Journal Of Clinical Pharmacology Research Articles

Pyromania Associated with Escitalopram in a Child

Journal of Child and Adolescent PsychopharmacologyVol. 21, No. 4 Letters to the EditorPyromania Associated with Escitalopram in a ChildMehmet Fatih Ceylan, İbrahim Durukan, Tümer Türkbay, Omer Faruk Akca, and Koray KaraMehmet Fatih CeylanDepartment of Child and Adolescent Psychiatry, Kayseri Education and Research Hospital, Kayseri, Turkey.Search for more papers by this author, İbrahim DurukanDepartment of Child and Adolescent Psychiatry, Gulhane Military Medical Academy, Ankara, Turkey.Search for more papers by this author, Tümer TürkbayDepartment of Child and Adolescent Psychiatry, Gulhane Military Medical Academy, Ankara, Turkey.Search for more papers by this author, Omer Faruk AkcaDepartment of Child and Adolescent Psychiatry, Gulhane Military Medical Academy, Ankara, Turkey.Search for more papers by this author, and Koray KaraDepartment of Child and Adolescent Psychiatry, Gulhane Military Medical Academy, Ankara, Turkey.Search for more papers by this authorPublished Online:18 Aug 2011https://doi.org/10.1089/cap.2010.0141AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Pyromania Associated with Escitalopram in a Child." , 21(4), pp. 381–382FiguresReferencesRelatedDetailsCited byKleptomania Induced by VenlafaxineCase Reports in Psychiatry, Vol. 2021A case of venlafaxine-induced kleptomania26 December 2015 | European Journal of Clinical Pharmacology, Vol. 72, No. 4 Volume 21Issue 4Aug 2011 InformationCopyright 2011, Mary Ann Liebert, Inc.To cite this article:Mehmet Fatih Ceylan, İbrahim Durukan, Tümer Türkbay, Omer Faruk Akca, and Koray Kara.Pyromania Associated with Escitalopram in a Child.Journal of Child and Adolescent Psychopharmacology.Aug 2011.381-382.http://doi.org/10.1089/cap.2010.0141Published in Volume: 21 Issue 4: August 18, 2011Online Ahead of Print:August 8, 2011PDF download

Optimizing Drug Development and Use in Patients With Kidney Disease

Optimizing Drug Development and Use in Patients With Kidney Disease

Integrating pharmacology and clinical pharmacology

I here reaffirm some of the points that I made in the manifesto for UK clinical pharmacology [1], in response to letters from others. Much of what I wrote in the manifesto addresses points that correspondents have made, but as some of the important points may not have been clear on a first reading, I shall reiterate them and add clarifications. I am surprised that Professor Page [2] should think that I have taken no cognizance of the erosion of the discipline of pharmacology in recent years. Nothing that I said, wrote or did, while I was President-Elect and President of the British Pharmacological Society (BPS) during 2006 to 2009, should have given that impression. If he doubts this, and my commitment to the integration of all pharmacological science across the clinical and non-clinical spectra, he may want to reread some of my articles in the newsletter of the BPS, previously called pA2, now called Pharmacology Matters[3, 4], and indeed the manifesto itself, where I wrote that ‘the importance of integrating pharmacology and clinical pharmacology cannot be overestimated’. In relation to this, I strongly believe that the distinction that many make between basic and applied science is a false dichotomy. As I wrote in the manifesto, ‘functions in biology emerge … as a result of integration of different components of relevant systems at different levels.’ This is true of pharmacology and clinical pharmacology. Although it is sometimes useful to refer separately to basic and applied science, it is the crosstalk between them, at all levels and from one level to another, that is important. I have recently had the opportunity to make these views known more widely, in my opening plenary lecture at WorldPharma 2010, the 16th World Congress of the International Union of Basic and Clinical Pharmacology (IUPHAR). The contents of that lecture have been posted on the BPS's website [5].

The Medicalization of Cannabis

The ‘History of Twentieth Century Medicine Group’ was established by the Wellcome Trust in 1990 to bring together ‘clinicians, scientists, historians and others interested in contemporary medical history’. Over time, and with the support of the Wellcome Trust, this group has evolved into the current ‘Wellcome Trust Centre for the History of Medicine’. This Centre, similar to that of the initially established group, brings together key interested individuals in one area of medicine to discuss and debate that particular area. These sessions are not simply a review of the published literature, but more importantly they are based on the individual's memories and personal experiences at the time. These discussions and debates are then published as a ‘Witness Seminar’, which is free to download from the Wellcome Trust website. This latest one, ‘The Medicalization of Cannabis’ is the 40th Witness Seminar to be published and is based on the discussions of 16 participants and the co-chairs Professor Virginia Berridge and Professor Tilli Tansey. The majority of clinical pharmacologists and other readers of the British Journal of Clinical Pharmacology will have some understanding and knowledge of the pharmacological actions of cannabis. This witness statement, based on the discussions and debates held, details the key discoveries in the history of cannabis from the identification of THC as the active ingredient of cannabis, through the characterization of the CB1 and CB2 cannabinoid receptors, to the licensing in Canada of the sublinguinal herbal cannabis extract for use in patients with multiple sclerosis. There is also discussion about the potential future of cannabis and its role in medicine. In addition to these significant events in the development of our understanding of cannabis and its potential medical uses, the witness seminar is made more interesting by those involved discussing their personal experiences in relation to these events. This provides a much greater insight into the cannabis research that has been undertaken than can ever be gleaned from reading published peer-reviewed papers. In particular, there are several references to serendipitous events, not only within the scientific field but also elsewhere in the public and political fields, which have significantly directed the research that has been undertaken on cannabis. It becomes apparent to the reader that without these events, we may not be where we are today with cannabis, both from a medical and political perspective. We are all aware that there is a lot more involved in our own areas of research than is reported in the papers that we publish in peer-reviewed journals and present at national and international meetings. The majority of the more personal insights into our own areas of research are often never discussed. In the Witness Seminars series, the Wellcome Trust attempts to document some of these personal experiences alongside the previously well documented published literature, so that this information is not lost with time. Reading this short Witness Seminar will remind all of us of our own trials and tribulations in regards to our own research, and also that for many of us the smallest opportunistic event or discovery can shape our own careers and that of many others in the future.

Placebo response in migraine

Sir I am currently in the process of revising the Guidelines for Drug Trials in Migraine of The International Headache Society. While browsing the literature for information on the placebo response in migraine randomised clinical trials (RCTs), I read with interest the extensive meta-analysis on this subject published by Macedo et al. in the European Journal of Clinical Pharmacology [1]. There is, however, one fundamental misunderstanding in this article, namely, the definition of headache relief. These authors state that headache relief is a 50% reduction in pain [1]. The RCTs used the standard that all migraine sufferers should have moderate or severe headache pain before drug administration and that headache relief, as defined by Glaxo [2], was a decrease in headache pain from moderate (2) or severe (3) to none (0) or mild (1) at 1 h (subcutaneous sumatriptan) or 2 h (oral and intranasal triptans) post-drug administration. Therefore, successful headache relief could be assessed as 3–0, 3–1, 2–0, or 2–1. The placebo response depends on many factors, such as study design, route of administration, and cultural elements (for example, Europe vs. North America [1]. In addition, an important determinant factor could also be whether the patients are treated as in-patients in headache clinics or whether they self-administer at home. In one crossover RCT in which a subcutaneous autoinjector with sumatriptan 6 mg was used to treat migraine, patients were recruited from general practice and treated migraine attacks at home. Headache relief was 61 and 6% at 60 min after the administration of the active drug and placebo, respectively [3]. The therapeutic gain (TG) was 55% (95% confidence interval 44–65%). Thus, the result obtained with the placebo was extremely low, but the TG was similar to the TG of 49 [1] and 51% [4] reported in meta-analyses. Finally, there is an increasing tendency to use pain free at 2 h as the primary efficacy measure in RCTs on acute treatment migraine [5], and pain free is what the migraine patients want to be [6].

Author’s response to the Letter to the Editor of Tfelt-Hansen

Sir, We have read with care the letter of Dr. Tfelt-Hansen regarding our article published in the European Journal of Clinical Pharmacology in which we assessed the placebo effect in migraine using meta-analytic techniques [1]. While we consider that his comments will help to clarify some of the issues raised in our article, we would like to address a number of specific points brought up by Dr. Tfelt-Hansen with the aim of improving the reader’s understanding of our contribution. Dr. Tfelt-Hansen expresses his concern regarding the definition of headache relief, stating the need to accept that headache relief should be defined as the decrease in its intensity from moderate (2) or severe (3) to none (0) or mild (1). In fact, in our article we write that ‘pain relief means a pain reduction higher than 50%’. In the case of severe pain, a pain reduction of 50% is a decrease in headache intensity from severe (3) to mild (1) or none (0). For moderate pain, a decrease in headache intensity to mild (1) or none (0) is considered to be a success. Therefore, we consider that our definition of ‘higher than 50%’ is not different from that suggested by Dr. Tfelt-Hansen. However, we do accept that his definition is clearer than the one used by us in our article, which is also in accordance with the Guideline of EMEA for the investigation of medicinal products for the treatment of migraine [2] and the International Headache Society Clinical Trials Subcommittee [3]. However, for practical purposes, the two definitions are almost equivalent. Dr. Tfelt-Hansen also suggests that pain free at 2 h is increasingly used as the primary efficacy measure. We fully agree with that point of view. In fact, all of the tables in our article [1] include both pain-free and pain-relief variables, which enable the reader to make a comparison. The first can be considered as a hard outcome and the second as a soft outcome. However, it is indisputable that the main objective of treatment should be to leave patients pain free, even though pain relief can obviously not be considered to be of minor importance in clinical practice. As expected, the magnitude of the placebo effect was higher when pain relief was used as a variable and decreased when the pain free was considered as a variable. Unfortunately, although pain free is desirable, it is not always achieved in clinical practice or in clinical trials. For example, in a recent study in acute migraine [4], the pain freedom at 2 h ranged from 17.2 to 31.3% with active treatments and was 9.6% with placebo. Values of pain relief at 2 h ranged from 49.8 to 56.4% but it was only 27.7% with placebo. These values are very similar to those obtained in our meta-analysis, i.e., 28.6% of pain relief and 8.8% of pain freedom. The main objective of our article was to analyze the significance of placebo effect differences according to clinical trial methodology independently of all other variables (disease, population, and even outcomes). If we assume that methodology may modify placebo results, then we may also assume that some aspects associated to clinical A. Macedo :M. Farre Department of Pharmacology, Therapeutics and Toxicology, Universitat Autonoma de Barcelona, Bellaterra, Spain

A response to: ‘A manifesto for clinical pharmacology from principles to practice’ by Jeff Aronson

I read with interest the recent provocative article entitled ‘A manifesto for clinical pharmacology from principles to practice’ from Jeffrey Aronson that appeared in the Journal [1]. Dr Aronson defines a clinical pharmacologist as ‘a medically qualified practitioner who teaches, does research, frames policy and gives information and advice about the actions and proper use of medicines in humans and implements that knowledge in clinical practice’. Dr Aronson goes on in his article to say he prefers ‘to refer to those who contribute to the discipline, but are not medically qualified as applied pharmacologists’. He further states that ‘without medical training there are many areas in which such individuals cannot fulfil all the aspects of the discipline of clinical pharmacology and are therefore not clinical pharmacologists’. Laudable as Dr Aronson's attempts to provide a ‘manifesto for clinical pharmacology’ may be, and certainly he has done much to highlight the poor prescribing behaviour of physicians in the UK, his article fails to address the ‘Elephant in the Room’ which is the erosion of the discipline of pharmacology over the last 25 years in both the UK and elsewhere in the world [2]. Pharmacology is defined as the ‘Science that deals with the actions, mechanisms of action, uses, adverse effects and fate of drugs in animals and humans’[3]. I would argue that the distinction between clinical and basic (or applied) pharmacology used by Dr Aronson and that is used by a number of societies throughout the world (including the British Pharmacological Society of which Dr Aronson is a Past President), is both artificial and divisive and such divisions have contributed to the dilution of the discipline of pharmacology at a time when there is increasingly a call for a more integrated approach to understanding diseases and treatments. This dilution is continuing with the increasing use of the term ‘translational medicine’. Surely pharmacology in its widest sense, from identifying new targets for drugs through the development of such drugs into safe and effective medicines, and ultimately ensuring their appropriate clinical use is the best example of translational medicine we have. It is also worth noting that the very Journal Dr Aronson chooses to publish his manifesto for Clinical Pharmacology actually states under the ‘General Information’ section at the front of the Journal that ‘the British Journal of Clinical Pharmacology is published monthly by Blackwell Publishing Ltd for the British Pharmacological Society. Papers on all aspects of drug action in man will be considered’. There is certainly no clarification that one has to be medically qualified or clinically trained to submit work of relevance to drug action in man. Surely pharmacologists of all persuasions should be working hard to restore the importance of our discipline which has done so much for medical science and mankind over the last two centuries, rather than arguing about terminology of one set of pharmacologists over another based on what degrees they have. After all most pharmacologists by definition have the common interest of drugs and how they work and their appropriate use as the core reason for getting out of bed in the morning (irrespective of whether they have a medical degree or not). There are many of my clinical colleagues who would surely satisfy point 2 in the summary on page 3 of Aronson's article as they are specialists in their chosen therapeutic and disease areas, but who certainly would not label themselves as clinical pharmacologists. Surely any manifesto should be for pharmacology and encourage basic scientists to work more closely with relevant clinical colleagues (whether they call themselves clinical pharmacologists or not) in order to expedite the discovery of new medicines, which sadly is in decline, and to ensure that such medicines are then used appropriately. Maybe the time has come to ditch the term clinical pharmacology (and indeed other such divisive terms such as molecular pharmacology) and we should return to the use of the term pharmacology to cover our subject area. After all whether you work to understand the interaction of a drug with its receptor at a molecular level or the use of such a drug in patients, the common interest between us is the drug and surely it is also drugs that distinguish pharmacologists from physiologists or many other branches of medical science.

Behind the rosiglitazone controversy

On 23 September 2010, the US FDA and the EMA issued statements announcing their response to data implicating the use of the antidiabetes drug rosiglitazone (Avandia®, GlaxoSmithKline plc, London, UK) with an increased risk of cardiovascular events, including acute myocardial infarction and stroke. The EMA has implemented an immediate suspension of the drug, meaning that it will no longer be available in Europe. The FDA stopped short of a total suspension, but has stated that use of the drug should be restricted to patients with Type 2 diabetes who cannot control their diabetes with other medications. In this article, Bernard Cheung of the Expert Review of Clinical Pharmacology Editorial Advisory Board gives his insight into the matter. Cheung graduated from the University of Cambridge (UK) and received a PhD in Clinical Pharmacology in 1995. He then joined the University of Hong Kong as the Lecturer in Clinical Pharmacology and later became Professor. He held the Chair in Clinical Pharmacology and Therapeutics at the University of Birmingham (UK) in 2007–2009. Cheung’s main research interest is in cardiovascular diseases and risk factors, including hypertension and the metabolic syndrome. He works on vasoactive peptides, such as adrenomedullin and urotensin II. He is also interested in clinical trials, meta-analyses, drug utilization and medication safety and is the Chief Editor of the Open Diabetes Journal, and an Executive Editor of the British Journal of Clinical Pharmacology.

The Emerging Scientific Discipline of Pharmacometrics

This supplement to the Journal of Clinical Pharmacology includes work presented at the first two meetings of the American Conference on Pharmacometrics in Tucson, Arizona (2008), and Mystic, Connecticut (2009), along with other invited contributions. The articles that comprise this supplement provide only a small sample of the diverse directions, perspectives, challenges, opportunities, and aspirations of the emerging scientific discipline of pharmacometrics. Pharmacometrics has expanded far beyond its initially defined focus on the analysis of measurements (metrics) associated with pharmacokinetics and biopharmaceutics.1 As an emerging quantitative science, pharmacometrics spans the spectrum from basic research into disease and mechanisms of drug action to the rational use of medicines in patient care. Quantitative modeling and simulation provide the foundation for this multidisciplinary effort that involves basic and applied university researchers, industry drug development scientists and decision makers, government regulatory scientists, clinicians, and other health professionals. Although the domain of pharmacometrics continues to broaden, three overarching themes are clearly guiding this evolution. These are Integration, Innovation, and Impact: (1) quantitative integration of multisource data and knowledge through the application of clinical, biomedical, biological, engineering, statistical, and mathematical concepts, resulting in (2) continuous methodological and technological innovation enhancing scientific understanding and knowledge, which in turn (3) has an impact on discovery, research, development, approval, and utilization of new medicines. The triplet of Integration—Innovation—Impact forms a circle of excellence (the logo of this supplement shown above right) that can provide the fuel of self-renewal that is necessary to expand pharmacometrics as a vibrant scientific discipline. This supplement is organized based on the themes of Integration—Innovation—Impact as outlined in the table of contents. The contributions include commentaries, white papers, reviews, and original research articles. We hope that this issue will stimulate the new thinking necessary to ensure the success and growth of pharmacometrics. We wish to acknowledge the leadership of the American College of Clinical Pharmacology for the opportunity to provide this supplement, including Michael Reed, president; Stephen Keith, CEO; and James Burris, publication committee chair. The encouragement and guidance of the editors of the Journal of Clinical Pharmacology, Dan Sitar, editor-in-chief, and Hartmut Derendorf, associate editor, have been essential to this publication. It is with great pleasure that we acknowledge Marjory Spraycar, editorial manager of JCP, for her professionalism and patience in all facets of the production of this supplement. Finally, we thank the more than 60 authors for their excellent contributions as well as the 40 committed reviewers for providing thorough and prompt reviews of the manuscripts. Financial disclosure: the articles in this supplement are sponsored by the American Conference on Pharmacometrics.

Completeness of Published Case Reports on Suspected Adverse Drug Reactions

Case reports of suspected adverse drug reactions (ADRs) are common in the biomedical literature. Standards for authors and editors for writing, submitting and publishing ADR case reports have been empirically established since the 1980s; however, these recommendations have not been widely disseminated or incorporated into practice. Comprehensive and standardized guidelines on good publication practice have recently been proposed. No study has been performed so far to assess the adherence of published ADR case reports to these guidelines. To describe the current situation with regards to the reliability and completeness of published ADR case reports. A random sample of 100 single ADR case reports published between 2005 and 2008 (25 for each year) was retrieved from Pfizer's pharmacovigilance database. Reliability and completeness were assessed by comparing the relevant information contained in the retrieved ADR case reports against the recommendations prescribed by the guidelines. Descriptive statistics and correlation analysis using the Statistical Package for Social Science (SPSS) were undertaken. The patient's medical history relevant to the ADR was reported in 92% of the case reports. Concerning the suspected drug, 11% of the reports included the proprietary name; duration, dosage, route and formulation were reported in 87%, 85%, 37% and 21% of the reports, respectively. Information on concomitant therapies was included in 71% of the reports. The description of the ADR contained details on management (99%), time-course (97%) and diagnostic tests (95%), while final outcome and seriousness were reported in 73% and 52% of the reports, respectively. A discussion on the possible mechanism for the ADR was present in 70% of the case reports. The possible implications for clinical practice of the reported drug-event association were described in 75% of the cases. Causality assessment was reported in 81%, and rating scales to support the causal link were used in 20% of the reports. The major predictive factor for the presence of an objective causality assessment was found to be publication in specialized pharmacoepidemiology or clinical pharmacology journals: 47% specialized versus 11% non-specialized (odds ratio = 6.93; 95% CI 2.37, 20.26). The findings of this study show that published ADR case reports, especially those coming from non-specialized journals, still lack important information necessary for comprehensive evaluation. As published ADR case reports are expected to be reported to regulatory authorities using the same approach as for spontaneous cases, it is paramount for their effective integration in the pharmacovigilance system that pharmaceutical companies and learned societies actively promote a culture of good publication practices.

Defining the Future of Pharmacometrics: The American Society of Pharmacometrics

The contributions in this Special Issue of the Journal of Clinical Pharmacology reflect the dramatic evolution during the past 60 years of the field we now call pharmacometrics. A few of the pivotal organizational developments that have promoted the growth in the breadth and depth of activity in pharmacometrics are readily identifiable: Launch of the Journal of Pharmacokinetics and Biopharmaceutics in 1973 Introduction of a new section on pharmacometrics in Journal of Pharmacokinetics and Biopharmaceutics in 1982 Inaugural meeting of the Population Approach Group of Europe (PAGE) in 1992 Inaugural meeting of the American Conference on Pharmacometrics (ACoP) in 2008 As noted in the editorial preface to this supplement, Integration—Innovation—Impact can provide the thematic foundation for continued growth of the scientific discipline of pharmacometrics. To guide the continued revolutions around the Integration—Innovation—Impact circle of excellence, we are proposing the establishment of the American Society of Pharmacometrics (ASoP). An important part of the mission of ASoP is to serve as the sponsoring organization for the American Conference on Pharmacometrics. In addition, ASoP will actively (1) engage other pharmacometric communities in North America, Europe, Asia, and Australia/New Zealand as we strive to innovate and expand in pharmacometrics; (2) work to integrate national and international initiatives, consortia, and educational efforts involving pharmacometrics; and (3) collaborate with editors of existing journals to enhance the impact of pharmacometrics. The success and future growth of the American Society of Pharmacometrics require the continuous commitment, contributions and leadership of all of us who understand the central role pharmacometrics has in advancing innovative science and technology, and in optimizing discovery, development, and utilization of new medicines for the treatment and prevention of disease to improve human health and well-being. Financial disclosure: The articles in this supplement are sponsored by the American Conference on Pharmacometrics.

Pharmacometrics 2020

This special issue of the Journal of Clinical Pharmacology is dedicated to pharmacometrics, covering topics related to methodological research, application to decisions, standardization, PhRMA survey, and growth strategy. Innovative methodological and technological advances in analyzing disease, drug, and trial data have equipped pharmacometricians with the know-how to influence high-level decisions, which in turn creates more pharmacometric opportunities. Pharmacometrics is revolutionizing drug development and regulatory decision making. To sustain the success and growth of this field, we need to up the ante. Strategic goals for pharmacometric groups in industry, regulatory agencies, and academia are proposed in this report. These goals should be of significance to all stakeholders who have a vested interest in drug development and therapeutics. The future of pharmacometrics depends on how well we all can deliver on the strategic goals.

Pregabalin Abuse, Dependence, and Withdrawal: A Case Report

Pregabalin Abuse, Dependence, and Withdrawal: A Case Report

Letter to the editor: pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism

Complete List of Authors: Mercier, Cedric; La Timone University Hosiptal, Medical Oncology Dahan, Laetitia; La Timone University Hospital, Digestive Oncology Ouafik, L'Houcine; North University Hospital, Transfer Oncology Laboratory Andre, Nicolas; La Timone university Hospital, Paediatric Oncology Ciccolini, joseph; North University Hospital of Marseille, Transfer Oncology Laboratory European Journal of Clinical Pharmacology

Depression and Diabetes: More on What the Relationship Might Be

Depression and Diabetes: More on What the Relationship Might Be

Anticholinergics, antimuscarinics or atropinics? About the words in pharmacology

We read with great interest the two excellent articles from Gnjidic et al.[1] and Gerden et al.[2] in recent issues of the British Journal of Clinical Pharmacology.

Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics [excerpts

Biotechnology Law ReportVol. 29, No. 2 TEXTSGuidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics [excerpts]Published Online:16 Jun 2010https://doi.org/10.1089/blr.2010.9977AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byFeasibility of a Platform Trial Design for the Development of Mobile Health Applications: A Review Asma Aqib, Bertrand Lebouché, Kim Engler, and Tibor Schuster11 August 2022 | Telemedicine and e-Health, Vol. 0, No. 0Optimal Patient Enrollment in Sequential Adaptive Clinical Trials with Binary ResponseSSRN Electronic JournalEthics and Ebola: Public Health Planning and ResponseSSRN Electronic JournalBayesian adaptive clinical trials: a dream for statisticians only?9 September 2011 | Statistics in Medicine, Vol. 31, No. 11-12Use of an Adaptive Study Design in Single Ascending-Dose Pharmacokinetics of A0001 (α-Tocopherylquinone) in Healthy Male Subjects7 March 2013 | The Journal of Clinical Pharmacology, Vol. 52, No. 1 Volume 29Issue 2Apr 2010 Information© 2010 Mary Ann Liebert, Inc.To cite this article:Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics [excerpts].Biotechnology Law Report.Apr 2010.197-215.http://doi.org/10.1089/blr.2010.9977Published in Volume: 29 Issue 2: June 16, 2010PDF download

Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines

It is somewhat remarkable to note that not until recently, nearly 12 years and tens of millions of treated patients after its initial approval, has the metabolism of clopidogrel, an inactive prodrug, begun to be more fully understood. Although this lack of knowledge may not be unique among common cardiovascular drugs, there are 4 characteristics of clopidogrel therapy that make this gap in understanding disconcerting: The potential for life-threatening complications (bleeding or thrombosis) at both ends of its therapeutic spectrum; the fact that 1 dose is supposed to fit all; the lack of a measureable, proven end point (such as blood pressure for antihypertensive drugs) that allows for titration to a target response; and the nearly mandatory need by many patients for clopidogrel, with no acceptable alternative until recently. Article see p 512 Historically, understanding the metabolism of a drug has been critical in identifying those patients most likely to benefit from and, more important, potentially be harmed by that drug. This is especially true for drugs with relatively narrow therapeutic windows, such as phenytoin, warfarin, and others. Although it seems safe to assume, on the basis of our extensive clinical experience, that the therapeutic window of clopidogrel is unlikely to be narrow, this certainly does not represent the depth of knowledge we would hope for after so much clinical experience and research. What we do know is that P2Y12 inhibition with thienopyridines is beneficial in preventing arterial thrombotic events, presumably requiring the achievement of some minimal level of receptor inhibition that may or may not vary on the basis of the patient and clinical scenario. We also know that it is associated with a significant increase in serious bleeding events, with higher levels of inhibition associated with greater bleeding. In the present and future practice environment, with a growing …

A Systematic Review and Empirical Analysis of the Relation Between Dose and Duration of Drug Action

There is a log-linear relation between the dose and duration of action of drugs with single-compartment pharmacokinetics and direct, reversible mechanisms of action. However, it has been suggested that this relation does not extend to drugs whose metabolites are active or slowly eliminated, drugs with saturable kinetics, and drugs with hit-and-run effects. The purpose of this study is to test this hypothesis and to quantify the relationship by way of a systematic review coupled to an empirical analysis. All issues of 4 clinical pharmacology journals from 1980 to 2005 are hand-searched for articles that present pharmacodynamic response versus time curves for 4 or more different doses. Data on duration of action, dose, and area under the plasma concentration versus time curve from zero to infinity (AUC) are abstracted and analyzed by panel data regression modeling, with within-study fixed effects. Duration of drug action is defined as the time during which a pharmacodynamic effect (or response) exceeds a nominal threshold. The generalized models of all observations from 33 publications, with duration of action as the dependent variable and the logarithm of the dose (or AUC) as the explanatory variable, yield significant log-linear relationships. The regressions for individual studies are correctly specified in 27 cases; there are insufficient data for analysis in 10 studies, and a log-linear specification is deemed inappropriate in 6. Analysis of published dose-ranging studies shows that the duration of action of a drug is directly proportional to the logarithm of dose across a wide range of different drugs, extending a result that was previously documented for very few compounds.

Human Nedd4L rs4149601 G Allele Generates Evolutionary New Isoform I With C2 Domain

To the Editor: We carefully read the recent article in Hypertension by Luo et al.1 They found that the human Nedd4L functional variant (rs4149601 [G/A]) shows significant functional relevance with various phenotypes of human hypertension. However, they repeatedly emphasized in the article that, “the cryptic splice variant rs4149601 (G/A) …