First-in-human: what dose to choose to elicit the desired effect (efficacy), without causing harm (safety)?
Implementation of the C-QTc study using MonolixSuite applications
International Council for Harmonisation (ICH) E14 guidance agreed to use a model-based study of concentration-QT data as a primary analysis in...
A library of tumor growth and tumor growth inhibition models for the MonolixSuite
Modular tumor growth (TG) and tumor growth inhibition (TGI) library
Comparison of pharmacokinetics and QTc effect of Quizartinib in Japanese and non-Japanese patients with Relapsed/Refractory (R/R) FLT3-ITD positive acute myeloid leukemia (AML) using population pharmacokinetic (PopPK) analyses
The PopPK and C-QTc analyses were conducted to compare the pharmacokinetic (PK) profiles and QTc effect of quizartinib in Japanese...
Quantitative Prediction of Cisplatin-Induced Acute Kidney Injury Using RENAsym, a Mechanistic Quantitative Systems Toxicology Model, and Renal Proximal Tubule Epithelial Cell In vitro Assays
Nephrotoxic drugs like cisplatin cause acute kidney injury (AKI) through complex cellular mechanisms that include mitochondrial dysfunction...
Quantitative Systems Toxicology Modeling Using DILIsym Suggests That Drug-Induced Liver Injury Can Be Enhanced by Co-administered Drugs and Mitigated by Mitochondrial Biogenesis
Drug-induced liver injury (DILI) can be enhanced by polypharmacy if co-administered drugs induce toxicity via mechanisms that have overlapping pathways.
Exposure-Response Modeling From the CLARITY Trial of Pimavanserin for Adjunctive Treatment of Major Depressive Disorder
Pimavanserin displays selective inverse agonist and antagonist activity at 5-hydroxytryptamine-2A (5-HT2A) receptors with lesser activity at 5-HT2C receptors, and no appreciable activity at adrenergic, dopaminergic, histaminergic, or muscarinic receptors.
Pediatric dose selection for fremanezumab (AJOVY) phase 3 migraine study using pharmacokinetic data from a pediatric phase 1 study and a population pharmacokinetic modeling and simulation approach
Previous examination of the relationship between fremanezumab exposures and baseline body weight supports a weight cutoff of 45 kg of pediatric dose selection, with the approved adult dose of 225 mg monthly being appropriate or patients weighing >= 45 kg
Exposure–Response Analyses to Support Optimal Dosing Regimens of Ceftolozane/Tazobactam in Patients With Hospital-Acquired Pneumonia (HAP)/Ventilator-Associated Pneumonia (VAP) in ASPECT-NP
Nosocomial pneumonia comprises hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) and is the most common nosocomial infection; mortality rates range from 3%–22% for nonventilated HAP (10%–40% for ventilated HAP) and from 6%–29% for VAP.
Probability of Target Attainment Analyses to Inform Ceftolozane/Tazobactam Dosing Regimens in Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia Patients With End-Stage Renal Disease on Intermittent Hemodialysis
Nosocomial pneumonia, including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), is a common type of hospital-acquired infection, with mortality rates estimated to be as high as 50%.
Ceftolozane/Tazobactam Probability of Target Attainment in Patients With Hospital-Acquired Pneumonia/ Ventilator-Associated Pneumonia
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are common hospital-acquired infections that are associated with mortality rates as high as 50%
Stochastic Assessment of Adaptive Volunteer Infection Study (aVIS) Designs in Malaria – A Case Study with Artefenomel
Traditional Malaria Volunteer infection studies use three consecutive single dose level cohorts (n=8).
Development and Evaluation of a Simulation Platform for Malaria Volunteer Infection Study (VIS) Designs
Traditional malaria volunteer infection studies have three consecutive single-dose cohorts.
Generalized PBPK Model for Evaluation of Inhalation Exposure of Volatile Organic Compounds
Physiologically based pharmacokinetic modeling (PBPK) is a valuable tool to evaluate inhalation exposure of volatile organic compounds (VOCs).
Quantitative Systems Toxicology (DILIsym) Modeling of the Acetaminophen Cellular Pathways for Liver Toxicity Supports that Acetaminophen is Not a Carcinogenic Hazard in Humans
Acetaminophen has a long history of safe use at therapeutic doses, but can cause liver injury at very high doses.
Synergy Between Two Mechanisms of Action Contributes to Species Differences in the Liver Safety Profile for PF-04895162
PF-04895162 (ICA-105665), a drug in development for the treatment of epilepsy, was terminated after transaminase elevations (up to grade...
Quantitative Systems Toxicology Modeling of Cisplatin Nephrotoxicity Using in vitro Assays of Proximal Tubule Epithelial Cells for Mechanistic Toxicity Pathways
Cisplatin-induced nephrotoxicity results in acute kidney injury (AKI) and is caused by various cellular mechanisms, including...
Using in silico-in vitro to in vivo Extrapolation (IS-IVIVE) to Predict the Oral Dose Required to Activate the Aryl Hydrocarbon Receptor (AhR)
Activation of AhR can have toxic effects on mammalian hosts
Mechanistic Modelling of the Linkage Between Proximal Tubule Cell Sublethal Injury and Tubular Sodium Reabsorption Impairment
Sublethal renal epithelial cell injury, a key manifestation of drug-induced acute kidney injury (AKI), is characterized by loss of brush border and cellular polarity of proximal tubular cells (PTCs).
Evaluating the Nephrotoxicity of Exemplar Compounds Using a Mechanistic Model of Drug-Induced Acute Kidney Injury
Drug-induced nephrotoxicity is a common source of acute kidney injury (AKI) and a condition that complicates clinical outcomes of vulnerable patients.