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Background BRII-732, a prodrug of islatravir (ISL), is a potent HIV-1 nucleotide reverse transcriptase translocation inhibitor. Following oral absorption, BRII-732 is rapidly converted to ISL, which is metabolized intracellularly to the active metabolite, ISL triphosphate (ISL-TP). Single doses of ISL as low as 0.5 mg significantly suppressed HIV-1 RNA by more than 1.0 log at day 7 in treatment-naive adults with HIV-1 infection. Current development work with BRII-732 is designed to provide optimal drug exposure to enable once weekly (QW) dosing, to be part of combination antiretroviral therapy to provide improved patient convenience and treatment adherence. Methods This was a Phase 1, randomized, double-blind, placebo-controlled study consisting of healthy adult subjects enrolled in five single ascending dose and two multiple ascending dose cohorts. The objectives of the study were to assess the safety, tolerability, and PK profiles of BRII-732 and ISL in plasma; ISL-DP and ISL-TP in human PBMCs. BRII-732 was orally administered in the fasted state using an oral solution formulation. Safety-related assessments included physical examinations, ECGs, vital signs, AEs, and standard clinical laboratory tests. Results BRII-732 as single dose or multiple doses was generally safe and well-tolerated when administered to healthy adult subjects. There were no Grade ≥ 3 AEs, SAEs, drug-related AEs leading to withdrawal or graded lymphocyte abnormalities. BRII-732 rapidly converted to ISL post BRII-732 oral administration with no detectable level (LLOQ = 1.0 ng/mL) of BRII-732 in systemic circulation at 0.5h. Dose proportional ISL exposure increases were observed over the dose range of 10 mg to 200 mg of BRII-732. No meaningful ISL accumulation in plasma was observed after 3 QW BRII-732 doses. ISL-DP and ISL-TP exposures in PBMC cells increased dose-dependently. Approximately 1.7-2.0 fold accumulation ratios for ISL-DP and ISL-TP are consistent with observed long terminal half-lives of 110-150 hours. Conclusion Safety, tolerability and PK profiles including ISL in plasma and ISL-TP in PBMC cells after single and multiple oral administrations of BRII-732 supports further development of BRII-732 as part of oral weekly combination antiretroviral therapy. Disclosures David A. Margolis, MD MPH, Brii Biosciences: Stocks/Bonds Ji Ma, PhD, Brii Biosciences: Stocks/Bonds Michael Watkins, PharmD, Brii Biosciences: Stocks/Bonds Yujin Wang, M.Sc., Brii Biosciences: Stocks/Bonds Chetana Trivedi, B.A., Brii Biosciences: Stocks/Bonds Chi-Chi Peng, PhD, Brii Biosciences: Stocks/Bonds Xuelian Wei, PhD, Brii Biosciences: Stocks/Bonds Lijie Zhong, PhD, Brii Biosciences: Stocks/Bonds Kamlesh Patel, PhD, Brii Biosciences: Stocks/Bonds Jean-Luc Girardet, PhD, Brii Biosciences: Stocks/Bonds Michael Wang, PhD MBA, Brii Biosciences: Stocks/Bonds Annalise VonderEmbse, PhD, Brii Biosciences: Stocks/Bonds Li Yan, MD PhD, Brii Biosciences: Stocks/Bonds Zhi Hong, PhD, Brii Biosciences: Ownership Interest Lianhong Xu, PhD, Brii Biosciences: Stocks/Bonds.

The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low ( 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here.

The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here. Electronic supplementary material The online version of this article (10.1208/s12248-020-00508-2) contains supplementary material, which is available to authorized users.

Cellular retinoic acid binding proteins (CRABPs) bind all-trans-retinoic acid (atRA) tightly. This study aimed to determine whether atRA is channeled directly to cytochrome P450 (CYP) CYP26B1 by CRABPs, and whether CRABPs interact directly with CYP26B1. atRA bound to CRABPs (holo-CRABP) was efficiently metabolized by CYP26B1. Isotope dilution experiments showed that delivery of atRA to CYP26B1 in solution was similar with or without CRABP. Holo-CRABPs had higher affinity for CYP26B1 than free atRA, but both apo-CRABPs inhibited the formation of 4-OH-RA by CYP26B1. Similar protein-protein interactions between soluble binding proteins and CYPs may be important for other lipophilic CYP substrates.

RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORγ protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORγ inverse agonists, with demonstrated oral bioavailability in rodents.

Objective: Development and validation of a novel assay, the Plated Hepatocyte Relay Assay (PHRA), for the determination of the metabolic fates of slowly metabolized compounds. Method: Cryopreserved human hepatocytes were cultured for 4 h followed by incubation with slowly metabolized compounds for 24 h (initial incubation). On the next day, the incubated media were collected and added to hepatocytes was similarly prepared on the day of incubation (48 h incubation; 1 st relay). The procedures were repeated on the next days (72 h (2 nd relay), 96 h (3rd relay), and 120 h (4 th relay) incubations). Results: A proof-of-concept study with two low clearance compounds, diazepam and tolbutamide, and a validation study with 15 ultra-low clearance compounds (CL non-renal non-renal 1- 5.1 mL/min/kg) were performed. Linear time-dependent disappearance of the parent compounds was observed for all compounds. Application of published free fraction values in combination with a correction factor with in vitro hepatic clearance results obtained with the PHRA accurately predicted in vivo hepatic clearance. Conclusion: PHRA represents a useful experimental system for the evaluation of the metabolic fates of low clearance compounds in drug development..