Day 1 :
IRCCS San Raffaele Pisana, Italy
Time : 09:00-09:25
Stefano Bonassi is a Doctor in Biological Sciences - University of Genova and a Specialist in Medical Statistics and Epidemiology - University of Pavia. He is a Faculty for PhD programs in Human Genetics of the Universidad Autonoma de Barcelona, Barcelona, Spain, and M2E2 International courses of Molecular Epidemiology of Chronic Diseases at the Maastricht University, the Netherlands. He is a reviewer of many journals such as Experimental Research; Mutagenesis; Cancer Epidemiology; Biomarkers & Prevention et al.
The concept of the exposome, representing the totality of exposures from gestation onwards, has been introduced as a complement to genomic data in the study of disease etiology. The original purpose of such investigations was the discovery of key biomarkers of exposure, to be used in exploring hypotheses about sources of exposure, dose-response relationships, mechanisms of action, disease causality and public health interventions. On the other hands, the implementation of systems approaches in clinical practice, and the development of complex predictive models which – under the 4 P’s perspective – include social, psychological, and life-style parameters in the therapeutic process, has determined the inclusion of epidemiologic knowledge into clinical studies. Th e possibility to model in the same playground the complexity of the exposome and the variety of real clinical practice will help to identify new ontologies and to improve disease recognition and treatment.
Prolong Pharmaceuticals, USA
Keynote: Toxicology studies and results for determining safety of a novel anti-neutropenic factor–ANF-Rho™
Time : 09:25-09:50
Hemant Misra received his PhD from Lucknow University in Medicinal and Pharmaceutical Chemistry and has published over 65 articles and a patent. He is VP Clinical Development for Prolong Pharmaceuticals. He has over 30 years of biopharmaceutical development, global clinical study management and corporate development experience. He has managed drug development, CGMP manufacturing, CTM, quality systems and multiple global clinical trials.
ANF-Rho is a novel polyethylene glycol-modified granulocyte colony stimulating factor that has biophysical and biological
properties that produce a distinct pharmacokinetic and pharmacodynamic profile as compared to pegfi lgrastim
(Neulasta®). ANF-Rho was evaluated in a series of studies to assess the pharmacokinetics, pharmacodynamics and toxicity in the rat and primate as compared to Neulasta®. Rats were made neutropenic by injection of cyclophosphamide to determine pharmacokinetic and pharmacodynamics eff ects of ANF-Rho. Both single and repeat dose toxicity studies administered for up to 5 once weekly doses. Endpoints for toxicological studies included clinical observations, body weights, food consumption, ophthalmic exams, neurotoxicity, clinical pathology, immunogenicity, necropsy and histopathology. Pharmacokinetics were determined following subcutaneous (SC) or intravenous (IV) administration of either 50, 75 or 100 μg/kg in Sprague Dawley rats and 10 or 100 μg/kg in cynomolgous primates. Neulasta was dosed at 100 μg/kg. Analysis of variance (ANOVA) with a Dunnet’s post-hoc test was performed to demonstrate signifi cant diff erences (p<0.05) between treatment groups. The halflife
of ANF-Rho SC in the rat ranged from 17.99 to 18.05 hours for the 3 doses as compared to 5.63 for the Neulasta group. Pharmacodynamic analysis of the area under the curve (AUC) kinetic analysis showed the absolute neutrophil count (ANC)
of ANF-Rho was equivalent at 4X lower dosage (25 vs. 100 ug/kg) and yielded signifi cantly higher ANC than Neulasta when administered at equivalent 100 μg/kg dosage. ANF-Rho yielded a 4-6 fold increased in de novo neutrophil (CD34+) counts. No observed toxicologically or signifi cant fi ndings for any endpoint in rats receiving a single dose of 100, 1000, 3000, 10000 or 25000 μg/kg of ANF-Rho in the rat for maximum tolerated dose (MTD) study. No clearly adverse eff ects were seen following treatment with ANF-Rho in rats over a 28 days treatment period with a calculated NOAEL of 1000 μg/kg. Primates were dosed with 250 or 750 μg/kg. Th e NOAEL was to be determined to be greater than 750 μg/kg. Rat neutropenia dosage model results found that the blood pharmacodynamics parameters of ANF-Rho were signifi cantly superior to Neulasta. Both PK and PD data demonstrate relatively predictable systemic exposures and activity following SC or IV dose levels in both rat and primate. The toxicology studies were unremarkable and suffi cient to support advancement of ANF-Rho into Phase I clinical studies.
Intertek Scientific & Regulatory Consultancy, Canada
Time : 09:50-10:15
Ashley Roberts gained his PhD from the University of Southampton. He is Senior Vice President of the Food & Nutrition Group at Intertek Scientific & Regulatory Consultancy and has published more than 60 papers and book chapters.
More than 40 different steviol glycosides have been identifi ed in the leaves of the Stevia rebaudiana (Bertoni) plant. Steviol
glycosides contain a steviol backbone attached to a number of diff ering sugar moieties including glucose, xylose and rhamnose. Metabolic studies indicate that following oral administration, these steviol glycosides pass undigested into the colon where they are then hydrolyzed to steviol prior to absorption. Once absorbed, steviol undergoes conjugation with glucuronic acid to form steviol glucuronide with the majority being excreted in the feces via the bile in rats and in the urine in human. The shared metabolic fate supported through in vitro studies using human fecal homogenates from healthy donors under anaerobic conditions, thereby supports that the ADI of 0-4 mg/kg/day which was determined for stevioside, is applicable to steviol glucosides in general. Th e ADI was based on the application of a 100-fold uncertainty factor to a NOAEL from a stevioside chronic rat study. In an attempt to increase the ADI, single dose stevioside pharmacokinetic studies were conducted in rats and
humans to derive a chemical-specifi c inter-species toxicokinetic adjustment factor. Th ese studies generated a chemical specific
adjustment factor of 1 and 2.8 based on comparative Cmax and AUC0-last data, respectively. Since these factors are lower than
the default value of 4.0 for inter-species differences in toxicokinetics, a higher ADI for steviol glycosides of between 6 and 16 mg/kg/bw/day is justified.
Aarhus University, Denmark
Time : 10:15-10:40
Eva Cecilie Bonefeld-Jørgensen was an Assistant Professor in 1996, Associated Professor and Head of Unit of Cellular and Molecular Toxicology in 1999, Professor and Director of Centre for Arctic Health & Molecular Epidemiology in 2008 at University of Aarhus. She has authored more than 170 publications and collaborated with a number of national and international institutions, lecturing at graduate and post-graduate level and been Project Coordinator for several international projects currently the Fetotox birth cohort study including China, Norwegian, Denmark and Greenland. She is the President for the Danish Society of Pharmacology and designated Expert for the human health working group at Arctic Monitoring Assessment Programme.
The incidence of breast cancer (BC) is increasing in almost all countries and is the most common cancer for women in affluent
countries. Th e differences that still exist between different ethnic groups might be explained by diff erences in reproductive and hormonal factors, genetic background, lifestyle and environmental exposures. The known risk factors only explain less than a third of all cases and more than 70% of women diagnosed with BC have no inherited or sporadic cancer. Environmental exposures to persistent organic pollutants (POPs) such as polychlorinated biphenyls and organochlorine pesticides and perfl uoroalkylated substances (PFAS) are among potential risk factors. Th ese compounds are potential endocrine disrupters altering the hormone homeostasis disturbing normal development, growth and function of mammary glands. Animal studies have indicated that PFAS increase mammary fi broadenomas and our recent case-control studies in Danish and Greenlandic Inuit women showed an association between the serum levels of PFAS and BC risk. Moreover, xenoandrogenic activity of
serum extracts containing the actual mixture of legacy POPs was a signifi cant risk factor in Inuit. Environmental exposures and genetic susceptibility diff er between ethnic groups. Th e genotype and allele frequency of genetic polymorphisms in P450 phase I and phase II genes differs between Inuit and Europeans. For Inuit women an increased BC risk was observed with high PFAS levels and carriers of at least one variant of CYP1A1(Val) and COMT(Met) or the common CYP17 A1 allele, and in Danish women, we observed polymorphisms in COMT, CYP17 and CYP19 can modulate the BC risk of PFOSA exposure.