The Expression Profiles of ADME Genes in Human Cancers And
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Pharmacogenomic Profiling of ADME Gene Variants
Review Pharmacogenomic Profiling of ADME Gene Variants: Current Challenges and Validation Perspectives Mariamena Arbitrio 1, Maria Teresa Di Martino 2, Francesca Scionti 2, Vito Barbieri 3, Licia Pensabene 4 and Pierosandro Tagliaferri 2,* 1 Institute of Neurological Sciences, UOS of Pharmacology, 88100 Catanzaro, Italy; [email protected] 2 Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, 88100 Catanzaro, Italy; [email protected] (M.T.D.M.); [email protected] (F.S.) 3 Medical Oncology Unit, Mater Domini Hospital, Salvatore Venuta University Campus, 88100 Catanzaro, Italy; [email protected] 4 Department of Medical and Surgical Sciences Pediatric Unit, Magna Graecia University, 88100 Catanzaro, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0961-3697324 Received: 5 October 2018; Accepted: 13 December 2018; Published: 18 December 2018 Abstract: In the past decades, many efforts have been made to individualize medical treatments, taking into account molecular profiles and the individual genetic background. The development of molecularly targeted drugs and immunotherapy have revolutionized medical treatments but the inter-patient variability in the anti-tumor drug pharmacokinetics (PK) and pharmacodynamics can be explained, at least in part, by genetic variations in genes encoding drug metabolizing enzymes and transporters (ADME) or in genes encoding drug receptors. Here, we focus on high-throughput technologies applied for PK screening for the identification of predictive biomarkers of efficacy or toxicity in cancer treatment, whose application in clinical practice could promote personalized treatments tailored on individual’s genetic make-up. Pharmacogenomic tools have been implemented and the clinical utility of pharmacogenetic screening could increase safety in patients for the identification of drug metabolism-related biomarkers for a personalized medicine. -
Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development
Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development Gerlie Gieser, Ph.D. Office of Clinical Pharmacology, Div. IV Objectives • Outline the Phase 1 studies conducted to characterize the Clinical Pharmacology of a drug; describe important design elements of and the information gained from these studies. • List the Clinical Pharmacology characteristics of an Ideal Drug • Describe how the Clinical Pharmacology information from Phase 1 can help design Phase 2/3 trials • Discuss the timing of Clinical Pharmacology studies during drug development, and provide examples of how the information generated could impact the overall clinical development plan and product labeling. Phase 1 of Drug Development CLINICAL DEVELOPMENT RESEARCH PRE POST AND CLINICAL APPROVAL 1 DISCOVERY DEVELOPMENT 2 3 PHASE e e e s s s a a a h h h P P P Clinical Pharmacology Studies Initial IND (first in human) NDA/BLA SUBMISSION Phase 1 – studies designed mainly to investigate the safety/tolerability (if possible, identify MTD), pharmacokinetics and pharmacodynamics of an investigational drug in humans Clinical Pharmacology • Study of the Pharmacokinetics (PK) and Pharmacodynamics (PD) of the drug in humans – PK: what the body does to the drug (Absorption, Distribution, Metabolism, Excretion) – PD: what the drug does to the body • PK and PD profiles of the drug are influenced by physicochemical properties of the drug, product/formulation, administration route, patient’s intrinsic and extrinsic factors (e.g., organ dysfunction, diseases, concomitant medications, -
ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential
pharmaceuticals Review ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential Subrata Deb * , Anthony Allen Reeves, Robert Hopefl and Rebecca Bejusca Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; [email protected] (A.A.R.); [email protected] (R.H.); [email protected] (R.B.) * Correspondence: [email protected]; Tel.: +224-310-7870 Abstract: On 11 March 2020, the World Health Organization (WHO) classified the Coronavirus Disease 2019 (COVID-19) as a global pandemic, which tested healthcare systems, administrations, and treatment ingenuity across the world. COVID-19 is caused by the novel beta coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the inception of the pandemic, treatment options have been either limited or ineffective. Remdesivir, a drug originally designed to be used for Ebola virus, has antiviral activity against SARS-CoV-2 and has been included in the COVID-19 treatment regimens. Remdesivir is an adenosine nucleotide analog prodrug that is metabolically activated to a nucleoside triphosphate metabolite (GS-443902). The active nucleoside triphosphate metabolite is incorporated into the SARS-CoV-2 RNA viral chains, preventing its replication. The lack of reported drug development and characterization studies with remdesivir in public domain has created a void where information on the absorption, distribution, metabolism, elimination (ADME) properties, pharmacokinetics (PK), or drug-drug interaction (DDI) is limited. By Citation: Deb, S.; Reeves, A.A.; understanding these properties, clinicians can prevent subtherapeutic and supratherapeutic levels of Hopefl, R.; Bejusca, R. ADME and remdesivir and thus avoid further complications in COVID-19 patients. Remdesivir is metabolized Pharmacokinetic Properties of by both cytochrome P450 (CYP) and non-CYP enzymes such as carboxylesterases. -
Addressing Toxicity Risk When Designing and Selecting Compounds in Early Drug Discovery
Addressing Toxicity Risk when Designing and Selecting Compounds in Early Drug Discovery Matthew D. Segall* and Chris Barber† * Optibrium Ltd., 7221 Cambridge Research Park, Beach Drive, Cambridge, CB25 9TL † Lhasa Limited, 22-23 Blenheim Terrace, Woodhouse Lane, Leeds, LS2 9HD Abstract Toxicity accounts for approximately 30% of expensive, late stage failures in development. Therefore, identifying and prioritising chemistries with a lower risk of toxicity, as early as possible in the drug discovery process, would help to address the high attrition rate in pharmaceutical R&D. We will describe how expert knowledge-based prediction of toxicity can alert chemists if their proposed compounds are likely to have an increased risk of causing toxicity. However, an alert for potential toxicity should be given appropriate weight in the selection of compounds to balance potential opportunities against downstream toxicity risk. If a series achieves good outcomes for other requirements, it may be appropriate to progress selected compounds and generate experimental data to confirm or refute a prediction of potential toxicity. We will discuss how multi- parameter optimisation approaches can be used to balance the potential for toxicity with other properties required in a high quality candidate drug, such as potency and appropriate absorption, distribution, metabolism and elimination (ADME). Furthermore, it may be possible to modify a compound to reduce its likelihood of toxicity and we will describe how information on the region of a compound that triggers a toxicity alert can be interactively visualised to guide this redesign. 7221 Cambridge Research Park Tel: +44 1223 815900 Email: [email protected] Beach Drive, Cambridge Fax: +44 1223 815907 Website: www.optibrium.com CB25 9TL, UK Optibrium Limited, registered in England and Wales No. -
Synthesis of 4-Hydroperoxy Derivatives of Ifosfamide and Trofosfamide by Direct Ozonation and Preliminary Antitumor Evaluation in V/Vo
[CANCER RESEARCH, 36, 2278-2281, July 1976] Synthesis of 4-Hydroperoxy Derivatives of Ifosfamide and Trofosfamide by Direct Ozonation and Preliminary Antitumor Evaluation in V/vo Hans-J. Hohorst, Gernot Peter, and Robert F. Struck Gustav-Embden-Zentrum der Biologischen Chemie, Abteilung KIr Zellchemie der J. W. Goethe-Universit~t, 6000 Frankfurt am Main, West Germany [H-J. H., G. P.], and Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205 [R. F. S.] SUMMARY reported routes (15, 17 to 19, 20), as well as to improve the yields. Two of us (11) have recently described such a syn- A one-step synthesis of 4-hydroperoxyifosfamide and 4- thesis of 4-hydroperoxycyclophosphamide, and application hydroperoxytrofosfamide is described. The method in- of this method to ifosfamide and trofosfamide and evalua- volves direct ozonation of ifosfamide and trofosfamide and tion of the products against leukemia L1210 in vivo are the offers improved yields in comparison with Fenton oxidation subjects of this report. The method is advantageous be- and greater convenience in comparison with ozonation of cause of its simplicity, its use of available starting materials, the appropriate 3-butenyl phosphorodiamidate. Evaluation the ease of isolation of products, and respectable yields. of the 4-hydroperoxy derivatives of cyclophosphamide, ifos- famide, and trofosfamide against leukemia L1210 in vivo suggests a superior effect for the ifosfamide derivative. MATERIALS AND METHODS Starting Materials. Cyclophosphamide, ifosfamide, and INTRODUCTION trofosfamide were obtained from Dr. Robert R. Engle, Drug Development Branch, National Cancer Institute, Silver Cyclophosphamide and its congeners ifosfamide and tro- Spring, Md., and from Asta Werke, 4800 Bielefeld, West fosfamide (1, 3) (Chart 1) are effective antitumor agents in Germany. -
Combination Effects of Radiotherapy / Drug Treatments for Cancer Recommendation by the German Commission on Radiological Protection with Scientific Background
Strahlenschutzkommission Geschäftsstelle der Strahlenschutzkommission Postfach 12 06 29 D-53048 Bonn http://www.ssk.de + Combination Effects of Radiotherapy / Drug Treatments for Cancer Recommendation by the German Commission on Radiological Protection with scientific Background Adopted at the 264th session of the SSK on 21 October 2013 Combination Effects of Radiotherapy / Drug Treatments for Cancer 2 The German original of this English translation was published in 2013 by the Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety under the title: Kombinationswirkungen Strahlentherapie/medikamentöse Tumortherapie Empfehlung der Strahlenschutzkommission mit wissenschaftlicher Begründung This translation is for informational purposes only, and is not a substitute for the official statement. The original version of the statement, published on www.ssk.de, is the only definitive and official version. Combination Effects of Radiotherapy / Drug Treatments for Cancer 3 Contents Preface ....................................................................................................................... 8 Recommendation ...................................................................................................... 9 Scientific background of the recommendation .................................................... 11 1 Introduction ..................................................................................................... 11 2 Drug licensing and pharmacovigilance ....................................................... -
Protocol of Clinical Study
Protocol of clinical study Title Therapy-Optimization Trial and Phase II Study for the Treatment of Relapsed or Refractory of Primitive Neuroectodermal Brain Tumors and Ependymomas in Children and Adolescents Inclusion Criteria: Disease Characteristics • Histologically confirmed Medulloblastoma, cerebral PNET or Ependymoma • Refractory or relapsed disease • Measurable disease by MRI or detection of tumor cells in cerebrospinal fluid Patients characteristics • Performance status ECOG ≥ 3 or Karnofsky Status ≥ 40% • Life expectancy ≥ 8 weeks Hematological: • Absolute leukocyte count ≥ 2.0 x 10^9 /l • Hemoglobin ≥ 10g/dl • Platelet count ≥ 70 x 10^9/l Renal: • Creatinine no greater than 1.5 times UNL • No overt renal disease Hepatic: • Bilirubin less than 2.5 times UNL • AST and ALT less than 5 times UNL • No overt hepatic disease • Pulmonary: • No overt pulmonary disease • Cardiovascular: • No overt cardiovascular disease Other: • Not pregnant or nursing • Negative pregnancy test • Fertile patients must use effective contraception Orphanet Database. Clinical trial 2009. http://www.orpha.net/data/eth/DE/ID60629Eng.pdf • No uncontrolled infection Prior concurrent therapy • More than 2 weeks since prior systemic chemotherapy • More than 4 weeks since prior radiotherapy • No other concurrent anticancer or experimental drugs Examinations required • Examination of lumbar CSF • Cranial and spinal MRI within 14 days prior to start of treatment Intervention 1: P-HIT-REZ 2005: Active Comparator Carboplatine, Etoposide, Thiotepa, Trofosfamide intravenous chemotherapy 2: P-HIT-REZ 2005: Active Comparator Temozolomide, Etoposide, Thiotepa oral chemotherapy 3: E-HIT-REZ 2005: Experimental Temozolomide, Etoposide, Trofosfamide Phase II Intravent. Etoposide: Experimental Etoposide Phase II Number of expected inclusions 200 patients Study start February 2006 Estimated Study Completion January 2016 Study phase Phase II Phase III Study Design National, multicentre, treatment, randomized, crossover assignment, active control efficacy study Orphanet Database. -
Importance of ADME and Bioanalysis in the Drug Discovery
alenc uiv e & eq B io io B a f v o a i l l a Journal of a b Vuppala et al., J Bioequiv Availab 2013, 5:4 n r i l i u t y o DOI: 10.4172/jbb.10000e31 J ISSN: 0975-0851 Bioequivalence & Bioavailability EditorialResearch Article OpenOpen Access Access Importance of ADME and Bioanalysis in the Drug Discovery Pradeep K Vuppala1*, Dileep R Janagam2 and Pavan Balabathula2 1Preclinical Pharmacokinetics Shared Resource, St. Jude Children’s Research Hospital, Memphis, TN, USA 2University of Tennessee Health Sciences Center, Memphis, TN, USA Editorial Bioanalytical support plays a vital role during the lead optimization stages. The major goal of the bioanalysis is to assess the over-all The hunt for new drugs can be divided into two stages: discovery ADME characteristics of the new chemical entities (NCE’s). Arrays and development. Drug discovery includes generating a hypothesis of of bioanalytical methods are required to completely describe the the target receptor for a particular disorder and screening the in vitro pharmacokinetic behavior in laboratory animals as well as in humans and/or in vivo biological activities of the new drug candidates. Drug [7]. Bioanalytical tools can play a significant role for the progress development involves the assessment of efficacy and toxicity of the new in drug discovery and development. Physiologic fluids such as blood, drug candidates. serum, plasma, urine and tissues are analyzed to determine the absorption and disposition of a drug candidate administered to a test To aid in a discovery program, accurate data on pharmacokinetics animal [8]. -
Pharmacoscan Solution Pharmacoscan Solution Preemptive Genotyping of Known Pharmacogenomics Markers in a Single Assay
DATA SHEET PharmacoScan Solution PharmacoScan Solution Preemptive genotyping of known pharmacogenomics markers in a single assay Personalized medicine is becoming a reality with the Key features advancement of technologies that allow us to understand • 4,627 markers in 1,191 genes of known the common variation in genes coding for drug metabolism pharmacogenomic value and drug transporters. However, attrition of drug • Comprehensive content of known pharmacogenomic candidates in the pharmaceutical industry continues to value including phase I and phase II enzymes, regulatory make the drug discovery process costly and lengthy. This and modifier genes, drug target genes, and phase III attrition is commonly due to poor pharmacokinetics and transporter genes toxicity—two risks that can be strongly influenced by the variability in drug responses due to genetic variation. The • Genotyping of highly predictive markers in genes, process of dissecting environmental factors, physiological including GSTM1, CYP1A2, CYP2D6, CYP2B6, CYP2A6, variables, and genetic characteristics (pharmacogenetics) SULT1A1, CYP2C19, and CYP2C9 that are in highly is complicated by the large numbers of drug-metabolizing homologous regions enzymes that contribute to the processing of most drugs. • Copy number variation (CNV) analysis for copy number states ranging from 0 to >3 for important ADME genes A molecular assay designed for multiethnic populations that targets functional variations in all the key genes • Star allele and translation tables for key actionable genes involved in the absorption, distribution, metabolism, and excretion (ADME) of commonly prescribed medications can help reduce the lengthy timelines and complexities within the drug discovery process. The Applied Biosystems™ PharmacoScan™ Solution offers such capability by providing broad coverage of industry-relevant, multiethnic content, and the capability to address markers in complex genes on a platform that has superior lot-to-lot reproducibility. -
Intravenous Ascorbate and Oncologic Agents
© PAUL S. ANDERSON 2013 INTRAVENOUS ASCORBATE AND ONCOLOGIC AGENTS Updated Data Review and Policies for concurrent use at Anderson Medical Specialty Associates, Southwest College of Naturopathic Medicine Research Institute and Medical Center and Bastyr University Clinical Research Center Paul S. Anderson 05/01/2013 © Paul S. Anderson – All rights reserved – Reproduction and redistribution only allowed with proper attribution. Abstract: Intravenous application of ascorbic acid (IVAA) has a long history in adjunctive oncology communities. Its use has stimulated much debate regarding efficacy, safety and appropriate inclusion in oncologic practice. The potential for both antagonistic and synergistic interactions between IVAA and chemotherapies or radiation has existed for some time as an unanswered or confusing question in the naturopathic and allopathic oncology community. The purpose of this publication is to summarize and update the state of understanding of this complicated topic for clinicians employing either standard or integrative oncology care. INTRAVENOUS ASCORBATE AND ONCOLOGIC AGENTS Introduction: Intravenous ascorbate has been used in oncology practice by naturopathic and alternative allopathic physicians for decades. Published data regarding this therapy shows that it continues to be one of the most commonly employed alternative IV therapies. This popularity has both stimulated awareness of this therapy and concern regarding not only the safety and efficacy of IVAA in the oncology patient but also for the potential of antagonistic -
Nephroblastoma High-Dose Chemotherapy with Autologous Stem Cell Rescue in Children with Nephroblastoma
Bone Marrow Transplantation (2002) 30, 893–898 2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Nephroblastoma High-dose chemotherapy with autologous stem cell rescue in children with nephroblastoma B Kremens1, B Gruhn2, T Klingebiel13, C Hasan3, H-J Laws4, E Koscielniak12, B Hero5, B Selle6, C Niemeyer7, FG Finckenstein8, A Schulz9, A Wawer10, F Zintl2 and N Graf11 1Department of Pediatric Hematology/Oncology, University of Essen, Germany; 2Department of Pediatric Hematology/Oncology, University of Jena, Germany; 3Department of Pediatric Hematology/Oncology, University of Bonn, Germany; 4Department of Pediatric Hematology/Oncology, University of Du¨sseldorf, Germany; 5Department of Pediatric Hematology/Oncology, University of Cologne, Germany; 6Department of Pediatric Hematology/Oncology, University of Heidelberg, Germany, 7Department of Pediatric Hematology/Oncology, University of Freiburg, Germany; 8Department of Pediatric Hematology/Oncology, University of Hamburg, Germany; 9Department of Pediatric Hematology/Oncology, University of Ulm, Germany; 10Department of Pediatric Hematology/Oncology, University of Halle, Germany; 11Department of Pediatric Hematology/Oncology, University of Homburg/Saar, Germany; 12Department of Pediatric Hematology, Oncology and Immunology, Olga-Hospital, Stuttgart, Germany; and 13Department of Pediatric Hematology/Oncology, University of Frankfurt, Germany Summary: Keywords: Wilms tumor; high-dose chemotherapy; auto- logous bone marrow transplantation Children with Wilms tumor who have a particular risk of failure at relapse or at primary diagnosis were treated with high-dose chemotherapy (HDC) and auto- logous peripheral blood stem cell rescue in order to A child with newly diagnosed Wilms tumor (WT) has a improve their probability of survival. From April 1992 probability of about 85% of being cured with multimodal to December 1998, 23 evaluable patients received HDC treatment nowadays. -
Cisplatin, Gemcitabine, and Treosulfan in Relapsed Stage IV Cutaneous Malignant Melanoma Patients
British Journal of Cancer (2007) 97, 1329 – 1332 & 2007 Cancer Research UK All rights reserved 0007 – 0920/07 $30.00 www.bjcancer.com Cisplatin, gemcitabine, and treosulfan in relapsed stage IV cutaneous malignant melanoma patients *,1,2,3 1 1 2 J Atzpodien , K Terfloth , M Fluck and M Reitz 1 2 Fachklinik Hornheide an der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster, Dorbaumstr. 300, Mu¨nster 48157, Germany; Europa¨isches Institut fu¨r Tumor Immunologie und Pra¨vention (EUTIP), Bad Honnef, Germany To evaluate the efficacy of cisplatin, gemcitabine, and treosulfan (CGT) in 91 patients with pretreated relapsed AJCC stage IV À2 cutaneous malignant melanoma. Patients in relapse after first-, second-, or third-line therapy received 40 mg m intravenous (i.v.) À2 À2 Clinical Studies cisplatin, 1000 mg m i.v. gemcitabine, and 2500 mg m i.v. treosulfan on days 1 and 8. Cisplatin, gemcitabine, and treosulfan therapy was repeated every 5 weeks until progression of disease occurred. A maximum of 11 CGT cycles (mean, two cycles) was administered per patient. Four patients (4%) showed a partial response; 15 (17%) patients had stable disease; and 72 (79%) patients progressed upon first re-evaluation. Overall survival of all 91 patients was 6 months (2-year survival rate, 7%). Patients with partial remission or stable disease exhibited a median overall survival of 11 months (2-year survival rate, 36%), while patients with disease progression upon first re-evaluation had a median overall survival of 5 months (2-year survival rate, 0%). Treatment with CGT was efficient in one-fifth of the pretreated relapsed stage IV melanoma patients achieving disease stabilisation or partial remission with prolonged but limited survival.