Day 2 :
Keynote Forum
Akwete Lex Adjei
Rhodes Pharmaceuticals L.P, USA
Keynote: Steady-state bioavailability of extended-release methylphenidate Capsules vs. immediate-release methylphenidate tablets in healthy adult volunteers
Time : 10:00-11:00
Biography:
Akwete Lex Adjei has completed his PhD from the University of Texas, Austin and his Postgraduate work on complexation of xanthine drugs in non-ideal solvent systems. He has held positions at several pharmaceutical companies and he is currently an Executive Director of R&D at Rhodes Pharmaceuticals, L.P. He has been the author/co-author of 38 published peer-reviewed articles and 15 books or book chapters and has almost 50 patents for his work in this area.
Abstract:
A novel formulation of extended-release (ER) methylphenidate hydrochloride that utilizes multiple layers of coatings on beads for encapsulation into hard gelatin capsule shells (Aptensio®, MPH-MLR) was evaluated to determine the relative bioavailability vs. immediate-release methylphenidate tablets (IR, Ritalin®) as single and multiple doses in the fed state. A single-center, 4-day, multiple-dose, randomized, open-label, 2-period crossover study design assessed the relative bioavailability of MPH-MLR 80 mg once daily versus Ritalin® IR 25 mg 3 times daily (TID) in 26 healthy adults. Serial blood samples were collected at pre-specified time points over the 4-day dosing period for determination of methylphenidate concentration and pharmacokinetic analyses. Relative bioavailability of MPH-MLR versus Ritalin® (75 mg total daily dose normalized to a single dose of MPH-MLR) as a single dose under fed conditions, and at steady state under fed conditions, was determined based on AUC0-t, AUC0-inf and Cmax of methylphenidate. MPH-MLR administration produced a rapid initial peak, a moderate decline until ~5 hours postdose, and a gradual increase until ~7 hours postdose. Cmax was lower for MPH-MLR 80 mg than methylphenidate IR 25 mg on Day 1. Exposure was similar with 90% CI limits for the geometric mean ratios of log-transformed AUC0-t that were within the 80%-125% equivalence range. Day 4 partial AUC0-4 (74.49±15.23 hr.ng/mL) for MPH-MLR exceeded Ritalin IR 25 mg 3 times daily (66.01±17.41 hr.ng/mL), and therefore was not bioequivalent. MPH-MLR capsules administered once daily and methylphenidate IR administered TID provided comparable maximum methylphenidate concentrations and systemic exposure in the fed state.
- Clinical Trials I Challenges in Drug Design I Biosimilars
Chair
Mewa Singh
Meda Biotech LLC, USA
Co-Chair
Sue Duran
Auburn University, USA
Session Introduction
Stephen Tindal
Catalent, USA
Title: Accelerating preclinical development for poorly bioavailable compounds by assessing multiple oral technologies in parallel
Time : 11.15-11.45
Biography:
Stephen Tindal holds a Bachelor’s degree in Chemistry and Analytical Science from Loughborough University, UK. He has worked at Catalent for 29 years, holding positions in R&D responsible for Formulation, Process Development and also for Clinical and Commercial Operations. He has specialized in solving Complex Data Analysis challenges such as Low Bioavailability and Atypical Analytical Data. He is the part of Catalent’s Science and Technology Team at New Jersey, USA.
Abstract:
During the pre-clinical stage of the drug development process, scientists often face a set of challenges to deliver the desired quality target product profile (QTPP), with the top three being bioavailability (usually solubility), API availability and speed of execution. It may be necessary to partner with a variety of different companies, each with specific technologies, expertise and approaches. There may be a reticence to commit to enabling technologies, as it may be easier to begin with simpler strategies, like powder in a bottle and to iterate (with follow on approaches) once more data is available. However, in-house approaches may satisfy a desire for speed, they also run the risk of burning time and resources if ultimately not successful, and this is likely given the increasing number of poorly soluble molecules. It is increasingly essential to examine and rank multiple delivery options in parallel, to collect data about the relative dose capability, PK enhancement and manufacturability in order to select drug candidates to advance to clinical phase I. This talk will provide an overview of a structured assessment and parallel formulation feasibility assessment approach that is designed to reveal the most suitable pathway to enhance bioavailability and accelerate development by: Understanding the classification of poorly bioavailable compounds using the developability classification system; Understanding how a structured and high throughput parallel screening approach can expedite preclinical development; and to learn how enabling technologies such as lipid based formulation, solid dispersion and particle size reduction can be applied.
Erich von Borries Medrano
Instituto Politecnico Nacional, Mexico
Title: Starch-guar gum extrudates: microstructure, physicochemical properties and in vitro digestion
Time : 11:45-12:15
Biography:
Erich von Borries Medrano has completed his Master degree in Advanced Technology from Centro de Investigacion en Ciencia Aplicada y Tecnologia Avanzada - Instituto Politecnico Nacional (CICATA-IPN). He is a PhD Student of CICATA-IPN, a center focused on applied science and technology development. He is investigating how different additives results in resistant starch formation.
Abstract:
Starch-guar gum mixtures were obtained by extrusion using a three-variable Box-Behnken statistic design. Morphology, expansion index, viscosity, crystallinity and digestion in vitro of the extruded samples were analyzed through response surface methodology (RSM). The extrusion temperature and the moisture content were the factors that significantly affected the physicochemical properties of the samples. Starch-guar gum samples showed expansion index and viscosity up to 1.55 and 1,400 mPas, respectively. The crystallinity of the samples was modified by adding guar gum to the extrudates showing correlation between long-range order (X-ray diffraction) and short-range order (FTIR spectroscopy). Guar induced micro-structural changes and its role in gelatinization-melting processes was significant. The rate of glucose release decreased from 0.47 to 0.43 mM/min when the extrusion temperature decreased. However, adding guar gum to starch had no significant effect on glucose release. Overall, the extrusion temperature and the moisture content were the factors that significantly affected the physicochemical properties of the extruded samples.
Zafer Sezer
Erciyes University, Turkey
Title: Overview of bioavailability/bioequivalence trials in a phase 1 clinic in Turkey
Time : 13:50- 14:20
Biography:
Zafer Sezer was graduated from Istanbul University, CerrahpaÅŸa Medical Faculty as a Medical Doctor in the year 1999. He has completed his Post-doctoral research in Pharmacology Department of Erciyes University, School of Medicine. He has been working as a Principal Investigator in Hakan Çetinsaya GCP and Research Center since 2008. Additionally, he is a Member of Erciyes University Clinical Researches Ethical Committee.
Abstract:
Multisource pharmaceutical products need to conform to the same standards of quality, efficacy and safety as required of the originator’s product. Testing the bioequivalence between a product and a reference in a pharmacokinetic study with a limited number of subjects is one way of demonstrating therapeutic equivalence. Bioavailability/bioequivalence (BA/BE) trials have been conducted in our clinic, Turkey, since 2000. We have collaborations with several companies from foreign countries. We want to evaluate the phase 1 trials which were carried in our clinic between the years 2005 and 2015. The distribution of these 947 trials according to years was as follows: 151 in 2005, 118 in 2006, 123 in 2007, 120 in 2008, 88 in 2009, 84 in 2010, 68 in 2011, 51 in 2012, 54 in 2013, 36 in 2014 and 54 in 2015. If we group these trials, we can see that the largest group is antibiotics. Furthermore, the antihypertensive medicines, anti-seizures, antipsychotics, anti-depressants, analgesic medicines, peptic ulcer medicines, anti-diabetic medicines, antihyperlipidemic medicines and the rest consists of the other groups. The number of trials and medicine groups which were studied in our clinic, change according to years. For example number of BA/BE trials related antibiotics are less than previous years. As a result BA/BE trials are improving in Turkey. They are conducting according to Turkish Regulations Regarding Clinical Trials of Drugs and Biologics which is similar to EMEA and FDA regulations.
Somdutta Saha
GlaxoSmithKline, USA
Title: Structural Approaches for Targeted Therapy
Time : 14:20-14:50
Biography:
Somdutta Saha is presently working as a Post-doctoral Scientist at GlaxoSmithKline, Pennsylvania site where the broad focus is to computationally search for immunomodulators of microbial origin to chemo-genomic fine tuning the microbial imbalance in several autoimmune disorders and inflammatory bowel disease (IBD). She has received her PhD degree in Bioinformatics from the University of Arkansas for Medical Sciences where she has investigated the fundamental aspects of antigen-antibody interaction in the tumor microenvironment using several computational approaches under the mentorship of Dr. Thomas Kieber-Emmons.
Abstract:
Tumor associated carbohydrate antigens (TACAs) are a class of glycans with important structural and signaling functions playing a major role in cell proliferation, differentiation, and apoptosis relevant to oncology. Tumor cells expressing TACAs influence prognosis and survival of cancer patients. We have used structure-based approaches to study antigen-antibody interactions in the tumor micro-environment and designed a peptidyl ligand that mimics the molecular topology of TACAs even though they are chemically dissimilar but functionally equivalent molecular structures. The work on antibody-TACA interactions suggests that in designing antibodies, careful consideration should be made in using mutations that enhance the rigidity of an antibody. Our work also suggests that electrostatics play a major role in the recognition of the model antigen examined. Discrimination against wanted targets through repulsive electrostatic interactions might be more fruitful than a strong optimization of target binding. Increased specificity toward one target leads to decreased affinity toward others. Models for TACA targeting reagents are typified by TACA reactive monoclonal antibodies, lectins, and perhaps oncolytic viruses that target sialylated receptors. Peptides reactive with TACA may, in particular, be interesting carbohydrate binding agents, forming the basis of novel drugs that combine the advantages of antibodies and small molecules. We have developed a peptidyl ligand that binds to the TF or T antigen (Galβ1- 3GalNAc). The designed peptidyl ligand was observed functionally to mediate cell signaling of TF expressing cell lines, suggesting that TF antigens might be functionally interesting.
Biography:
Sue Hudson Duran, Professor at Auburn College of Veteinary Medicine; Adjunct Professor Harrison School of Pharmacy; and GMP Pharmacist. As Education Chair of the International College of Veterinary Pharmacy, she developed teaching modules for pharmacis practicing veterinary pharmacy. Sue works with a team of scientists on development of new animal formulations for improvement in therapies. The team also develops human alternatives to antimicrobials such as anti-sera.. She was a consultant to the FDA and served on compounding and educational programs in veterinary medicine and was a member of the Center for Veterinary Medicine, FDA veterinary medical advisory committee.
Abstract:
Therapies and compliance of treatment in horses and cattle are a challenge for veterinarians and owners. The goal of our research team is to develop new antifungals and antimicrobials using appropriate hydrogels and other delivery systems. Voriconazole-hydrogel has been studied in an in-vitro model using the Franz Cell diffusion apparatus and cadaver horse eye tissues. Drug levels in the cornea and sclera were measured. Formulations release the drug for up to 28 days above the minimum inhibitory concentration needed to treat most fungal eye infections. The next step is testing the product in horses. Other formulations that have been studies for efficacy and release time include gentamicin, vancomycin and amikacin-impgregnated calcium sulfate and polymethylmetacrylate (PMMA) beads for successful treatment of osteomyelitis in dogs and horses and topicaly antiprotozoal drugs in cattle for Trichomonas. Indeed, successful alternatives are needed for ease of treatment in animals.