Meetings and Events

Upcoming Events

2016

Integrating In Silico Predictions with Physiologically Based Pharmacokinetic (PBPK) Modeling
February 29, 2016, 2:00 PM EST
Presenter: Michael S. Lawless, Simulations Plus, Inc.

This webinar will cover two applications of PBPK modeling: 1)  predicting oral bioavailability (F%) from 2D structure and 2) using in silico modeling to predict the unforeseen renal failure caused by SGX523, a c-MET kinase inhibitor.

See below for full abstract. Register here.

After registering, you will receive a confirmation email containing information about joining the webinar.

ASCCT webinars are open to the general public. Members receive access to webinar recordings after the event. Please register today!

Integrating In Silico Predictions with Physiologically Based Pharmacokinetic (PBPK) Modeling

Michael S. Lawless, John DiBella, and Michael B. Bolger
Simulations Plus, Inc.

This webinar will cover two applications of PBPK modeling: 1)  predicting oral bioavailability (F%) from 2D structure and 2) using in silico modeling to predict the unforeseen renal failure caused by SGX523, a c-MET kinase inhibitor.

Our strategy for predicting F% involves the integration of artificial neural network ensemble (ANNE) model predictions with PBPK modeling. Predicted aqueous and biorelevant solubility, pKa, logD, gastrointestinal permeability, fraction unbound in human plasma, blood to plasma concentration ratio, and Michaelis-Menten Km and Vmax parameters for five major cytochrome P450 (CYP) isoforms (1A2, 2C9, 2C19, 2D6, and 3A4) were used as inputs for the PBPK models.  A hierarchical set of models was used to determine CYP metabolism.  First, classification models predicted whether or not a compound was a substrate for each of the five major CYPs.  Next, sites of metabolism were predicted for those compounds which were projected to be substrates.  Finally, Km and Vmax predictions were made for each predicted site of metabolism. Oral bioavailability for each drug was computed using a PBPK model for a 35-year-old American male. The tissue:plasma partition coefficients for the PBPK models were calculated using the Lukacova method.1 Absorption of the compound was simulated with the Advanced Compartmental Absorption and Transit (ACAT™) model in humans under fasted conditions. CYP metabolism in gut and liver was accounted for utilizing built-in enzyme expression levels in gut and liver along with predicted Km and Vmax values.

In order to test our predictions, we created a database of 62 drugs which included their reported percent oral bioavailability and dose.  We attempted to evaluate the use of our CYP clearance predictions, so each compound’s major clearance route was known to be mediated by CYP enzymes. The reported F% values varied from 3% (fluphenazine) to 99% (diazepam, galantamine, glimepiride, indomethacin, and tamsulosin) with an average of 60%.  All molecules were correctly predicted to be substrates of the CYPs associated with their major clearance pathways.  Furthermore, these pathways had the highest predicted CYP intrinsic clearance in 42 of the 62 molecules. Overall, 68% of the molecules were predicted within 2-fold of their reported oral bioavailability.

PBPK Modeling of SGX523

SGX523 is a quinoline-containing molecule that was a promising c-MET kinase inhibitor with an IC50 of 4 nM and >1,000-fold selectivity over other protein kinases.  In a phase 1 clinical trial, the six patients that received ≥80 mg daily doses all developed renal failure.  Follow-up studies revealed that the cause of renal toxicity was drug-induced nephropathy due to kidney lumen precipitation of a metabolite of SGX523 that was not detected in preclinical studies in rats and dogs.  Aldehyde oxidase transforms the quinoline ring into a quinolinone.  Generation of the quinolinone metabolite is species-dependent; it is formed in human and monkey liver S-9 but not in dog S-9 incubations.  Here, we demonstrate the use of predicted physicochemical and biopharmaceutical properties to predict the toxicokinetics of SGX523 and its oxidized quinolinone metabolite.   These predicted properties were then used in a mechanistic oral absorption and PBPK simulation of the plasma and renal concentrations versus time.  Oxidative metabolism results in conversion of the basic quinoline (predicted pKa of 4.2) group in SGX523 to an acidic lactam ring with a predicted pKa of 11.0.  This also results in decreased solubility; the predicted aqueous solubility drops from 2.4 µg/mL in SGX523 to 0.56 µg/mL in its quinolinone metabolite.  Our PBPK simulations show high concentrations of the quinolinone metabolite in the lumen of the kidney, beyond its solubility, creating the probability of precipitation. Thus, our in silico analysis predicts the observed renal toxicity in humans and monkeys due to crystallization of the metabolite in the kidney.

1V. Lukacova, N. Parrott, T. Lave, G. Fraczkiewicz, M. Bolger, W. Woltosz. General approach to calculation of tissue:plasma partition coefficients for physiologically based pharmacokinetic (PBPK) modeling, AAPS National meeting, Atlanta, November 15-20, 2008.

 

17th International Conference on QSAR in Environmental and Health Sciences

June 13-17, 2016
Miami Beach, FL

Abstract deadline: December 4, 2015
Early Bird reg: March 1, 2016

Since 1983, this Conference has been an important international gathering in the field of Environmental and Health Sciences, bringing together scientists developing and using (Q)SARs.

This meeting will bring together both developers and users of (Q)SAR methodologies from around the world, and in addition to a comprehensive program offer opportunities for career development with many courses and an on-going “Jobs Fair” to connect employers with potential employees.

The ASCCT will provide funds for up to three students traveling to the conference. Specifically, it will cover the early bird registration fee for the conference as well as provide $500 to cover additional travel costs. See registration details here.

To apply, students should provide their submitted abstract plus a short (no more than 200 words) statement of purpose to the ASCCT Secretary by February 15th, 2016. Winners will be notified in time to register for the early bird registration deadline.

Agenda tracks include:

  • Track 1: Experience from a regulatory accepted use of (Q)SAR models: The ICH M7 guidance for pharmaceutical impurities
  • Track 2: Using read-across and (Q)SAR models to support industrial applications (including REACH)
  • Track 3: Best practices in the development of fit-for-purpose (Q)SAR models
  • Track 4: (Q)SAR Methodologies
  • Track 5: Using (Q)SARs as part of hazard and risk assessment

Poster session, panel discussions, and a debate will also be held. Several continuing education sessions will be offered, including one on Describing Adverse Outcome Pathways.

Visit the conference web site for more information.

 

Past Educational Member Webinars

ASCCT members, click here to access recordings of past webinars listed below. Contact the Secretary for more information or to suggest a topic for a future webinar.

  • The GARD assay for skin and respiratory sensitization | Andy Forreryd, Lund University
  • COSMOS: Automated in silico tools for in vitro to in vivo extrapolation| Alicia Paini, European Commission Joint Research Centre
  • Threshold of Toxicological Concern – an approach for safety assessment and its applicability to cosmetics-related chemicals | Chihae Yang, Altamira, LLC and Molecular Networks
  • Medical Device Irritation Testing: An In Vitro Alternative | Kelly Coleman, Medtronic Biomaterials Dept
  • Developing Confidence in 21st-Century Risk Assessments | Craig Rowlands, Dow Chemical Company
  • COSMOS DB: A New Database of Toxicological Information to Support Knowledge Discovery | Mark Cronin, Liverpool John Moores University and COSMOS project coordinator
  • High Content Imaging Approaches in Neurotoxicology and Neurodegeneration Research | Marcel Leist, University of Konstanz and CAAT Europe
  • EURL ECVAM's Approach to Validation of Alternative Methods | Valerie Zhuang, EURL ECVAM
  • Using the AOP Framework to Develop HTS Assays for Thyroid-Disrupting Chemicals | Katie Paul, US EPA
  • The Role of Non-Animal Methods in the Regulation of Nanomaterials in the United States | Erik Janus, Steptoe and Johnson LLP (Recording not available)
  • Human Induced Pluripotent Stem Cell-derived Model Systems | Maureen Bunger, Cellular Dynamics
  • Incorporating New Technologies into Toxicity Testing and Risk Assessment | Russell Thomas, The Hamner Institutes for Health Science
  • The Virtual Embryo | Nicole Kleinstreuer, US EPA
  • Tox21 Program Update | Raymond Tice, National Toxicology Program, NIH
  • Evidence-Based Toxicology (EBT) for the 21st Century | Martin Stephens, Johns Hopkins University
  • Effectopedia: The Online Encyclopedia of Adverse Effect Pathways | Gilman Veith and Hristo Aladjov, International QSAR Foundation
  • MetaPath: A Metabolism Pathway Database | Patricia Schmeider, US EPA

Past Events

Fourth Annual Scientific Meeting of the American Society for Cellular and Computational Toxicology: Promises and Challenges of a More Flexible Approach to Toxicology Testing

The fourth annual ASCCT meeting explored new approaches to toxicology testing with plenary lectures given by Warren Casey, Director of NICEATM and Craig Rowlands from the Dow Chemical Company. The meeting featured a diverse poster session, a panel discussion on the assessment and application of IATA, and ten oral presentations chosen from a very competitive field of abstracts. Members elected two new members to the Board of Directors: Gertrude-Emilia Costin and Shaun McCullough. View Program.  ASCCT members, click here to view all presentations.
 
Third Annual Scientific Meeting of the American Society for Cellular and Computational Toxicology: Where Chemistry and Biology Meet: AOPs as a Framework for Advancing Toxicology

Dr. Robert Kavlock of the US Environmental Protection Agency opened the meeting with a discussion on the development of the Adverse Outcome Pathways concept, in which AOPs offer a biological context to facilitate the development of Integrated Approaches to Testing and Assessment (IATA) for regulatory decision-making. Drs. Jennie Larkin and Ajay Pillai from NIH discussed BD2K and LINCS, two community-building programs. Other presenters explored the development of different tools used to test toxicity. A poster session and reception concluded the meeting. View Program. ASCCT members, click here to view all presentations.

Second Annual Scientific Meeting of the American Society for Cellular and Computational Toxicology: The Future Is Here: Practical Applications of Emerging Scientific Tools
Human Organs on Chips as Replacements for Animal Testing, the keynote address given by Donald E. Ingber, M.D., Ph.D., of the Wyss Institute at Harvard, kicked off the meeting which featured a dozen lectures and poster presentations on making toxicology a more human-relevant science. Other topics included methods to replace live animals in eye irritation tests and computer-based virtual embryos that show how chemical exposures might affect developing embryos. View Program.

First Annual Scientific and Business Meeting of the ASCCT
The first annual ASCCT meeting focused on advances in the fields of in vitro and computational toxicology. Dr. Melvin Andersen, associate director of The Institute for Chemical Safety Sciences at The Hamner Institutes for Health Sciences and ASCCT board member, gave a plenary lecture on Computational Cellular Pathway Modeling: Combining Key In Vitro and In Silico Tools to Enhance Modern Safety Assessment. Dr. Suzanne Fitzpatrick, senior advisor for toxicology at the U.S. Food and Drug Administration gave a plenary lecture on an Overview of the FDA-DARPA-NIH Collaboration on Human/Organ on a Chip. View Program.

Institute for In Vitro Sciences Practical Methods for In Vitro Toxicology Workshop
Attendees gained hands-on laboratory experience and instruction in the practical application of the lectured topics. Topics for the three and a half day course included: (i) international regulatory acceptance status of in vitro assays, (ii) predicting organ specific toxicity (e.g., ocular, dermal and hepatic), (iii) using cell and organ culture models with histological, biochemical, and molecular endpointsm, and (iv) data interpretation.

2010 In Vitro Alternatives Forum
Thank you for contributing to a successful forum. Read the post-meeting report.

8th World Congress for Alternatives and Animal Use
Thank you for helping to make the ASCCT/ESTIV luncheon session a success. A manuscript outlining the discussions that took place during the session has been published. You can view the entire proceedings here.