Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease

Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease

Authors: Terrett JA, Ly JQ, Katavolos P, Hasselgren C, Laing S, Zhong F, Villemure E, Déry M, Larouche-Gauthier R, Chen H, Shore DG, Lee WP, Suto E, Johnson K, Brooks M, Stablein A, Beaumier F, Constantineau-Forget L, Grand-Maître C, Lépissier L, Ciblat S, Sturino C, Chen Y, Hu B, Elstrott J, Gandham V, Joseph V, Booler H, Cain G, Chou C, Fullerton A, Lepherd M, Stainton S, Torres E, Urban K, Yu L, Zhong Y, Bao L, Chou KJ, Lin J, Zhang W, La H, Liu L, Mulder T, Chen J, Chernov-Rogan T, Johnson AR, Hackos DH, Leahey R, Shields SD, Balestrini A, Riol-Blanco L, Safina BS, Volgraf M, Magnuson S, Kakiuchi-Kiyota S
Publication: J Med Chem
Keywords: animal scaling, dose selection, fih, first-in-human, gastroplus, in vitro–in vivo extrapolation, IVIVE, PBPK modeling, physiologically based pharmacokinetics, translational science
Software: GastroPlus®

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease.

Regulatory Requirements and Applications of Physiologically Based Pharmacokinetic Models

Regulatory Requirements and Applications of Physiologically Based Pharmacokinetic Models

Authors: Cuquerella-Gilabert M, Garcia-Arieta A, Mangas-Sanjuán V, Reig López J
Publication: ADME Processes in Pharmaceutical Sciences
Keywords: drug pharmacokinetics, European Medicines Agency (EMA), PBPK modeling, U.S. Food and Drug Administration (FDA)

Physiologically based pharmacokinetic (PBPK) models have become a key tool to reduce the uncertainty and assure the best benefit-risk decisions in a model-informed drug discovery and development process.

Pharmacokinetic Simulation Study: Exploring the Impact of Clinical Parameters on Lamotrigine for Different Patient Populations with Implications for Liver Function Assessment and Therapeutic Drug Monitoring

Pharmacokinetic Simulation Study: Exploring the Impact of Clinical Parameters on Lamotrigine for Different Patient Populations with Implications for Liver Function Assessment and Therapeutic Drug Monitoring

Authors: Costa B, Silva I, Oliveira JC, Reguengo H, Vale N
Publication: Scientia Pharmaceutica
Keywords: DILIsym, disease populations, gastroplus, hepatic impairment, liver safety, PBPK modeling, physiologically based pharmacokinetics, QST, systems toxicology
Software: DILIsym®, GastroPlus®

Lamotrigine, widely used for managing epilepsy and bipolar disorder, carries potential side effects, including severe anticonvulsant hypersensitivity syndrome (AHS) or drug rash with eosinophilia and systemic symptoms (DRESS), which may lead to hepatotoxicity.

Physiologically Based Pharmacokinetic Absorption Model for Pexidartinib to Evaluate the Impact of Meal Contents and Intake Timing on Drug Exposure

Physiologically Based Pharmacokinetic Absorption Model for Pexidartinib to Evaluate the Impact of Meal Contents and Intake Timing on Drug Exposure

Authors: Nakayama S, Lukacova V, Tanabe S, Watanabe A, Mullin JM, Suarez-Sharp S, Shimizu T
Publication: Clinical Pharmacology in Drug Development
Keywords: admet predictor, drug exposure, gastroplus, intestinal absorption, PBPK modeling
Software: ADMET Predictor®, GastroPlus®

Pexidartinib is a systemic treatment for patients with tenosynovial giant cell tumor not amenable to surgery.

Development of a physiologically based pharmacokinetic model for levetiracetam in patients with renal impairment to guide dose adjustment based on steady-state peak/trough concentrations

Development of a physiologically based pharmacokinetic model for levetiracetam in patients with renal impairment to guide dose adjustment based on steady-state peak/trough concentrations

Authors: Wang R, Wang T, Han X, Chen M, Kliment T, Li S
Publication: Xenobiotica
Keywords: disease modeling, dose optimization, gastroplus, kidney disease, PBPK modeling, physiologically based pharmacokinetics, special populations
Software: GastroPlus®

Levetiracetam may cause acute renal failure and myoclonic encephalopathy at high plasma levels, particularly in patients with renal impairment.

Predicting Human Dermal Drug Concentrations Using PBPK Modeling and Simulation: Clobetasol Propionate Case Study

Predicting Human Dermal Drug Concentrations Using PBPK Modeling and Simulation: Clobetasol Propionate Case Study

Authors: van Osdol W, Novakovic J, Le Merdy M, Tsakalozou E, Ghosh P, Spires J, Lukacova V
Publication: Novel Approaches for Cutaneous Pharmacokinetics
Keywords: dermal drug concentrations, gastroplus, parameter sensitivity analysis, PBPK modeling
Software: GastroPlus®

Quantitative in silico tools may be leveraged to mechanistically predict the dermato-pharmacokinetics of compounds delivered from topical and transdermal formulations by integrating systems of rate equations...

Accelerated and Biopredictive In Vitro Release Testing Strategy for Single Agent and Combination Long-Acting Injectables

Accelerated and Biopredictive In Vitro Release Testing Strategy for Single Agent and Combination Long-Acting Injectables

Authors: Jain KMH, Ho T, Hoe S, Wan B, Muthal A, Subramanian R, Foti C
Publication: J Pharm Sci
Keywords: gastroplus, in vitro release testing, in vitro-in vivo correlation, IVIVC, ivivr, lai, pbbm, PBPK modeling, physiologically based biopharmaceutics modeling
Software: GastroPlus®

The purpose of this study was to develop an in vitro release testing (IVRT) strategy to predict the pre-clinical performance of single agent and combination long acting injectable (LAI) suspension products.

Simulations Plus Extends Collaboration with Major Toxicology Research Agency

Simulations Plus Extends Collaboration with Major Toxicology Research Agency

Keywords: admet predictor, Division of Translational Toxicology (DTT), gastroplus, in silico toxicology, U.S. National Institute of Environmental Health Sciences (NIEHS)
Software: ADMET Predictor®, GastroPlus®

Research project with NIEHS includes focus on qualification of in silico methods for prioritization, assessment of risk, and identification of safety margins for chemical use.

Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD)

Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD)

Authors: Adiwidjaja J, Spires J, Brouwer KLR
Publication: Pharm Res
Keywords: disease modeling, gastroplus, NAFLD, NAFLDsym, NASH, PBPK modeling, physiologically based pharmacokinetics, special populations
Software: GastroPlus®

This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling...

The AI‑driven Drug Design (AIDD) platform: an interactive multi‑parameter optimization system integrating molecular evolution with physiologically based pharmacokinetic simulations

The AI‑driven Drug Design (AIDD) platform: an interactive multi‑parameter optimization system integrating molecular evolution with physiologically based pharmacokinetic simulations

Authors: Jones J, Clark RD, Lawless M, Miller D, Waldman M
Publication: Journal of Computer-Aided Molecular Design
Keywords: admet predictor, artificial intelligence, Artificial Intelligence-driven Drug Discovery (AIDD), de novo drug design, gastroplus, physiologically based pharmacokinetic simulations, QSAR, QSPR
Software: ADMET Predictor®, GastroPlus®

Computer-aided drug design has advanced rapidly in recent years, and multiple instances of in silico designed molecules advancing to the clinic have demonstrated the contribution of this field to medicine.

Human biomonitoring and toxicokinetics as key building blocks for next generation risk assessment

Human biomonitoring and toxicokinetics as key building blocks for next generation risk assessment

Authors: Reale E, Zare Jeddi M, Paini A, Connolly A, Duca R, Cubadda F, Benfenati E, Bessems J, S Galea K, Dirven H, Santonen T, M Koch H, Jones K, Sams C, Viega S, Kyriaki M, Campisi L, David A, Antignac JP, B Hopf N
Publication: Environ Int
Keywords: adverse outcome pathway, AOP, gastroplus, nam, new approach methodology, next generation risk assessment, ngra, pbk modeling, PBPK modeling, physiologically based kinetics, reverse dosimetry
Software: GastroPlus®

Human health risk assessment is historically built upon animal testing, often following Organisation for Economic Co-operation and Development (OECD) test guidelines and exposure assessments.

Development of an extemporaneous preparation formulation using a simple and non-solubilizing matrix for first in human clinical study

Development of an extemporaneous preparation formulation using a simple and non-solubilizing matrix for first in human clinical study

Authors: Chiang CW, Tang S, Boonstra JM, van Tilburg LP, Liu J, Chiang PC, Rich S, Wu N, Nguyen HQ, Zhang W, Hou HH, Leung DH
Publication: Int J Pharm
Keywords: enabled formulation, formulation assessment, gastroplus, mechanistic absorption, parameter sensitivity analysis, pbbm, PBPK modeling, physiologically based biopharmaceutics
Software: GastroPlus®

Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study.

Chronic kidney disease and physiologically based pharmacokinetic modeling: a critical review of existing models

Chronic kidney disease and physiologically based pharmacokinetic modeling: a critical review of existing models

Keywords: disease populations, gastroplus, PBPK modeling, physiologically based pharmacokinetics, renal impairment
Software: GastroPlus®

Physiologically based pharmacokinetic (PBPK) modeling is a paradigm shift in this era for determining the exposure of drugs in pediatrics, geriatrics, and patients with chronic diseases where clinical trials are difficult to conduct.