Elevations in serum alanine aminotransferase (ALT) were observed in phase I clinical studies for a novel inpatient anti-infective therapy (Compound X).
Mechanistic Modeling with Dilisym® Predicts Species Differences in CKA Via Multiple Hepatotoxicity Mechanisms
To predict species differences in CKA-mediated hepatotoxicity using DILIsym®, a mechanistic model of drug-induced liver injury (DILI)
Mechanistic Modeling of Drug-Induced Liver Injury Due to mtDNA Depletion in DILIsym®
To simulate drug-induced liver injury (DILI) due to mitochondrial DNA (mtDNA) depletion in DILIsym using Fialuridine (FIAU) as an exemplar compound.
MembranePlus™: a tool to study in vitro/in vivo transport and drug-drug interaction
MembranePlus (Simulations Plus, Inc.) was used to analyze the concentration-time profiles in donor and receiver compartments after apical and basolateral administration of 50 μg/mL (81.5 μM) indinavir alone...
Physiologically Based Pharmacokinetic (PBPK) Modeling of Amoxicillin in Neonates and Infants
An amoxicillin PBPK model was previously developed and validated in healthy adults as well as adults with altered renal function [1-2]. The purpose of this study was to explore the utility of the model...
Quantitative Estimation Of Predictive Uncertainty
The performance of QSAR models has traditionally been evaluated in terms of aggregate statistics – sensitivity, specificity, root mean square error (RMSE), R2, etc. – for some kind of test set.
Physiologically based pharmacokinetic (PBPK) model for intramuscular injection of aripiprazole
Aripiprazole is an atypical antipsychotics drug that is widely used in the treatment of agitation associated with schizophrenia, schizoaffective disorder, schizophreniform disorder or bipolar I disorder.
Relationship of Cariprazine Plasma Concentration to Efficacy and Safety in Patients With Schizophrenia or Bipolar Mania
Population exposure‑response analysis was undertaken to describe the relationship of drug concentrations to measures of clinical efficacy and safety in patients with schizophrenia or bipolar mania.
The Steady-State Pharmacokinetic Profile Across a Range of Patient Body Weight Categories Supports Weight-Based Dosing for Intravenous Reslizumab
Reslizumab is an IgG4 kappa humanized monoclonal antibody that targets interleukin-5, leading to marked reductions in airway eosinophil levels, and is indicated as an ‘add-on’ maintenance treatment for adult...
Physiologically Based Pharmacokinetic (PBPK) Model to Describe Absorption and Disposition of Inhaled Capreomycin
The current work describes the simulation of capreomycin pharmacokinetics (PK) after IV and pulmonary administration. Capreomycin is an antibiotic used to treat tuberculosis. It is eliminated mainly by...
Use of Pharmacokinetic-Pharmacodynamic Modeling and Simulations to Predict Efficacy Outcomes with Eslicarbazepine Acetate 800 mg Once Daily as Monotherapy
Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED), approved as adjunctive treatment for partial-onset seizures (POS) in the USA, Europe, and Canada, and as monotherapy for...
Integrating Predictions from Complementary Cytochrome P450 (CYP) Models
Many structure-activity classification models have been published for predicting whether a given compound is likely to inhibit and/or be subject to metabolism by a given cytochrome P450 (CYP) isoform, and...
QSAR-based Prediction of Ames Mutagenicity for ICH M7 Submissions
The “Ames test”, originally developed by Bruce Ames and his group, is a way to measure the mutagenic potential of chemicals.1 It uses strains of Salmonella typhimurium and Escherichia coli as an...
Beyond IC50 and simple PK models – Considerations for discovery chemists
While developing the Simulation Module [1] – an in silico tool for conducting PK simulations based on the Advanced Compartmental Absorption and Transit (ACAT™) model [2] – we have discovered a handful of...
Mechanistic Modeling Predicts Drug-Induced HyperbilirubinemiaThat Involves Inhibition Of Enzymes And Transporters
Elevated serum ALT and bilirubin indicates high risk of fatal drug-induced liver injury. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting enzymes and/or transporters.
in silico Prediction of Oral Bioavailability
Oral bioavailability (F%) is an important pharmacokinetic property that can determine the fate of a compound in clinical trials. Predicting F% directly from the 2D structure of the molecule prior to first…
Using Physiologically Based Pharmacokinetic Modeling for in vitro – in vivo Extrapolation to Predict Chemical Exposure
Mechanistic absorption and physiologically based pharmacokinetic (MA/ PBPK) models are useful tools in risk assessment. These models incorporate complex processes related to a compound’s disposition...
QSAR Modeling Independent of Input Tautomers
The quality and predictivity of QSAR models used in drug design and development often depend on the tautomeric and valence structures used to represent the molecules of interest. This is because the...
in silico Modeling of Aryl Hydrocarbon Receptor (AhR) Activation
Sustained activation of AhR is the molecular initiating event (MIE) in several adverse outcome pathways (AOPs)1: Lethality to fish and bird embryos, Causing uroporphyria in birds, Producing liver tumors in...
Mechanistic Absorption and Physiologically Based Pharmacokinetic Modeling of Itraconazole and Its Application for Drug-Drug Interaction with Midazolam in Adult Populations
Itraconazole (ITZ) is a BCS Class II triazole antifungal (Sporanox; Janssen Pharmaceutica, Titusville, NJ). It is a substrate and potent inhibitor of CYP3A4. The primary metabolite hydroxy-itraconazole...