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http://dx.doi.org/10.1111/bcp.15740 | DOI Listing |
Clin Transl Sci
July 2025
EMD Serono, Billerica, Massachusetts, USA.
Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. This work aimed to investigate the potential for drug-drug interactions with strong inhibitors and inducers of both cytochrome P450 (CYP) 3A4/5 and P-glycoprotein (P-gp) with tepotinib. Two clinical studies were conducted to investigate the effect of the strong CYP3A4/P-gp inhibitor itraconazole (200 mg once daily) (NCT05203822) and the strong CYP3A4/P-gp inducer carbamazepine (titrated to 300 mg twice daily) (NCT05213481) on the pharmacokinetics of single dose tepotinib 500 mg (450 mg active moiety) in healthy participants.
View Article and Find Full Text PDFComput Chem Eng
July 2025
University of Pennsylvania, Chemical and Biomolecular Engineering, Philadelphia, 19104, PA, USA.
This study presents a multiscale modeling framework for simulating and predicting the behavior and biodistribution of nanoparticles (), focusing on applications such as targeted drug delivery. The framework encompasses two coupled models: (1) a DeepONet-enabled Fokker-Planck equation to model the NP drift-diffusion in the red-blood cell-free layer () that predicts NP margination and concentration profiles taking hematocrit and vessel radius as inputs, built on top of a hemorheological model of shear-induced blood flow and (2) a physiologically based pharmacokinetic (PBPK) model that uses the predicted concentration profiles in microvasculature to inform the biodistribution of NPs across different organ in the body.
View Article and Find Full Text PDFCPT Pharmacometrics Syst Pharmacol
August 2025
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Baden-Württemberg, Germany.
Despite predicting poor functional outcomes and being a significant patient burden, there are no approved pharmacotherapies to treat symptoms of cognitive impairment associated with schizophrenia (CIAS). Iclepertin (BI 425809) is a potent and selective inhibitor of glycine transporter-1 (GlyT1) that was in Phase III development for the treatment of CIAS. Iclepertin is metabolized by the cytochrome P450 (CYP) 3A4 enzyme and also induces CYP3A4 at supratherapeutic concentrations, so drug-drug interactions (DDIs) with CYP3A4 perpetrators and substrates may be expected.
View Article and Find Full Text PDFPharmaceutics
March 2025
Boehringer Ingelheim Pharma GmbH & Co. KG, 55218 Ingelheim, Germany.
: The drug candidate BI 730357 is a Biopharmaceutics Classification System (BCS) Class II compound showing atypical absorption after oral administration in fasted and fed healthy individuals, for which conventional traditional deconvolution methods could not explain formulation dependencies. : A physiologically based pharmacokinetic (PBPK) model of BI 730357 was developed using the Open Systems Pharmacology (OSP) PBPK software tool PK-Sim, which could describe the pharmacokinetics in fasted and fed subjects after single and multiple doses. A Weibull function was used to describe the in vivo formulation kinetics, whereas colonic absorption was adopted as the main driver to describe the late phases of observed pharmacokinetics after oral administration.
View Article and Find Full Text PDFPrediction of hepatotoxicity in humans remains an unresolved challenge. Recently, an in vitro/in silico method was established to predict blood concentrations of test compounds with an increased risk of causing human hepatotoxicity. In the present study, we addressed the question whether gene expression data can improve the quality of hepatotoxicity prediction compared to cytotoxicity analysis alone.
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