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Eisert W.G.,Boehringer Ingelheim GmbH | Stangier J.,Drug Metabolism and Pharmacokinetics | Wienen W.,Pulmonary Research | Clemens A.,Boehringer Ingelheim GmbH | Van Ryn J.,Boehringer Ingelheim
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Dabigatran is a highly selective, reversible, and potent thrombin inhibitor and is orally available as the prodrug, dabigatran etexilate. It has shown antithrombotic efficacy in animal models of thrombosis, with a rapid onset of action and predictable pharmacodynamic response. Peak plasma concentrations of dabigatran occur 1 to 2 hours after ingestion of the prodrug. The terminal half-life of dabigatran is 12 to 14 hours in elderly volunteers. Dabigatran is not metabolized by cytochrome P450 isoenzymes and does not interact with food. Dabigatran has a low potential for drug-drug interactions and is predominantly renally excreted. Dabigatran etexilate as chronic therapy effectively prevents the recurrence of venous thromboembolism and cardioembolic stroke. For the first time, it has been demonstrated clinically that there may be an effective and safe alternative to warfarin. © 2010 American Heart Association, Inc.


Lin K.,Genentech | Tibbitts J.,Drug Metabolism and Pharmacokinetics | Shen B.-Q.,Genentech
Methods in Molecular Biology | Year: 2013

Pharmacokinetic and absorption, distribution, metabolism, and excretion (ADME) characterization of antibody-drug conjugates (ADCs) reflects the dynamic interactions between the biological system and ADC, and provides critical assessments in lead selection, optimization, and clinical development. Understanding the pharmacokinetics (PK), ADME properties and consequently the pharmacokinetic-pharmacodynamic properties of ADCs is critical for their successful development. This chapter discusses the PK properties of ADCs, types of PK and ADME studies in supporting different stages of development, general design of PK/ADME studies with a focus on ADC-specific characteristics, and interpretation of PK parameters. © Springer Science+Business Media, LLC 2013.


FOR EMEA MEDIA ONLY - NOT FOR SWISS/AUSTRIAN/US JOURNALISTS Data from nine abstracts for Eisai's epilepsy treatments perampanel and rufinamide will be presented at the 70th Annual Meeting of the American Epilepsy Society (AES), 2-6 December, Houston, Texas, which provide further insight into their long-term use in people with epilepsy. Perampanel is indicated in the European Union for patients aged 12 years and older, for adjunctive treatment of partial-onset seizures (POS), with or without secondarily generalised seizures, and for adjunctive treatment of primary generalised tonic-clonic (PGTC) seizures in patients with idiopathic generalised epilepsy (IGE).[1] Rufinamide is indicated in the European Union for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in patients with epilepsy aged four years and older.[2] "These data provide real world insights into the activity of perampanel and rufinamide in potential patients over a wide range of ages. Through new and continued research with perampanel and rufinamide, we aim to further educate the epilepsy community about these debilitating diseases," comments Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. The development of its epilepsy portfolio underscores Eisai's human health care (hhc) mission, the company's commitment to innovative solutions in disease prevention, cure and care for the health and wellbeing of people worldwide. Eisai is committed to the therapeutic area of neurology and to address the unmet medical needs of people with neurological conditions and their families. Perampanel abstracts at AES (presented in the George R Brown Convention Center, Hall A3, Level 3): Rufinamide abstracts at AES (in the George R Brown Convention Center, Hall A3, Level 3): Perampanel is a first-in-class, non-competitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor antagonist on post-synaptic neurons.[1] AMPA receptors, widely present in almost all excitatory neurons, transmit signals stimulated by the excitatory neurotransmitter glutamate within the brain, and are believed to play a role in central nervous system diseases characterised by excess neuroexcitatory signalling, including epilepsy.[3] Since launch, approximately 52,000 people living with epilepsy have been treated with perampanel.[4] Rufinamide is a triazole derivative that is structurally unrelated to currently marketed antiepileptic drugs (AEDs).[5],[6] It is believed to regulate the activity of sodium channels in the brain which carry excessive electrical charges.[5] Rufinamide was approved for adjunctive therapy for seizures associated with Lennox-Gastaut Syndrome in Europe (under the brand name Inovelon) in 2007 in patients four years of age and older. Rufinamide is available as film-coated tablets containing 100mg, 200mg and 400mg rufinamide and as a 40mg/ml oral suspension.[2] Epilepsy is one of the most common neurological conditions in the world, affecting approximately six million people in Europe, and an estimated 50 million people worldwide.[7] Epilepsy is a chronic disorder of the brain that affects people of all ages. It is characterised by abnormal discharges of neuronal activity which causes seizures. Seizures can vary in nature and severity, from brief lapses of attention or jerking of muscles, to severe and prolonged convulsions. Depending on the seizure type, seizures may be limited to one part of the body, or may involve the whole body. Seizures can also vary in frequency from less than one per year, to several per day. Epilepsy has many possible causes but often the cause is unknown. Eisai is committed to developing and delivering highly beneficial new treatments to help improve the lives of people with epilepsy. The development of AEDs is a major strategic area for Eisai in Europe, the Middle East, Africa, Russia and Oceania (EMEA). In the EMEA region, Eisai currently has four marketed treatments including: About Eisai Co., Ltd. Eisai Co., Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. We define our corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call our human health care (hhc) philosophy. With over 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realise our hhc philosophy by delivering innovative products in multiple therapeutic areas with high unmet medical needs, including Oncology and Neurology. As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing countries. For more information about Eisai Co., Ltd., please visit http://www.eisai.com 1.    Fycompa® (perampanel) Summary of Product Characteristics (SmPC) Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002434/WC500130815.pdf Accessed November 2016 2.    Inovelon® (rufinamide) Summary of Product Characteristics (SmPC). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000660/WC500032938.pdf Accessed November 2016 3.    Lee K et al. AMPA Receptors as Therapeutic Targets for Neurological Disorders 2016;103:203-261 5.    Wier H et al. Rufinamide for Pediatric Patients with Lennox-Gastaut Syndrome. Pediatric Drugs 2011;13(2):97-106 6.    Xu M et al. Pharmacokinetics and Tolerability of Rufinamide Following Single and Multiple Oral Doses and Effect of Food on Pharmacokinetics in Healthy Chinese Subjects. European Journal of Drug Metabolism and Pharmacokinetics 2016;41(5):541-548 7.     Epilepsy in the WHO European Region: Fostering Epilepsy Care in Europe. Available at: http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf Accessed November 2016


FOR EMEA MEDIA ONLY - NOT FOR SWISS/AUSTRIAN/US JOURNALISTS Final data to be presented for the first time at American Epilepsy Society in Houston, Texas Data presented today at the American Epilepsy Society (AES), Houston, Texas, show that adjunctive Inovelon® (rufinamide) in children aged one to four years with inadequately controlled Lennox-Gastaut Syndrome (LGS) is well tolerated and cognitive development and behaviour is comparable to other adjunctive treatments.[1] Rufinamide is indicated in the European Union for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in patients aged four years and older.[2] Study 303 (NCT01405053), a global, randomised, multicentre, two-year open-label study was conducted to evaluate the cognitive development and behavioural effects, safety, and pharmacokinetics of adjunctive rufinamide treatment in paediatric subjects aged one to four years with inadequately controlled Lennox-Gastaut Syndrome.[3] The primary endpoint of Study 303 was the change in Child Behaviour Checklist (CBCL) Total Problems Score from baseline to the end of the treatment period (106 weeks), which examines cognitive development and behavioural effects of subjects treated with rufinamide.[1],[3] In Study 303, 25 children received rufinamide and 12 received another approved anti-epileptic drug as add-on to their existing regimen.[1] Using the Child Behaviour Checklist, the cognitive development and behaviour of children who received rufinamide was comparable to that of subjects who received another approvedanti-epileptic drug (LS mean difference [95% CI] +2.60 [-10.5,15.7]; p=0.6928).[1] The treatment-emergent adverse event (TEAE) incidence was similar between the rufinamide group (88.0%) and the any-other anti-epileptic drug group (83.3%), with most events considered mild or moderate. Vomiting (20%, n=5) and somnolence (16%, n=4) were the only treatment-related TEAEs reported in >2 children who received rufinamide.[1] "Lennox-Gastaut Syndome is a rare and severe form of epilepsy where children can have up to 100 seizures a day, causing multiple developmental issues. It is important to understand the impact of anti-epileptic drugs on the behavioural and cognitive development of these children. These data show adjunctive rufinamide has an impact on behavioural development comparable with other treatments," comments Alexis Arizmanoglou, Associate Professor of Neurology and Child Neurology, College de Medicine des Hopitaux de Paris. Lennox-Gastaut Syndrome is a severe form of childhood-onset epilepsy that appears most often in children aged two to six. It is characterised by frequent and multiple seizure types, behavioural issues, mental retardation and resistance to medication or therapies.[4] Although incidence is estimated to 0.1 in 100,000 people per year, the prevalence is high (5-10% of people with epilepsy), representing 1-2% of all childhood epilepsies.[4] "Eisai is committed to the ongoing development of rufinamide for this very rare and severe condition. Eisai seeks to improve the lives of patients and families through continued development of our products in epilepsy," comments Neil West, Vice President, Global Neurology Business Group, Eisai EMEA. Rufinamide is a triazole derivative that is structurally unrelated to currently marketed antiepileptic drugs (AEDs).[5],[6] It is believed to regulate the activity of sodium channels in the brain which carry excessive electrical charges.[5] Rufinamide was approved for adjunctive therapy for seizures associated with Lennox-Gastaut Syndrome in Europe (under the brand name Inovelon) in 2007 in patients four years of age and older. Rufinamide is available as film-coated tablets containing 100mg, 200mg and 400mg rufinamide and as a 40mg/ml oral suspension.[2] Epilepsy is one of the most common neurological conditions in the world, affecting approximately six million people in Europe, and an estimated 50 million people worldwide.[7] Epilepsy is a chronic disorder of the brain that affects people of all ages. It is characterised by abnormal discharges of neuronal activity which causes seizures. Seizures can vary in nature and severity, from brief lapses of attention or jerking of muscles, to severe and prolonged convulsions. Depending on the seizure type, seizures may be limited to one part of the body, or may involve the whole body. Seizures can also vary in frequency from less than one per year, to several per day. Epilepsy has many possible causes but often the cause is unknown. Eisai is committed to developing and delivering highly beneficial new treatments to help improve the lives of people with epilepsy. The development of AEDs is a major strategic area for Eisai in Europe, the Middle East, Africa, Russia and Oceania (EMEA). In the EMEA region, Eisai currently has four marketed treatments including: About Eisai Co., Ltd. Eisai Co., Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. We define our corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call our human health care (hhc) philosophy. With over 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realise our hhc philosophy by delivering innovative products in multiple therapeutic areas with high unmet medical needs, including Oncology and Neurology. As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing countries. For more information about Eisai Co., Ltd., please visit http://www.eisai.com 1. Arzimanoglou A et al. Safety and Cognitive Development Effects of Adjunctive Rufinamide in Pediatric Subjects With Inadequately Controlled Lennox-Gastaut Syndrome (LGS): Final Results From Study 303. Presented at American Epilepsy Society 2016 3. Study of Rufinamide in Pediatric Subjects 1 to Less Than 4 Years of Age With Lennox-Gastaut Syndrome Inadequately Controlled With Other Anti-epileptic Drugs (NCT01405053). Available at: https://clinicaltrials.gov/ct2/show/record/NCT01405053 Accessed November 2016 4. Tyagi S, et al. Pharmacological management of Lennox-Gastaut Syndrome-a difficult-to-treat form of childhood-onset epilepsy: an overview. International Journal of Pharma and Bio Sciences. 2010:1(3).  Available at: http://www.ijpbs.net/issue-3/82.pdf . Accessed August 2016 5. Wier H et al. Rufinamide for Pediatric Patients with Lennox-Gastaut Syndrome. Pediatric Drugs 2011;13(2):97-106 6. Xu M et al. Pharmacokinetics and Tolerability of Rufinamide Following Single and Multiple Oral Doses and Effect of Food on Pharmacokinetics in Healthy Chinese Subjects. European Journal of Drug Metabolism and Pharmacokinetics 2016;41(5):541-548 7. Epilepsy in the WHO European Region: Fostering Epilepsy Care in Europe. http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf (Accessed June 2016)


Srinivas N.R.,Dr Reddys Institute of Life science | Mullangi R.,Drug Metabolism and Pharmacokinetics
Biomarkers in Medicine | Year: 2015

Bioanalysis is an important aspect of drug discovery process regardless of the chosen therapeutic area. There is a general misconception that bioanalysis is seldom important during the drug discovery process because there is no scrutiny of the data from a regulatory perspective. However, bioanalytical data gathered during the discovery stage enable several key decision(s) inclusive of termination of the program and/or creating adequate differentiation from the lead competitive molecules. The review covers various stage gate screens and experimental designs where bioanalytical data are extensively used for making an informed decision during the process of drug discovery. © 2015 Future Medicine Ltd.


Cuyckens F.,Drug Metabolism and Pharmacokinetics | Wassvik C.,Research Informatics and Integrative Genomics | Mortishire-Smith R.J.,ADME Tox | Tresadern G.,Research Informatics and Integrative Genomics | And 2 more authors.
Rapid Communications in Mass Spectrometry | Year: 2011

Travelling wave ion mobility spectrometry - mass spectrometry (TWIMS-MS) was evaluated as a tool for structural identification of metabolites of small molecule drugs in cases where the exact position of the biotransformation could not be identified by conventional tandem mass spectrometry. Test sets of compounds containing biotransformations at aromatic positions were analyzed. These present a problem for traditional MS methods since an atomic level localization of the biotransformation cannot normally be determined from MS n spectra. In addition to ion mobility measurements of the intact metabolite ions, ion mobility measurements of product ions were also made and the results compared with calculated values. This approach reduces the complexity of the problem, making theoretical calculations easier and more predictable when a modeled collision cross section (CCS) is required. A good relative correspondence between theoretical and measured CCSs was obtained allowing the identification of the exact position of the biotransformation. It was also demonstrated that authentic standards with substructures identical to those in the unknown can be used to assign the exact position of the biotransformation. In this approach the identification was based on the comparison of the drift times or CCSs for product ions of the standard, with those of the same product ions in the unknown. Copyright © 2011 John Wiley & Sons, Ltd.


Wang L.,University of Washington | Prasad B.,University of Washington | Salphati L.,Drug Metabolism and Pharmacokinetics | Chu X.,Merck And Co. | And 4 more authors.
Drug Metabolism and Disposition | Year: 2015

We quantified, by liquid chromatography tandemmass spectrometry, transporter protein expression of BSEP, MATE1, MRP3, MRP4, NTCP, and OCT1 in our human liver bank (n = 55) and determined the relationship between protein expression and sex, age and genotype. These data complement our previous work in the same liver bank where we quantified the protein expression of OATPs, BCRP, MDR1, and MRP2. In addition, we quantified and compared the interspecies differences in expression of the hepatobiliary transporters, corresponding to the above human transporters, in liver tissue and hepatocytes of male beagle dogs, cynomolgus monkeys, Sprague-Dawley rats, and Wistar rats. In all the species, the sinusoidal OATPs/Oatps were the most abundant hepatic transporters. However, there were notable interspecies differences in the relative abundance of the remaining transporters. For example, the next most abundant transporter in humans and monkeys was OCT1/Oct1, whereas it was Mrp2 and Ntcp in dogs/Wistar rats and Sprague-Dawley rats, respectively. In contrast, the protein expression of the efflux transporters BCRP/Bcrp, MDR1/Mdr1, MRP3/Mrp3, MRP4/Mrp4, and MATE1/Mate1 was much lower across all the species. For most transporters, the expression in the liver tissues was comparable to that in the unplated cryopreserved hepatocytes. These data on human liver transporter protein expression complete the picture of the expression of major human hepatobiliary transporters important in drug disposition and toxicity. In addition, the data on expression of the corresponding hepatobiliary transporters in preclinical species will be helpful in interpreting and extrapolating pharmacokinetic, pharmacological, and toxicological results from preclinical studies to humans. © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Lim H.K.,Drug Metabolism and Pharmacokinetics
Xenobiotica; the fate of foreign compounds in biological systems | Year: 2012

Raloxifene was metabolized predominantly by CYP3A4 in human liver microsomes to a pair of carbon-carbon (RD1-2) and ether (RD3-4) linked homodimers in an nicotinamide adenine dinucleotide phosphate-dependent manner. The major homodimer formed by human liver microsomes (RD3) was different from the major homodimer formed by peroxidases (RD1). RD1, 3 and 4 were identified by both mass spectrometry (MS) and nuclear magnetic resonance (NMR) as symmetrical carbon-carbon (both carbon 7 from benzo[b]thiopen-6-ol) linked homodimer, asymmetrical ether (oxygen from 4-hydroxyphenyl and carbon 7 from benzo[b]thiopen-6-ol) linked homodimer and asymmetrical ether (oxygen and carbon 7 from benzo[b]thiopen-6-ol) linked homodimer, respectively. The structures of the homodimers RD1, 3 and 4 provided evidence for free radical metabolism of raloxifene by predominantly CYP3A4 in human liver microsomes to oxygen-centered phenoxy radicals from 4-hydroxyphenyl and benzo[b]thiopen-6-ol moieties. Further delocalization to ortho carbon-centered radical was only observed for benzo[b]thiopen-6-ol derived phenoxy radical.


Li A.C.,Drug Metabolism and Pharmacokinetics | Chovan J.P.,Drug Metabolism and Pharmacokinetics | Yu E.,Drug Metabolism and Pharmacokinetics | Zamora I.,Lead Molecular Design S.L.
Xenobiotica | Year: 2013

1. There has been a lack of in vivo metabolite profiling update of hydrocodone since the original report on species differences was published in 1978. As such, the mechanism for its analgesic activity in different species has been ambiguous. To address safety concern from regulatory agencies, hydrocodone metabolite profiles in rats and dogs are updated herein aided by a newly developed software, Mass-MetaSite. 2. Samples collected from rats and dogs dosed orally with hydrocodone were analyzed with reversed phase liquid chromatography coupled with LTQ-Orbitrap. The exact mass measurement data collected with data-dependent acquisition methodology were analyzed both traditionally, using Xcalibur Qual Browser and MetWorks, and by Mass-MetaSite. 3. Profiling of hydrocodone metabolites in rat and dog plasma reflected previously reported species differences in circulating metabolites. While hydrocodone mainly underwent O-demethylation and ketone reduction in rats forming hydromorphone and reduced hydromorphone, which were then subsequently cleared via glucuronide conjugation, hydrocodone in dogs was cleared predominantly by N-demethylation and N-oxidation. 4. Given the success ratio of metabolite detection offered by Mass-MetaSite, the software will be able to aid chemists in early identification of drug metabolites from complex biomatrices. © 2013 Informa UK, Ltd.


Pahler A.,Drug Metabolism and Pharmacokinetics | Brink A.,Drug Metabolism and Pharmacokinetics
Drug Discovery Today: Technologies | Year: 2013

Technological advances in mass spectrometry (MS) such as accurate mass high resolution instrumentation have fundamentally changed the approach to systematic metabolite identification over the past decade. Despite technological break-through on the instrumental side, metabolite identification still requires tedious manual data inspection and interpretation of huge analytical datasets. The process of metabolite identification has become largely facilitated and partly automated by cheminformatics approaches such as knowledge base metabolite prediction using, for example, Meteor, MetaDrug, MetaSite and StarDrop that are typically applied pre-acquisition. Likewise, emerging new technologies in postacquisition data analysis like mass defect filtering (MDF) have moved the technology driven analytical methodology to metabolite identification toward generic, structure-based workflows. The biggest challenge for automation however remains the structural assignment of drug metabolites. Software-guided approaches for the unsupervised metabolite identification still cannot compete with expert user manual data interpretation yet. Recently MassMetaSite has been introduced for the automated ranked output of metabolite structures based on the combination of metabolite prediction and interrogation of analytical mass spectrometric data. This approach and others are promising milestones toward an unsupervised process to metabolite identification and structural characterization moving away from a sample focused per-compound approach to a structure-driven generic workflow. © 2013 Elsevier Ltd.

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