John Posner

• PhD FRCP
• Consultant at King's College London

Serum amyloid-A (SAA) is associated with inflammatory disorders such as rheumatoid arthritis, Familial Mediterranean Fever, sarcoidosis, and vasculitis. There is accumulating evidence that SAA is a reliable biomarker for these autoinflammatory and rheumatic diseases and may contribute to their pathophysiology. Hyperinflammatory syndrome associated...

Background: Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-p...

Monoclonal antibodies (mAbs) are immunoglobulins designed to target a specific epitope on an antigen. Immunoglobulins of identical amino-acid sequence were originally produced by hybridomas grown in culture and, subsequently, by recombinant DNA technology using mammalian cell expression systems. The antigen-binding region of the mAb is formed by th...

Introduction Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatr...

Background: S-222611, an oral, reversible EGFR and HER2 inhibitor, has been shown to be well-tolerated as monotherapy at a dose of 800mg daily with good anti-tumor activity in patients previously treated with other anti-HER2-based regimens. This study evaluated the tolerability and safety of daily oral administration of S-222611 (S) in combination...

BACKGROUND S-222611 is an oral, reversible ErbB tyrosine kinase inhibitor of EGFR and HER2 with potent pre-clinical activity. MTD was not reached during the dose-escalation phase, (maximum dose 1600 mg QD). PK and efficacy data supported a daily dose of 800 mg. An expansion cohort of patients has been treated to further explore safety and efficacy....

Background and rationale: S-222611 is a novel, oral, reversible inhibitor of EGFR, HER2 and HER4 with an improved preclinical profile compared with first-generation pan-HER inhibitors. Research objectives: We conducted a phase I study to determine safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary eff...

This chapter provides a general overview of the background and burgeoning opportunities and challenges associated with global pharmaceutical biosimilar drug development. As biosimilar pioneers, EU regulations are highlighted. Secondary emphasis is on the USA, where regulations have only recently been promulgated. Biosimilar overviews for selected ‘...

In this chapter, the key features of controlled clinical trials are described. Trial objectives at each phase of drug development are summarised. The essential elements of trial design are then described. These include use of placebo and active-comparator controls, blinding, primary and secondary endpoints, surrogate and clinical endpoints, paralle...

In this chapter, the objectives of exploratory development and the planning of studies to meet those objectives are discussed. The preclinical requirements for administration of a new molecular entity to humans are presented briefly. Use of healthy volunteers in exploratory studies is described. There are a variety of designs for the first-in-human...

The Textbook of Pharmaceutical Medicine is the standard reference for everyone working and learning in pharmaceutical medicine. It is a comprehensive resource covering the processes and practices by which medicines are developed, tested and approved, and the recognised text for the Diploma in Pharmaceutical Medicine from the Faculty of Pharmaceutic...

The risk of haemorrhage in elderly and other higher risk groups of patients treated with dabigatran etexilate is similar to or greater than that of warfarin, which should be unacceptable. As well as adjusting dosage according to estimated creatinine clearance, the value of individualising dosage on the basis of a test of coagulation should be explo...

3100 Background: S-222611 is a novel oral, potent, reversible tyrosine kinase inhibitor with antiproliferative activity in human tumor cell lines expressing EGFR and/or HER2 in vitro and in mouse xenograft models. We conducted the first study in patients (pts) with solid tumors expressing EGFR or HER2. Methods: Daily oral doses of S-222611 were esc...

Clinical pharmacology is the study of pharmacodynamics and pharmacokinetics in humans. The relationship between dose, concentration and pharmacodynamic response may be explored using biomarkers for both desired and undesired effects of drugs. The action of drugs is due to receptor affinity, efficacy and the concentration of drug at the site of acti...

In this chapter, the objectives of exploratory development and the planning of studies to meet those objectives are discussed. The preclinical requirements for administration of a new molecular entity to humans are presented briefly. Use of healthy volunteers in exploratory studies is described. There are a variety of designs for the first-in-human...

The purpose of this study was to investigate renal glucose excretion as a function of blood glucose concentration and to evaluate the within-subject variability and between-subject variability in subjects with type 2 diabetes. Twenty-two subjects with type 2 diabetes [age 58 (12) years, diabetes duration 7 (6) years, endogenous creatinine clearance...

This study, conducted by the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI), was designed to determine the amount of Phase 1 activity in the UK in the period 1999-2000, the timelines involved for submissions to ethics committee and responses from ethics committees. A questionnaire was completed by AHIPPI members from phar...

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of val...

The facilities in which clinical research is conducted obviously vary enormously with circumstances. High quality research which has far reaching consequences can be performed in some of the poorest countries in the world using the most basic facilities. Conversely, research of inferior quality is sometimes performed in teaching hospitals and purpo...

The essential elements of a protocol are: A scientific rationale The objectives of the proposed study A description of the study population Inclusion and exclusion criteria for recruitment of subjects The number of subjects to be recruited A precise description of the procedures that will be performed including: Dosages of drugs that will be admini...

This book is about the practical aspects of performing clinical drug research starting from the conception of an idea through to publication of a completed piece of research in a peer reviewed scientific journal. In the last two or three decades it has become progressively more difficult to perform good clinical research.

The first administration of a new chemical or biological substance to humans may be conducted in a Phase I unit of a pharmaceutical company or contract research organisation (CRO) or in a hospital by an academic investigator. There has been an expansion of all such activities in recent years and the whole Phase I area has been put on a much more pr...

Lamotrigine, a sodium channel blocker that selectively inhibits the neuronal release of glutamate, has been shown to produce analgesia in acute and chronic pain models in rats without causing noticeable sedation. After oral administration it also reduces pain scores, as assessed by the cold pain test, in volunteers. The purpose of this study was to...

The novel selective 5-hydroxytryptamine (5-HT)1B/1D agonist, zolmitriptan (Zomig, formerly known as 311C90), has shown good efficacy in the acute oral treatment of migraine. Zolmitriptan acts both centrally and peripherally, therefore it is important to assess central nervous system effects. At single doses of 25-50 mg (up to 8 times the likely the...

The potential effects of food and gender on the pharmacokinetics of tucaresol were investigated in healthy volunteers. Ten males (mean weight 76.5 kg, age 27-42 years) and eight females (mean weight 58.9 kg, age 18-44 years) received a single oral dose of 200 mg tucaresol on two occasions in random order. On one occasion, tucaresol was given after...

Objective Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of migraine. In this study we investigated the cardiovascular and central nervous system effects and the pharmacokinetics of zolmitriptan in young and elderly adults.Methods Twelve young adult and 12 elderly volunteers received single doses of 5, 10, and 15 mg zolmitriptan dur...

Changes in both digoxin and aciclovir renal clearance following coadministration with some other renally eliminated drugs have been reported. The potential interaction of valaciclovir, with its antiherpetic metabolite aciclovir, and digoxin was investigated. Twelve healthy volunteers (seven males, five females) participated in an open, randomized,...

Zolmitriptan (Zomig, formerly known as 311C90), a selective 5HT1B/1D agonist is under development as an acute oral treatment for migraine. Despite the use of prophylactic medication, such as propranolol, breakthrough attacks often occur in patients. Consequently we investigated the effects of propranolol on the pharmacokinetics of, and cardiovascul...

Members of the new class of antimigraine compounds, 5HT1B/1D agonists, as well as ergotamine, may cause vasoconstriction through stimulation of 5HT receptors on peripheral vessels. The cardiovascular effects of 20 mg oral zolmitriptan (Zomig, formerly 311C90), 2 mg oral ergotamine and the combination were assessed in a randomized double-blind, plac...

This double-blind, randomised, two-period crossover study investigated the effect of pizotifen on the pharmacokinetics and tolerability profile of zolmitriptan (formerly 311C90), a novel selective 5-HT1D receptor agonist for acute migraine therapy. 13 healthy volunteers (mean age 31 years, range 19 to 41 years; mean weight 75kg, range 62 to 89kg) r...

Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT1D agonist for the acute treatment of migraine. After an initial test i.v. infusion, bioavailability was assessed by comparison of AUC after an i.v. infusion (3.5 mg) and an oral tablet (10 m...

Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radio...

To examine the population pharmacokinetics of lamotrigine in patients newly diagnosed with epilepsy and receiving oral lamotrigine monotherapy for up to 48 weeks. The population consisted of 158 Caucasians and 5 Asians of whom 81 were males and 82 females. Age and weight ranged between 14 and 76 years and 41-107 kg, respectively. A one-compartment...

Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5-HT1D-receptor agonist is under development as an acute treatment for migraine. The tolerability, pharmacokinetics and effects on blood pressure and heart rate of multiple doses of 5 or 10 mg (5 doses administered over 24 h) were compared, in healthy adult volunteers, wit...

This study investigated potential pharmacokinetic or pharmacodynamic interactions between the novel anti-migraine compound zolmitriptan (Zomig, formerly 311C90) and paracetamol and/or metoclopramide. In an open-label, randomised, crossover study, 15 healthy volunteers received single oral doses of 10 mg zolmitriptan alone, 1 g paracetamol alone, 10...

The aim of this study was to compare the pharmacokinetics of the anti-epileptic agent, lamotrigine, in patients with chronic renal failure and healthy volunteers. Non-compartmental pharmacokinetics of a single oral dose (200 mg) of the anti-epileptic agent, lamotrigine, and its main metabolite, lamotrigine N2-glucuronide, were determined for 10 pat...

Lamotrigine (LTG) is a novel antiepileptic drug cleared mainly by glucuronidation. The pharmacokinetics of a single 100mg oral dose was investigated in 24 subjects with liver cirrhosis (LC) and in 12 healthy controls. 12 subjects with LC were classified as moderate (MLC) and 12 as severe (SLC), 5 of whom had gross ascites (SLC+A). Blood was sampled...

Non-invasive methods for assessment of the vascular effects of antimigraine drugs were evaluated with respect to their utility, variability and sensitivity in a double-blind, placebo-controlled, three-period crossover study in six healthy volunteers using an intravenous vasoconstrictor, methoxamine, as a probe drug. Changes in the internal diameter...

The potential pharmacokinetic interaction between atovaquone and phenytoin was investigated in 12 healthy male volunteers. Each volunteer received a single 600 mg oral dose of phenytoin in the two treatment periods. On one occasion phenytoin was taken alone and on the other pre-treatment with 2000 mg atovaquone taken as two doses of 1000 mg as a mi...

1This was a multi-centre, placebo controlled, randomized, dose-escalating design study in which five dosing regimens of 619C89/placebo were evaluated in 48 stroke patients. Loading infusions of 0.5, 1, 1.5, 2 and 2.5 mg kg−1 over 1 h were followed by respective maintenance infusions of 0.25, 0.5, 0.75, 1 and 1.25 mg kg−1 over 30 min at 8 hourly int...

The primary pathophysiological event in sickling is the intracellular polymerization of deoxygenated haemoglobin S. Tucaresol (589C80;4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a substituted benzaldehyde, was designed to interact with haemoglobin to increase oxygen affinity and has been shown to inhibit sickling in vitro. We administered tuc...

The pharmacokinetics of a single oral 200 mg dose of netivudine (1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil), a nucleoside analogue under development for use in varicella zoster virus infections, were studied in 12 renal failure (RF) subjects (creatinine clearance 15 +/- 7 mL/min) and 12 age-matched healthy subjects with normal creatinine cle...

The single- and multiple-dose pharmacokinetics of and tolerability to a new microfluidized suspension of atovaquone were studied in human immunodeficiency virus-seropositive patients with CD4 counts of < or = 200 cells per mm3 in order to define a dosing regimen for the treatment of Pneumocystis carinii pneumonia. This was an open study with groups...

Valaciclovir is rapidly and extensively converted to acyclovir. In this study we investigated the potential interaction between oral valaciclovir and Maalox. On each of three occasions 18 healthy volunteers received a single oral dose of 1000 mg valaciclovir, or 30 mL Maalox 65 min after valaciclovir administration, or 30 mL Maalox 30 min before va...

1 311C90 is a novel and selective agonist at 5-HT1D receptors, with central and peripheral actions, currently in development for the acute oral treatment of migraine. 2 The pharmacokinetic and tolerability profiles of single oral doses from 1–50 mg 311C90 were investigated in 12 healthy male volunteers in a double-blind, placebo-controlled, dose-es...

To study the effects of the anti-herpetic drug netivudine on dihydropyrimidine dehydrogenase activity in elderly volunteers and to relate them to concentrations of netivudine and its metabolite 5-propynyluracil. Three groups of eight elderly volunteers received 400 or 800 mg netivudine or placebo once daily for 8 days. Plasma netivudine, 5-propynyl...

Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover...

1. Tucaresol is an orally administered antisickling agent which increases the oxygen affinity of haemoglobin. 2. The pharmacokinetics, effects on moderate graded exercise and psychometric performance of tucaresol were examined in a double-blind, placebo-controlled, parallel groups study in 12 healthy men. 3. Three doses of tucaresol were given at 4...

1. The bioavailability and disposition of 882C87, an anti-varicella zoster virus (VZV) agent, have been investigated in healthy young and elderly volunteers. 2. The mean bioavailability of a 200 mg tablet was 21.1% in the young (range 13.3-33.0%, n = 10) and 24.6% in the elderly (range 14.4-38.4%, n = 8), which is sufficient to achieve plasma conce...

447C88 (N-Heptyl-N'-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA: Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng.ml-1 (23 nM). It is poorly absorbed but 5 mg.kg-1.day-1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats. In this study, twelve h...

882C87 is a nucleoside analog with potent, specific activity against varicella-zoster virus. It is approximately seven times as potent as acyclovir with an in vitro 50% inhibitory concentration of 1 to 2 microM. The tolerability and pharmacokinetics of single doses of 882C87 have been investigated in a series of studies with healthy young and elder...

An investigator may be asked to conduct a study with a new molecular entity which has never been administered to man before, or else has only been administered to a small number of subjects in Phase I studies. Alternatively, he may undertake a trial during Phase II or III, when there is already a considerable amount of clinical data available.

This chapter is divided into five major sections starting with an attempt to dispel some of the misconceptions that many people have about computers. Next, you will be given some guidelines on how to plan for the automation of your own research environment. Before going into detail about computer hardware, we will focus on the software programs you...

Ethics is the branch of philosophy that deals with values relating to human conduct. Ethics is concerned with concepts such as good or bad. These concepts are ubiquitous elements of human life, and are therefore also present in the pursuit of knowledge through science.

Clinical studies are undertaken in order to reach some conclusion about a treatment regime, and it is generally intended that this conclusion should be widely applicable — at least, to a larger group of patients than that studied in the trial itself. The patients recruited into the study therefore constitute just a sample of all of the patients to...

The success of a clinical trial is dependent not only upon the design of a study protocol, but also upon the methods employed to ensure that clinical data are of high quality and in a suitable format for statistical analysis. These processes fall under the broad heading of ‘data handling’ and cover everything from data capture to monitoring, editin...

Even if the ethics, design, protocol and planning of a clinical research study have been considered thoroughly, and preparation is immaculate, there remains a substantial risk that the project will fail because of shortcomings in the actual conduct of the work. Problems may arise at any stage, and the following guidance clearly cannot cover all eve...

The principles of clinical research in a developing country are not different from those in a developed country. Every study must have clear objectives, a satisfactory study design and analysis and be ethical. The essential steps necessary for conduct of successful research described in detail in other chapters of this book are similar in this situ...

Communication is essential for the progress of science. Only after you have documented your work in such a way that other scientists can analyse it and build on it, is your study complete. Communication has also become important for career development, and every research worker looking for promotion is expected to present a record of successful com...

The term Good Clinical Practice (GCP) suggests that it relates to a standard of practical clinical medicine; it does not. It is a standard, or more precisely, a set of standards that have been developed for the conduct of clinical trials with investigative new drugs. These standards can actually be applied to any experimentation in humans.

A Guide to Clinical Drug Research provides practical advice, from the conception of an idea, planning a study and writing a protocol, through to the conduct of a study, data collection and analysis, and publication. It tells investigators what information they should expect sponsoring companies to provide, particularly when there is only limited in...

1. Atovaquone is a potent antiprotozoal slowly and irregularly absorbed after administration as tablets to fasting volunteers. A series of studies was performed to investigate the effects of food, bile and formulation on atovaquone absorption. 2. In 18 healthy male volunteers, a high-fat breakfast administered 45 min before 500 mg atovaquone as tab...

1. Tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid) interacts stoichiometrically with haemoglobin to increase oxygen affinity. By decreasing the proportion of insoluble deoxy sickle haemoglobin at capillary oxygen concentrations, tucaresol may be of therapeutic benefit in sickle cell anaemia. 2. In this study, which involved the...

1. PGD2 (DP)-receptors mediate inhibition of platelet aggregation and vasodilatation. If receptor reserve were greater on platelets it might be possible to separate these effects. To determine whether such a difference in receptor reserve exists, we have examined the effects of a highly selective DP-receptor partial agonist 192C86 on platelet aggre...

Some patients may experience problems swallowing large tablets such as the standard 800-mg acyclovir (Zovirax®) tablet. A new film-coated tablet has been developed to facilitate administration. When placed in a glass of water, it disintegrates in around 1.5 min forming a dispersion which the patient can drink. However, in cases where dispersion in...

Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by capsaicin in nine healthy male...

The cardiovascular effects of a novel enkephalin analogue, 443C81 (Tyr-D-Arg-Gly-Phe(4NO2)-Pro.NH2), were studied in healthy volunteers. According to a double-blind, cross-over, randomised, balanced design, six men received two different doses of 443C81 or saline as intravenous (i.v.) infusions on three occasions. Mean +/- SD plasma concentrations...

The onset of effect of acrivastine, a new H1-antagonist, has been assessed using antagonism of histamine-induced bronchoconstriction in sensitive volunteers. Acrivastine administered 30, 45, 60 or 90 min before challenge produced a right-shift of the histamine dose-response curve of at least 8-fold indicating that a clinically desired degree of H1-...

443C81 is a synthetic enkephalin thought to act on peripheral opiate receptors. The analgesic, central, cardiovascular and endocrine effects of two i.v. doses of 443C81 were investigated in 12 healthy male volunteers. Its effects were compared with those of placebo and the classical opiate dipipanone given orally using a double dummy design. 443C81...

A single oral dose of lamotrigine was administered to seven volunteers with Gilbert's Syndrome (unconjugated hyperbilirubinaemia). Plasma samples were assayed by high performance liquid chromatography (h.p.l.c.) and pharmacokinetic parameters were compared with those of a group of nine normal volunteers. In the subjects with Gilbert's Syndrome mean...

The speed of onset of H1-antagonism by 8 mg acrivastine and 60 mg terfenadine was compared by bronchial challenge of volunteers with histamine. Active treatments or placebo were administered 1 or 2 h before challenge in a double-blind, randomized, balanced crossover manner to 10 subjects. Acrivastine and terfenadine significantly attenuated the res...

We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 µg·kg−1 for 60 min and increasing to a maximum of 2.0 µg·kg−1·min−1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 1...

1 Oxidative metabolism of antipyrine (AP) was compared in 11 elderly (greater than 65 years) and 12 young (less than 40 years) volunteers. All subjects were non-smokers, consumed little if any alcohol and were in good health. 2 After a single dose of AP 500 mg, its clearance from saliva and profiles of the parent drug and its major metabolites in u...

Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross-over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of...

The analgesic activity of an opiate was studied in 12 healthy volunteers using a cold-induced pain (CP) model. Effects on the central nervous system (CNS) were also measured. According to a double-blind, randomised, balanced, cross-over design with an interval of 7 days between occasions, subjects received single oral doses of 2, 4 and 8 mg dipipan...

The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single...

Two double blind cross-over studies were performed using a submaximal effort tourniquet test (SETT) in healthy volunteers to investigate the role of endogenous opioids in placebo analgesia. In the first study IV naloxone significantly inhibited analgesia, miosis and sedation produced by the opioid dipipanone 10 mg in 12 subjects. In the second nalo...

Three double blind, placebo controlled, cross-over studies were conducted to assess the activity of analgesics in healthy volunteers using a modified submaximal effort tourniquet test (SETT). On each study day tests were performed in a silent cubicle at 21 degrees C immediately before and then hourly after drug administration. After exsanguination...

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Serum thyroxine (T4), triiodothyronine (T3), resin uptake of T3 (RT3U), thyroid stimulating hormone (TSH) and TSH response to thyrotropin releasing hormone (TRH) were measured in 92 patients treated with amiodarone for up to 4 years. Two patients developed thyrotoxicosis, while euthyroid hyperthyroxinemia occurred in 29 (32%). Hypothyroidism was di...