Ellen A. Cannady’s research while affiliated with Eli Lilly and Company and other places

Aim: Evaluate steady-state pharmacokinetics and potential interactions between select statins and evacetrapib. Patients & methods: This open-label, two-part study included 62 healthy native Chinese subjects. Part 1 evaluated pharmacokinetics and pharmacodynamics of evacetrapib after 1 or 14 once-daily doses. Part 2 evaluated pharmacokinetics and pharmacodynamics of simvastatin, atorvastatin and evacetrapib administered alone, and of statin + evacetrapib coadministered. Results: Evacetrapib estimated accumulation ratio following once-daily dosing was 2.7. Simvastatin or atorvastatin coadministration reduced evacetrapib AUC 0–24 by 12% (90% CI: -0.1 to -22%) or 10% (90% CI: -23–5%), respectively. Evacetrapib coadministration increased simvastatin or atorvastatin AUC 0–24 by 123% (90% CI: 91–159%) or 16% (90% CI: 6–27%), respectively. Evacetrapib administered alone and with a statin increased high-density lipoprotein cholesterol, decreased low-density lipoprotein cholesterol, and was well tolerated. Conclusion: The significant increase in simvastatin exposure after evacetrapib coadministration was unexpected compared with previous evacetrapib and simvastatin interaction studies.

Baricitinib is a potent and selective Janus kinase (JAK)1 and JAK2 inhibitor, and is approved for the treatment of moderately to severely active RA in adults in Europe, Japan, and other countries. This study evaluated the carcinogenic potential of baricitinib in Tg. rasH2 mice and Sprague-Dawley (Crl:CD) rats. Baricitinib was administered daily by oral gavage to Crl:CD rats for up to 94 weeks (dose levels of 0, 1, 3, or 8 mg/kg for males and 0, 3, 8, or 25 mg/kg for females) and to Tg. rasH2 mice for 26 weeks (dose levels of 0, 15, 40, or 300 mg/kg for males and 0, 10, 30, or 150 mg/kg for females). Baricitinib was well tolerated with no incidence of compound-related neoplasms at any dose levels in rats and mice. In mice, non-neoplastic events observed were bone marrow hypocellularity and increased adipocytes. In rats, baricitinib administration was associated with a dose-dependent increase in survival, with a decreased incidence of neoplasm (hematopoietic and mammary), potentially secondary to drug-related decreased weight gain. The incidence of proliferative changes such as neoplastic and hyperplastic lesions in the mammary glands of females and in the livers of males and females also decreased. In conclusion, baricitinib is not considered to be carcinogenic.

Supplementary Table S1 In vitro half‐maximal inhibitory concentration (IC50), R values, and drug‐drug interaction (DDI) indices for Baricitinib.

Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, undergoes active renal tubular secretion. Baricitinib was not predicted to inhibit hepatic and renal uptake and efflux drug transporters, based on the ratio of the unbound maximum eliminating-organ inlet concentration and the in vitro half-maximal inhibitory concentrations (IC50). In vitro, baricitinib was a substrate for organic anion transporter (OAT)3, multidrug and toxin extrusion protein (MATE)2-K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Probenecid, a strong OAT3 inhibitor, increased the area under the concentration-time curve from time zero to infinity (AUC[0–∞]) of baricitinib by twofold and decreased renal clearance to 69% of control in healthy subjects. Physiologically based pharmacokinetic (PBPK) modeling reproduced the renal clearance of baricitinib and the inhibitory effect of probenecid using the in vitro IC50 value of 4.4 μM. Using ibuprofen and diclofenac in vitro IC50 values of 4.4 and 3.8 μM toward OAT3, 1.2 and 1.0 AUC(0–∞) ratios of baricitinib were predicted. These predictions suggest clinically relevant drug-drug interactions (DDIs) with ibuprofen and diclofenac are unlikely.

Background: Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was under development for the treatment of cardiovascular (CV) disease. The purpose of this pre-postnatal study in rabbits was to evaluate the effects of evacetrapib on pregnancy, parturition, and lactation of the maternal animals and on the growth, viability, development, and reproductive performance of the first filial (F1) offspring. The rabbit is considered a relevant species for toxicity testing with evacetrapib as it demonstrates significant CETP expression, whereas mice and rats do not express significant levels of CETP. Methods: Evacetrapib was administered daily by oral gavage from gestation day (GD) 7 through lactation day (LD) 41 at dose levels of 0, 10, 30, and 100 mg/kg/day. Results: There were no adverse effects on maternal survival, clinical signs, gestation length, parturition, and litter size. There were no effects on F1 clinical observations, body weight, sexual maturation, conditioned eye blink, functional observational battery, or pathology findings. Treatment-related decreases in F1 postnatal survival and equivocal reductions in F1 mating, fertility, and copulation/conception indices without changes in sperm parameters or pathology of reproductive organs were noted in F1 animals. Conclusions: The maternal no observed adverse effect level (NOAEL) after evacetrapib administration in female rabbits was 100 mg/kg/day. Based on the decreased F1 postnatal survival and equivocal changes in F1 fertility, the NOAEL for F1 neonatal developmental was 30 mg/kg/day. Birth Defects Research, 2017.© 2017 Wiley Periodicals, Inc.

Background: The purpose of these studies was to evaluate the effects of evacetrapib on male and female fertility and on embryo-fetal development (EFD). Methods: Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was administered daily by oral gavage starting 2 weeks (for female) or 4 weeks (for male) before mating, during cohabitation, and until necropsy in the male rat fertility study or through gestation day (GD) 17 in the female rat combined fertility/EFD study. For rabbit EFD studies, animals were dosed from GDs 7 to 19 or from 1 week before mating through GD 19. Dose levels of evacetrapib ranged from 60 to 600 mg/kg for rats and from 1 to 100 mg/kg/day for rabbits. Results: Parental findings in rats included decreased body weight and food consumption and moribund euthanasia in animals given 600 mg/kg/day and decreased food consumption at 300 mg/kg/day. There were no adverse effects on estrus cycling, fertility indices, sperm parameters, maternal reproductive parameters, male reproductive tissue, or fetal viability, growth, or external/visceral morphology. An increase in the incidence of 14th rudimentary ribs, a minor, transient variation considered nonadverse, was the only significant developmental finding in rats given 600 mg/kg/day. Slight decreases in body weight and food consumption at 100 mg/kg/day were the only maternal effects observed in rabbits with no adverse developmental effects noted. Conclusion: No adverse effects on fertility or EFD were observed in rats at doses up to 600 mg/kg/day and no adverse effects on EFD were noted in rabbits at doses up to 100 mg/kg/day. Birth Defects Research 00:000-000, 2017. © 2017 Wiley Periodicals, Inc.

The G protein-coupled receptor 40 (GPR40) also known as Free Fatty Acid Receptor 1 (FFAR1) is highly expressed in pancreatic, islet cells and responds to endogenous fatty acids resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083) and 3 (LY2922470) demonstrated potent, efficacious and durable dose dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical and early development data of this new class of GPR40 agonists.

Table S1. Causes of Achlorhydria