Prediction of Transporter-Mediated Drug-Drug Interactions and Phenotyping of Hepatobiliary Transporters Involved in the Clearance of E7766, a Novel Macrocycle-Bridged Dinucleotide.

E7766 represents a novel class of macrocycle-bridged dinucleotides and is under clinical development for immuno-oncology. In this report, we identified mechanism of systemic clearance E7766 and investigated the hepatobiliary transporters involved in the disposition of E7766 and potential drug interactions of E7766 as a victim of organic anion-transporting polypeptide (OATP) inhibitors. In bile-duct cannulated rats and dogs, E7766 was mainly excreted unchanged in bile (>80%) and to a lesser extent in urine (<20%). Sandwich-cultured human hepatocytes (SCHHs), transfected cells, and vesicles were used to phenotype the hepatobiliary transporters involved in the clearance of E7766. SCHH data showed temperature-dependent uptake of E7766 followed by active biliary secretion. In vitro transport assays using transfected cells and membrane vesicles confirmed that E7766 was a substrate of OATP1B1, OATP1B3, and multidrug resistance-associated protein 2. Phenotyping studies suggested predominant contribution of OATP1B3 over OATP1B1 in the hepatic uptake of E7766. Studies in OATP1B1/1B3 humanized mice showed that plasma exposure of E7766 increased 4.5-fold when coadministered with Rifampicin. Physiologically based pharmacokinetic models built upon two independent bottom-up approaches predicted elevation of E7766 plasma exposure when administered with Rifampicin, a clinical OATP inhibitor. In conclusion, we demonstrate that OATP-mediated hepatic uptake is the major contributor to the clearance of E7766, and inhibition of OATP1B may increase its systemic exposure. Predominant contribution of OATP1B3 in the hepatic uptake of E7766 was observed, suggesting polymorphisms in OATP1B1 would be unlikely to cause variability in the exposure of E7766. SIGNIFICANCE STATEMENT: Understanding the clearance mechanisms of new chemical entities is critical to predicting human pharmacokinetics and drug interactions. A physiologically based pharmacokinetic model that incorporated parameters from mechanistic in vitro and in vivo experiments was used to predict pharmacokinetics and drug interactions of E7766, a novel dinucleotide drug. The findings highlighted here may shed a light on the pharmacokinetic profile and transporter-mediated drug interaction propensity of other dinucleotide drugs.

Paclitaxel-loaded crosslinked hyaluronic acid films for the prevention of postsurgical adhesions.

PURPOSE: Post surgical adhesion formation results in significant morbidity for surgical patients. The purpose of this study was to investigate the use of paclitaxel (PTX) as an inhibitor of adhesion formation in rats and to design and characterize a controlled release film formulation of the drug for application to exposed surgical sites. METHODS: The rat cecal side wall abrasion model was used to investigate the anti-adhesion properties of PTX. The drug was administered by either intraperitoneal injection (i.p.), as the cremophor formulation (Taxol) or by application of carbodiimide crosslinked hyaluronic acid (HA) films containing PTX. The HA films were also characterized by measurements of elasticity, degree of swelling in water and drug release rates. RESULTS: Taxol administered by i.p. injection at 4 mg/kg on a daily basis for between 3 and 5 days resulted in a significant reduction in adhesion formation. All animals in the control group (n = 10) had some form of adhesion following abrasion whereas the percent of animals without adhesions significantly increased and the mean incidence of adhesion formation decreased in the three Taxol treated groups. The application of 5% PTX loaded HA films had a similar significant effect in increasing both the % of animals without adhesions and in reducing the mean incidence of adhesions. CONCLUSIONS: Paclitaxel is an effective inhibitor of adhesion formation in rats. HA crosslinked with 2 mM water soluble carbodiimide and containing 10% glycerol and 5% PTX are flexible, mucoadhesive, biocompatible controlled release films suitable for application to surgical sites for the prevention of adhesion formation.