Day 1 :
Keynote Forum
Xiaodong Wang
Tesaro, Inc, USA
Keynote: Relative bioavailability of rolapitant tablets compared with rolapitant capsules and the effect of food on rolapitant pharmacokinetics in healthy subjects
Time : 9:30-10:20
Biography:
Xiaodong Wang is a senior director at Tesaro, Inc., an oncology-focused biopharmaceutical company in Waltham, MA, USA. He currently leads a group in Clinical Pharmacology and Drug Disposition supporting the development and regulatory submission of several drug candidates in the late phase of the Tesaro pipeline. Before joining Tesaro, he worked at several other biopharmaceutical companies, leading efforts to characterize the clinical pharmacology and pharmacometrics of small and large molecules at Bristol-Myers Squibb and Genentech. He received his PhD from the Department of Pharmaceutical Sciences, State University of New York at Buffalo, USA.
Abstract:
Rolapitant (VARUBI®/VARUBY®), a selective and long-acting neurokinin-1 receptor antagonist, is approved in oral tablet formulation for the prevention of delayed chemotherapy-induced nausea and vomiting in adults in the US and EU. These studies assessed the relative bioavailability of rolapitant tablet formulations compared with rolapitant capsules used in Phase 3 studies and the effect of food on rolapitant tablet pharmacokinetics (PK) in healthy subjects. An open-label, single-dose, parallel-group study was conducted in 84 healthy subjects to evaluate the relative bioavailability of two test formulations of rolapitant (high shear tablets and fluid bed tablets; each 2 x 90 mg) versus the reference capsules (4 x 45 mg). A second open-label, single-dose, parallel-group study was conducted in 80 healthy subjects to assess the effect of a high-fat meal on rolapitant PK (2 x 90 mg the intended commercial formulation of high shear tablets).
Bioavailability was similar for the test tablets verses capsules. For tablets versus the capsules, the 90% confidence intervals (CI) for the geometric mean Cmax and AUC ratios were contained within the equivalence limits of 0.80 to 1.25. For the food effect assessment, the 90% CIs for the geometric mean AUC ratios (fed/fasted) were within 0.8 to 1.25.
These data suggested that the bioavailability of rolapitant following administration as 2 x 90 mg high shear tablets and 2 x 90 mg fluid bed tablets was comparable to that following administration of 4 x 45 mg of the reference capsules. In addition, rolapitant can be taken without regard to meals
Keynote Forum
Fatah Kashanchi
George Mason University, USA
Keynote: Effect of exosomes on cART HIV-1 infected latent model
Time : 10:45-11:30
Biography:
He is the Director of Research at the George Mason University Biodefense Program in the Washington D.C proper. He have obtained more than $15.3 M in funding (NIH, DOD, DOE, and Keck) since my departure from NIH in 2000. He have published 196 peer-reviewed manuscripts (h index = 53), and served as an editorial board and reviewer for Retrovirology, JBC, J. Virol, Virology, NAR, 4 PLoS Journals, Cell, Molecular Cell, Nature, Medicine, and Science Translational Medicine. He am also a regular NIH study section member and have served on 141 panels since 2000.
Abstract:
HIV-1 infection results in a chronic illness since long-term HAART can lower viral titers to an undetectable level. However, discontinuation of therapy rapidly increases virus burden. Moreover, patients under HAART frequently develop various metabolic disorders, neurocognitive abnormalities and cardiovascular diseases. To purify vesicles, we routinely use a combination or ultracentrifugation and nanoparticle capture to concentrate our EVs from various bodily fluids for downstream assays including proteomics, Elisa, PCR, enzymatic extracellular vesicles and functional assays.
We have previously shown that exosomes containing trans-activating response (TAR) element RNA enhance susceptibility of undifferentiated naïve cells to HIV-1 infection (1-6). Up to a million copies of TAR RNA per microliter were also detected in the serum from HIV-1 infected humanized mice suggesting that TAR RNA may be stable in vivo. We recently have found another viral non-coding RNA that we termed TAR-gag which does not code for a protein, but present in the exosomes. Incubation of exosomes from HIV-1 infected cells with primary cells resulted in a dramatic increase of pro-inflammatory cytokines, IL-6 and TNF-β, indicating that exosomes containing TAR RNA could play a direct role in control of cytokine gene expression. Furthermore, the single stranded 5’ or 3’ processed stem RNA binding to TLRs activates the NF-кB pathway and regulates cytokine expression. In our most recent data, we find that the exosomes from infected cells are increased in numbers when cells are treated with specific anti-viral drugs or innate immune molecules such as IFN-a. Finally, we find that the exosomes from uninfected cells allow increased gene expression, which may explain why the latent cells show transcriptional leakiness.
Our results directly indicate that HIV viral release and exosome release have overlapping biogenesis pathways including the ESCRT pathway. Similar results are also seen from other neuro-tropic RNA viral infections including HTLV-1, Ebola, RVFV, and Zika infection which will be discussed. Therefore targeting these particles may be a method to lower overall viral burden in infected immunocompromised hosts.
- Pharmacology- PK & PD approach
Session Introduction
Sunil Kumar Dubey
BITS-Pilani, India
Title: Exploring the compartmental pharmacokinetics and bio-distribution of donepezil hydrochloride
Time : 11:35-12:00
Biography:
Dr. Sunil Kumar Dubey has been working in the area of clinical pharmacology, pharmacokinetics of racemic drugs (especially focused on CNS drug candidates) and also on designing nanocarriers like polymeric nanoparticles, micelles and polymersomes etc. for effective drug delivery. He also has expertise in the field pharmacokinetic and pharmacodynamic parameters modelling and simulation. He has been working in the thrust areas of CNS since long. His commitment to work and capability to successfully completing independent projects is reflected from his projects taken and international peer-reviewed publications.
Abstract:
Donepezil hydrochloride is a potent, acetylcholinesterase inhibitor used for the treatment of Alzheimer’s Disease. The objective of this study was to explore the compartmental pharmacokinetics and tissue distribution studies of donepezil after intravenous administration in Wistar rats. A simple HPLC–PDA assay method was developed and validated for rapid determination of donepezil hydrochloride, a potent acetylcholinesterase inhibitor in rat plasma and tissues. Solid-phase extraction method have been optimized using loratadine as an internal standard (IS). Chromatographic separation was detected on Waters Nova-Pak C18 column (3.9 × 150 mm, 5µm) using isocratic mobile phase of acetonitrile and ammonium formate (pH 6.4; 0.01M) (62:38 %v/v) at flow rate of 1 mL/min. All validation parameters were performed as per the guidelines of bioanalytical method validation. Weighted linear regression analysis was also performed on the calibration data. The method was successfully applied for exploring the compartmental pharmacokinetics and tissue distribution studies of donepezil after intravenous bolus administration at dose of 5 mg/kg in wistar rat. Experimental plasma concentration-versus-time profiles were fitted to compartmental pharmacokinetic models (Fig.1). One-, two-, three-compartment models were tested to characterize the pharmacokinetic parameters and statistically model was validated. Tissue distribution studies were also performed to assess the bio distribution studies (Fig.2). These parameters were analyzed for statistical significance by unpaired Student’s t-test. All validation parameter results were within the acceptable range described in guidelines. The method showed linearity in the concentration range of 50-5000 ng/mL with LOD of 20 ng/mL and LLOQ of 50 ng/mL. The mean absolute recoveries were found to be 79.86 ± 1.55 % for donepezil. Three-compartmental micro model was fitted to the plasma concentration-versus-time profiles and it was statistically validated by Akaike information criterion (AIC), Schwarz Bayesian criteria (SBC) and regression coefficient. Tissue distribution results showed that donepezil was well distributed in highly perfused tissues.
- BCS & IVIVC Based Biowaivers
Session Introduction
Aleksander Mendyk
ThothProTM, Gdansk, Poland
Title: Open source software for comparison of dissolution profiles
Time : 12:00-12:25
Biography:
Aleksander Mendyk, PhD, DSc. is an expert in application of artificial&computational intelligence methods in pharmaceutical sciences, in vitro in vivo correlations development and bioequivalence assessment. With his background as a pharmacist and a programmer experience he’s a software developer and programmer both in Open Source and commercial applications. Currently employed in the Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, JUMC, Cracow, Poland (http://www.farmacja.cm.uj.edu.pl) and in the software company ThothProTM, Gdansk, Poland (http://thothpro.com).
Abstract:
Statement of the Problem: Dissolution testing has become standard tool for pharmaceutical industry both in quality control and product development. For generic companies it is a regulatory requirement to demonstrate similarity of dissolution profiles between reference product (R) and the generic product candidate (T). Several methods of dissolution profiles comparison could be classified into two main groups: (1) model based and (2) model independent. Application of any comparison method requires software to be developed for this purpose. This could be either in-house, commercial or open source. We propose open source software for calculation of FDA similarity factor (f2) and model based comparison of dissolution profiles.
Methodology: R statistical environment was chosen to write scripts and GUI (Shiny package). Bootstrap based bias corrected and accelerated confidence interval (BCa) was implemented for f2. In case of model based comparison, a method of Mahalanobis distance was chosen with Hotelling T2 test to determine similarity region for two dissolution curves. A multivariate statistical distance (MSD) for the raw dissolution profiles was also considered for the curves comparison.
Findings: Software was published on the sourceforge.net server [2, 4] under GNU GPL v3 license meaning that it is free of charge both for private and professional use. Due to the portability of R environment this software is OS–independent and was successfully tested under various Windows and Linux environments.
Conclusion & Significance: Implementation of BCa allows to use f2 for dissolution profiles comparison even when RSD exceeds 10% (20% at the first time point) and MSD is an alternative of direct curves comparison as per relevant EMA/FDA guidelines. Model based methods are commonly used for second opinion when inconclusive or borderline results of f2 analysis were found. Thus both packages enhance tooling for dissolution profiles comparison in difficult cases
- Clinical Research Vs Clinical Trails
Session Introduction
Maligne Guillermo E
Gador S.A, Argentina
Title: Interchangeability of Two Oral Perampanel Formulations: A Randomized, Open Label, Single-Dose, 2-Way Crossover Study in Healthy Volunteers.
Time : 12:25-12:50
Biography:
Over 12 years of experience working in the pharmaceutical industry. 17 years medical development as physician. 4 years in Basic Research Project CONICET Fellowship (National Scientific Council). 8 years of experience advising Oncologist Clinical Trials in Early and Late Phases for clinical research. Phase I and Bioequivalence studies, including First in Human/Healthy Volunteers studies, generic drugs and vasoconstriction assay (VCA)
Abstract:
Background: Perampanel is a glutamate non-competitive receptor antagonist that is effective as adjunctive treatment for epilepsy. No studies regarding comparative bioavailability between a generic perampanel formulation and the brand-name product have been published in the literature. The goal of the present investigation was to compare the bioavailability and to evaluate the bioequivalence between a novel pharmaceutical equivalent 12 mg film-coated tablet formulation and the reference product.
Methods: An open label, randomized-sequence, two-period, two-treatment, single-dose, crossover design study in healthy volunteers (n=24) was conducted. The treatment was split out by a 42 days wash-out period. The informed consent was signed by all volunteers. Healthy subjects of both genders, including non-pregnant and non-lactating females between 21-55 years with Quetelet index between 19-29 kg/m2 were enrolled. Blood samples were withdrawn in vacutainers with EDTA over 168 h and plasma levels of perampanel were measured by HPLC/ fluorescence method. Pharmacokinetic variables (Cmax, AUC0-last, and AUCinf) after a single oral administration dose of the test and reference treatments were analyzed by a non-compartmental PK model using natural log transformed data and were compared by ANOVA for a two-treatment crossover design. Bioequivalence between the two formulations was evaluated using the 90% Confidence Interval (CI) comprised between 80-125% corresponding to the ratio of the geometric means for log-transformed PK parameters.
Results: A similar bioavailability between products was determined. Test and reference formulations showed no statistically significant differences in relation to the fixed effect of period, sequence, treatment and volunteers within sequence as random effect for PK variables. The estimated point and 90% CI of the ratios of Cmax, AUC0-last and AUCinf were 0.92 (0.83-1.03), 1.04(0.98-1.10) and 0.98 (0.86-1.11), respectively. The formulations showed comparable safety/tolerability.
Conclusion: The new pharmaceutical equivalent perampanel 12 mg film-coated tablet formulation was also bioequivalent to the reference product. Therefore, both drugs are interchangeable.
- Workshop
Session Introduction
R.N. Saha
Birla Institute of Technology & Science Pilani, UAE
Title: Bioavailability, bioequivalence and biodistribution studies
Biography:
R N Saha is Shri B K Birla & Shrimati Sarala Birla, Chair Professor (Senior Professor of Pharmacy) and Director of BITS Pilani Dubai Campus. In 2011 he has been awarded Shri B K Birla and Shrimati Sarala Birla Chair Professorship at BITS Pilani for contributions in teaching and research. He has vast experience in the field of Pharmacy especially in Pharmaceutics, novel drug delivery systems and Pharmacokinetics. He received “Pharmacy Professional of the Year 2013” Award given by Indian Association of Pharmaceutical Scientists and Technologists. He is also recipient of “The Best Pharmacy Teacher Award” for the year 2005, awarded by the Association of Pharmaceuticals Teachers if India (APTI), in recognition of his contribution in teaching and research in the fi eld of Pharmacy. He is also member of many scientific associations and societies like Association of Pharmaceutical Teachers of India (APTI); Indian Pharmaceutical Association (IPA); Indian Society of Technical Education (ISTE); Controlled Release Society Inc., USA; American Association of Pharmaceutical Scientists (AAPS), USA; American Chemical Society, USA; Controlled Release Society, Indian Chapter.
Abstract:
These are very important for formulation and drug delivery purpose as well as for new drug. This workshop will cover, what are bioavailability, bioequivalence, biodistribution studies, their importance, how they are studied and results are interpreted. Biodistribution study is very important for new drug to know where the drug is distributed and in what proportion. Mathematical modeling, experimental design will be covered. For design of novel drug delivery system, knowledge of biodistribution can help to modify distribution and make selective distribution. As analysis is very important for above studies, also analytical and statistical tools used for above studies will also be covered in brief.
Sunil Kumar Dubey
Birla Institute of Technology & science Pilani, India
Title: Analytical and statistical tools for bioavailability & bioequivalence studies
Biography:
Sunil Kumar Dubey has been working in the area of clinical pharmacology, pharmacokinetics of racemic drugs (especially focused on CNS drug candidates) and also on designing nanocarriers like polymeric nanoparticles, micelles and polymersomes, etc. for effective drug delivery. He also has expertise in the field pharmacokinetic and pharmacodynamic parameters modeling and simulation. He has been working in the thrust areas of CNS. His commitment to work and capability to successfully completing independent projects is reflected from his projects taken and international peer-reviewed publications.
Abstract:
Analytical and boanalytical techniques play a very important role in drug discovery. The analytical and bioanalytical techniques are the important tools for identification and characterization of the newly discovered drug molecules. Statistical tools employed for assessing bioequivalence are critical in getting drug approvals during ANDA filings. Hence, this workshop will provide insights into following areas:
• Novel Approaches to Analytical and Bioanalytical Methods
• Analytical & Bioanalytical Method Development and Validation
• Applications of Analytical and Bioanalytical Methods
• LCMS/MS of Small Organic Molecules.
• Statistical tools for assessing Bioequivalence
- Drug Safety: Pharmacovigilance Scope
Session Introduction
Rajeev Taliyan
BITS Pilani, India
Title: Epigenetic modulation in Alzheimer Disease: Study of class specific HDAC inhibitors in ameliorating insulin resistance induced Alzheimer's type of dementia
Time : 16:45-17:10
Biography:
Dr. Taliyan is currently working as an Assistant Professor in the Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani-campus, Rajasthan. He has vast experience in the field of Neuropharmacology, Cardiovascular pharmacology and Drug toxicology. He has been awarded with many prestigious awards at international and national level including, Prof. Manjeet Singh Gold medal award at IPSCON-2015; PP Suryakumari Gold medal Award at IPSCON-2014. He has been invited by several Research and Academic institutes for delivering guest lectures. He has published several papers in peer reviewed international and national journals and in conferences of international and national repute. He is life member of Indian Pharmacological Society and Association of Pharmaceutical Teacher of India Society,
Abstract:
Numerous epidemiological studies have demonstrated that insulin resistance contributes to Alzheimer’s disease (AD) pathogenesis. However the molecular mechanisms is still remain elusive but various studies have highlighted the epigenetic alterations and involvement of histone deacetylases (HDACs) in insulin resistance and cognitive deficits[1-2]. In our previous study, we have explored the potential of pan HDAC inhibitor, SAHA, in high fat diet induced insulin resistance [3-4]. In the present study, we have investigated the potential of isoform specific HDAC inhibitors in insulin resistance induced cognitive impairment in mice. Methods: Mice were subjected to either normal pellet diet (NPD) or high fat diet (HFD) for 8 weeks. Serum insulin, glucose, triglycerides, total cholesterol and HDL-cholesterol levels were measured weekly. A battery of behavioural parameters was performed to assess cognitive functions. HFD fed mice were treated with Class I specific HDAC inhibitor, CI-994 or Class II specific HDAC inhibitor, MC-1568 once daily for 2 weeks. Results: HFD fed mice exhibit characteristic features of insulin resistance, showed a severe deficit in learning and memory. HFD feeding results in significant increase in Amyloid beta1-42 levels as compared with NPD fed mice. By contrast, the mice treated with MC-1568 showed significant improvement in insulin resistance condition, marked decrease in Amyloid beta1-42 and significantly ameliorate the HFD induced decrease in BDNF and CREB level as compared to HFD group. Whereas, the mice treated with Class I HDAC inhibitor, CI-994 failed to show any improvement in insulin resistance and cognitive deficits. Conclusion: Based upon these results, it could be suggested that Class II HDAC inhibitors exert better neuroprotective effects as compared to Class I HDAC inhibitors associated with insulin resistant condition.
Naglaa Gamil Shehab
Dubai Pharmacy College, UAE
Title: Remedies -Drugs interaction of some anticoagulant and antidepressant drugs
Time : 16:20-16:45
Biography:
Naglaa Gamil Shehab is graduated from Faculty of Pharmacy, Cairo University, Egypt and she received the PhD from the same college. She got the best research award three times from Egypt, Saudi Arabia and from Amsterdam, Netherland. She is a member in American society of Pharmacognosy and in Italo-Latin American Society of Ethnomedicine. She is also a reviewer for many international natural products Journals. She published at least 30 scientific papers also contribute in publication of scientific book. Her interest field is in bioactivity of medicinal plants. She have been an associate professor, the Head of Pharmacognosy and Phytochemsitry Department, Chief Academic Officer and a member in the research committee in Dubai Pharmacy College since 2005.
Abstract:
Dabigatran etexilate is a new oral drug with little side effects than other anticoagulant drugs. It has a direct thrombin inhibition and is used to treat deep vein thrombosis and pulmonary embolism. Escitalopram belongs to the group of medications called selective serotonin reuptake inhibitors (SSRIs). It works by increasing levels of a neurotransmitter called serotonin in the brain. Increased serotonin levels can lead to an improved mood. This study aims to evaluate the synergistic or the antagonistic interaction which may occur between some common remedies with the oral administration of Dabigitran and Cipralex.
- Bioavailability Studies and Assessment
Session Introduction
Asmita Gajbhiye
Dr. Hari Singh Gour Central University, India
Title: Bioavailability enhancement of flavonoids through vesicular complex with soya phosphatidylcholine
Time : 17:10-17:35
Biography:
Prof. Asmita Gajbhiye Patil is currently working as Professor and Head at Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar (M.P.) India. She received her Doctoral degree in Pharmaceutical Sciences (2006) from Kakatiya University, Warangal (A.P.) India. She completed her Masters (1996) from the Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalay, Sagar. Since 1998, she is working as Assistant Professor, Associate Professor and Professor in the University and has 20 years of teaching experience. She has authored 40 publications in various journals of national and international repute. Her publications reflect her research interests in both the fields of medicinal chemistry as well as pharmacology. She had filed a patent also. She has completed several major projects sponsored by various agencies eg DST, MPCST, ICMR, CSIR and UGC. Dr. Asmita was a member of member of Executive Council, member of Research Council, member of Mahila Kalyan Samiti of Dr. Harisingh Gour Vishwavidyalaya, Sagar (M.P). She was the Coordinator for conduct of University centralized evaluation. Presently she is holding the post of an Anti-Discrimination officer at Dr. Harisingh Gour Vishwavidyalaya, Sagar. She is honoured with the awards of National level i.e. Mother Teressa Shiksha Rattan Award 2016 by International Bussiness Council and National Mahila Rattan gold medal 2017 by International Institute of Education and Management, New Delhi.
Abstract:
Quercetin, mangifirin, kaempferol are a well-known flavonoidal compounds found in plants, foods, and beverages. These flavonoids have shown several pharmacological activities including antioxidant, anti-inflammatory, anticancer, and antiviral properties. In spite of a variety of biological effects, they are very poorly soluble in water, which has limited their absorption upon oral administration and rapid clearance from intestine. Therefore, it is required to develop a drug delivery system to resolve this problem.
Some phytoconstituents that are not effectively bioavailable, by binding them to phosphatidylcholine, they can be made in highly bioavailable form. One of the most important group of phytoconstituents is the flavonoid which can be bind with soya phosphatidylcholine (SPC). The resulting phytosomes formed are protected from distruction by digestive secretions and gut bacteria. The phytosomes intensifies herbal compounds by improving absorption, increasing bioavailablility and enhancing therapeutic potential. The phytosomes contains active ingredients of herb surrounded and chemically bound with phosphatidylcholine which is one of the chief components of the membranes in the human cells.
Phytosomes of Quercetin, mangifirin and kaempferol were successfully prepared through complexation with soya phosphatidylcholine (SPC) which were characterized by spectroscopic (IR and NMR), microscopic (TEM) and colorimetric (DSC) analysis. The pharmacokinetic study was performed for the assessment of bioavailability.
The IR, NMR and DSC spectra of phytosomes were showed by different peaks as compared to that of phytosomes. Pharmacokinetic study revealed significant increased absorption of phytosomes.
The prepared complexes were characterized by solubility studies, DSC, TLC, FTIR and 1H-NMR spectroscopic analysis. These physicochemical and spectroscopic investigations clearly showed evidence for the formation of quercetin–soya phosphatidylcholine complex.
The result of pharmacokinetic study clearly indicates that vesicular complex is more easily absorb than individual ingredients and hence it can be concluded that drug-SPC complex is more bioavaliable than individual ingredients.