resulting in no comparisons of the predictive model performance among the different Pgp substrates.…”

“…PBPK models for verapamil and norverapamil were reported to account for the effects of both Pgp and CYP3A inhibition on DDIs with digoxin and midazolam, respectively 20 . Subsequently, the vendor‐verified verapamil and norverapamil models from Simcyp (Certara UK Ltd., Simcyp Division, Sheffield, UK) have been applied to the DDI prediction with bosutinib, dabigatran etexilate, and rivaroxaban with or without modifications 27–30 . Pgp K i values used in these models were 0.10 to 0.16 μM for verapamil and 0.04 to 0.3 μM for norverapamil, whereas PBPK models often utilized the lower end of the reported in vitro K i values as the worst‐case scenario.…”

Photocaged DNA-Binding Photosensitizer Enables Photocontrol of Nuclear Entry for Dual-Targeted Photodynamic Therapy

“…To predict whether the addition of WinterGreen via a carbamate linkage would increase the cellular permeability of Br-DAPI, we measured the −Log P e value (i.e., effective permeability) using a parallel artificial membrane permeability assay (PAMPA). Previous reports on an amidine-based prodrug masked by a carbamate linkage measured the formal charge of the amidine at pH 7.4 to be reduced from 1+ to 0, where the p K a of the nitrogen dropped from 12.4 to 6.7 . The −Log P e of Br-DAPI was measured to be 7.04 ± 0.01, while BB-1 and BB-2 were 5.90 ± 0.01 and 5.69 ± 0.01, respectively (Figure S1).…”

“…Previous reports on an amidine-based prodrug masked by a carbamate linkage measured the formal charge of the amidine at pH 7.4 to be reduced from 1+ to 0, where the pK a of the nitrogen dropped from 12.4 to 6.7. 31 The −Log P e of Br-DAPI was measured to be 7.04 ± 0.01, while BB-1 and BB-2 were 5.90 ± 0.01 and 5.69 ± 0.01, respectively (Figure S1). Based on experimental data for commonly used drugs, −Log P e values <6 are considered to have good membrane permeability via passive diffusion.…”

“…Br-DAPI contains two aryl amidines, each carrying a 1+ charge (overall 2+ charge state) at physiological pH, making the molecule very polar. We reasoned that modification of an amidine with a large hydrophobic moiety would increase the overall hydrophobicity, and if the moiety was linked via a carbamate, the amidine pK a would be lowered (as observed in other aryl amidine compounds 31 ), thereby reducing the overall charge state to 1+, leading to an increase in cell permeability and subsequent potency. Moreover, since Br-DAPI is a DNAbinding/intercalating agent, although not observed in cell culture studies, it is likely that unwanted dark toxicity in healthy cells in vivo would occur.…”