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IMPORTANT: This event spans two separate days (Sep 22 and Sep 29). The speakers listed below will be presenting on Sep 29.

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2:00 – 2:40 pm

Amantadine as a biomarker drug for detection and therapeutic monitoring of cancer
Donald Miller, Ph.D., Professor, Dept. of Pharmacology & Therapeutics, Kleysen Institute for Advanced Medicine, University of Manitoba
Dr. Donald Miller received his B.Sc. in Chemistry from Bethel College (1985), Newton, Kansas, and his Ph.D. in Pharmacology and Toxicology from the University of Kansas (1991). He was a Marion Merrell Dow Postdoctoral Research Fellow in Dr. Ronald Borchardt’s laboratory at the University of Kansas where he studied biological approaches for enhancing drug delivery and drug absorption (1991-1993). Dr. Miller is presently a Professor in the Department of Pharmacology and Therapeutics at the University of Manitoba. He is an internationally recognized expert in drug transporters and blood-brain barrier function, having served on both NIH and CIHR grant and fellowship review panels, as well as reviewer and site visit examiner for Austrian and European Union based program grant initiatives. He has participated on External Scientific Advisory Boards for Vireo Systems Inc. (US-based nutraceutical company) and SFB35 –Transporters in Health and Disease – a multiple researcher project scheme type grant from the University of Vienna. His research interests include understanding cellular and molecular mechanisms regulating blood-brain barrier function under normal and pathological conditions and identification of methods for enhancing drug delivery to the brain. Dr. Miller’s research program includes examination of blood-brain barrier changes during brain tumor development and identification of methods for increasing the delivery of chemotherapeutic agents to brain tumor; identification and characterization of drug efflux transport proteins in the blood-brain barrier and the molecular mechanisms influencing activity and expression; and the design and development of nanoparticle drug delivery platforms for CNS applications.
Abstract: Spermidine/spermine N(1)-acetyltransferase (SAT1) is a critical enzyme in the polyamine pathway and the rate-limiting enzyme in the catabolism of polyamines. Under normal conditions, SAT1 has a relatively low expression and short half-life. However, SAT1 is inducible and expression of SAT1 is increased in a number of cancers. The increased expression of SAT1 in tumor tissue suggests that acetylated metabolites produced by SAT1 could be used as blood or urine biomarkers for the detection of a variety of cancers. The antiviral drug amantadine undergoes selective SAT1-mediated acetylation to a stable metabolite that is eliminated in the urine. In this regard, amantadine may be a more sensitive cancer biomarker than the endogenous acetylated polyamines. Evidence for the application of acetyl amantadine as an early biomarker for lung cancer will be presented. In addition, using physiologically-based pharmacokinetic (PBPK) modeling of amantadine and acetyl amantadine, predictions concerning SAT1 expression and activity within the tumor compartment and potential applications in early tumor detection will be presented.

2:40 – 3:20 pm

Insights into association of cancer cachexia and catabolic clearance with response gained from pembrolizumab exposure-response assessments
Julie Stone, Ph.D., Scientific AVP, Dept. of PPDM, Merck
Dr. Julie Stone joined Merck in 1995 following graduate studies in biomedical engineering at the University of Pennsylvania and postdoctoral research in pharmacokinetic modeling at Hoffmann-La Roche. At Merck, she has provided pharmacology and pharmacometrics support for a variety of programs, including 12 approved drugs: CANCIDAS™ (caspofungin), CRIXIVAN™ (indinavir), and PROPECIA™ (finasteride), JANUVIA™ (sitagliptin), ISENTRESS™ (raltegravir), VICTRELIS™ (boceprevir), IVEMEND™ (fosaprepitant), VANIHEP™ (vaniprevir), BELSOMRA™ (suvorexant), ZONTIVITY™ (vorapaxar), ZEPATIER™ (grazoprevir/elbasvir), and KEYTRUDA™ (pembrolizumab). As a senior scientist on the research ladder, she divides time between individual scientific contributions in areas including Alzheimers Disease, immuno-oncology, osteoporosis, and antivirals with setting and overseeing wider scientific strategy of quantitative pharmacology and pharmacometrics application in drug development. In this role, she works to bring the power that the sophisticated quantitative tools of modeling offer together with effective, impact focused communication to enable better informed decisions and regulatory interactions.
Abstract: Clinical dose-ranging studies and exposure-response analyses provide key data underpinning dose selection and defense in development programs. Recent experience from the pembrolizumab programs suggests that monoclonal antibody (mAb) programs may face additional complexity in interpreting data with respect to dose due to strong associations of clearance with patient health factors. For pembrolizumab, randomized dose-ranging studies (2 vs. 10 mg/kg) in melanoma and NSCLC provided key data (including Overall Survival (OS)) for exposure-response analyses and dose selection decisions. No significant difference in OS was found between the doses studied for pembrolizumab, but trends suggestive of exposure-dependency were identified. These trends derived from a clearance-OS association, rather than a true exposure relationship, which likely reflects the patients’ overall catabolic state which may be tied to health factors such as cachexia which directly affect patient outcomes. To support dose selection in future mAb programs (and avoid confounding of patient health effects on clearance), it is recommended to include dose-ranging studies with associated exposure-response analyses, avoid single-dose studies prior to establishment of dose, and collect robust PK data and catabolism biomarkers.

3:20 – 4:00 pm

Reevaluation of using the mental and physical test scores to determine the extent of mercury toxicity – monitoring test scores using the chelation agent N,N’bis-(2-mercaptoethyl) isophthalamide
Chris Kemper, Ph.D., PK/PD/Bioanalytical Consulting, Pharma Navigators, LLC
Dr. Chris Kemper has had a long and highly varied career in PK/bioanalytical (and now PD) drug development. It started as a non-degreed technician in one of the few Drug Metabolism departments in industry (SWRI in Rensselaer). Since then he acquired a B.Sc. in Chemistry (RPI), Ph.D. in Pharmacology (U of Louisvile Health Sciences Center) and, in 2018, a M.S. in Pharmacometrics at the U of Maryland (Baltimore), when he was 68 (a true glutton for punishment). He has had many industrial drug development positions and is currently on his own in PK/PD/Bioanalytical consulting with an international clientele. He is best known for his involvement with drug metabolism and bioanalytical discussion groups in the US and Europe and the Gordon Conference on Drug Metabolism.
Abstract: NBMI ((N1,N3-bis(2-mercaptoethyl) isophthalamide, Emeramide) is a mercuric chelator developed for the treatment of mercury intoxication. Chelation therapy for mercury toxicity varies throughout the world and is generally encompassed by treatments for toxic metal poisoning. Conducting field studies that yield meaningful results is, not surprisingly, a challenge since the toxic effects of mercury have been known since antiquity and its use in uncontrolled settings is often illegal. One set of biomarkers that are easy to apply are subject evaluations of their physical (e.g., “always lack energy”) and mental (e.g., “problems with memory”) well-being improving or not during 15 days of treatment. While the original statistical analysis was good, it did not explore a few issues: 1) the duration of dosing on improvement of scores, 2) that the individual scores were not independent, and 3) observations were not coupled with plasma measurements of drug and total mercury. A mathematical model was applied using longitudinal discrete outcomes (improvement by day over 15 days) with the generalized estimating (GEE) and the generalized (non-linear) mixed effects modeling (GLMM) approaches. An example of the probability for improvement over time is shown below:

Subject weight, drug and mercury concentration, treatment (dose) and day on study almost always had significant effects on improving GEE and GLMM models, though the use of some covariates, especially mercury concentrations, introduced instabilities in modeling. Depending on the metric (again, “always lack energy”), the odds of a person achieving a “good” physical or mental effect with the drug could be as much as 4 times the odds of the same person with placebo.

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