Simulations Plus

Accelerating clinical development of new compounds demands efficient systems for evaluation and interpretation of trial results. Systematizing trial evaluation methods yields efficiency and confidence in results.

Cholangiocyte injury accounts for a quarter of drug-induced liver injury (DILI) cases and is associated with higher rates of morbidity and mortality than hepatocellular DILI (Chalasani et al., 2015).

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathophysiology, ranging from hepatic steatosis, through non-alcoholic steatohepatitis (NASH) and hepatic fibrosis, and in rare cases resulting in cirrhosis and liver failure.

Lixivaptan, a vasopressin-2 receptor antagonist, is under development for the treatment of autosomal dominant polycystic kidney disease (ADPKD), an orphan disease with minimal treatment options.

Regulatory agencies have encouraged the use of mechanistic absorption (MAM) and physiologically-based pharmacokinetic (PBPK) modeling to reduce cost and time to market for new and generic drug products.

Rivaroxaban is an oral anticoagulant which acts by inhibiting factor Xa of the coagulation network.

Lixivaptan, a vasopressin-2 receptor antagonist, is being developed for the treatment of autosomal-dominant polycystic kidney disease (ADPKD), an orphan disease that is an unmet medical need.

Bile acid transporter inhibition has been shown to be an important mechanism of drug-induced liver injury (DILI), but the biophase responsible for the transporter inhibition is unclear.

A recent bioavailability study raises questions about the universality of the permeability enhancing effect of chitosan on poorly permeable drugs.

In silico pharmacokinetic (PK) simulations are now routinely incorporated into drug development workflows, especially in the later stages.

Extensive progress has been made in identifying mechanisms for dose-dependent drug-induced liver injury (DILI) and in developing screening assays to reduce its incidence.

To quantitatively and mechanistically compare the liver toxicity potential of oral riluzole versus BHV-0223, combining clinical and mechanistic data, using DILIsym.

Dried blood spot (DBS) pharmacokinetic (PK) sampling was investigated as a potential alternative to plasma sampling for Phase 3 verubecestat (MK-8931) trials due to several potential advantages (ie, reduced cost, reduced clinical site burden, and lower blood volume requirements)

Losartan is a selective, competitive angiotensin 11 receptor type 1 (AT1) antagonist for hypertension treatment.

Resolution of elevations of the liver injury biomarker serum ALT despite continued drug dosing, termed “adaptation”, is commonly observed in clinical trials, but the underlying mechanisms behind this phenomenon remain unclear.

Crizotinib and pazopanib are oral receptor tyrosine kinase inhibitors (TKIs).

FMS-like tyrosine kinase 3 (FLT3) is expressed in hematopoietic progenitor cells, and signaling through FLT3 promotes these cells’ proliferation and differentiation.

Non-alcoholic fatty liver disease (NAFLD) is of growing concern, within developed countries, with recent estimates suggesting up to, 30% of the US population may be affected.

Lack of efficacy continues to be a problem in drug development. Piecemeal rules of thumb such as Lipinski’s Rule of Five [1] help avoid compounds likely to be poorly...