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Biomedical subjects

Dennis A Smith

Publications and source records attributed to Dennis A Smith.

17 recordsLinked to original sources
PubMed2006

R&D technology investments: misguided and expensive or a better way to discover medicines?

The pharmaceutical industry is in crisis owing to spiralling costs and a lack of new product launches. It is said that expensive investments in technology have not paid off. But is this really true? In this review, we explore some of the recent medicines that were, or are being, brought to market, and we discuss how they were discovered and what difference new technologies have made during the discovery of these medicines.

Drug Industry↗
PubMed2006

Metabolites and safety: What are the concerns, and how should we address them?

The issue of the safety of drug metabolites in humans is a complex one. In this commentary, a proposal is made regarding how to deal with drug metabolites observed in humans such that the safety of these molecules can be assured. The human radiolabeled ADME study, in which metabolites are identified and quantified in circulation and excreta, is proposed as the primary source of information on human metabolites from which decisions can be made regarding the need for further risk assessment. Although radiolabel ADME studies yield quantitative metabolite profiles that are commonly reported as a percentage of the total drug related material (for circulating metabolites) and a percentage of total dose (for excretory metabolites), it is essential to convert these values into absolute abundances. The structure of a metabolite, its abundance, the biofluid in which it is observed (circulation or excreta), and the toxicity mechanism of concern serve as the four most important characteristics for determination as to whether further safety consideration is warranted. Metabolites in circulation require consideration for toxicity that can arise by effects on specific receptors and/or enzymes (either target or off-target). Metabolites in excreta require consideration for their potential to indicate a body-burden to chemically reactive intermediary metabolites, which can yield toxicities of nonspecific mechanisms commonly associated with covalent binding (e.g., carcinogenicity, immunoallergic response, etc.). Through an analysis of 24 drugs removed from the market because of human toxicity, it was concluded that further testing of human metabolites would not have yielded any additional information that could have predicted human safety findings because human metabolites would have been present in the animal species routinely used in toxicology testing after the administration of the parent compound.

Animals↗
PubMed2006

Drug withdrawals and the lessons within.

Drug withdrawals over recent decades have triggered changes in the way that drug targets and screening programs are researched and designed. In the cases having the greatest impact, the reason for withdrawal was the reversible interaction of a drug or its metabolite with a single receptor, ion channel or enzyme (primary or secondary pharmacology). Once this interaction is identified, screens can be established and validated. When the mechanism is complex (eg, organ toxicity), however, such screens are difficult to implement and usually examine only the initial step, leading to considerable problems in extrapolation and risk definition. This review classifies drugs withdrawn from the US market over the last 25 years by their reasons for withdrawal, and examines how drug discovery programs have been modified in response to these events.

Animals↗
PubMed2005

Oral delivery of G protein-coupled receptor modulators: an explanation for the observed class difference.

G protein-coupled receptors (GPCRs) represent important targets for drug intervention. However, analysis of GPCR modulator drugs exhibits an important class difference, with many drugs available against aminergic GPCR targets, but relatively few against non-aminergic targets. The reason for this is that commonly drugs mimic the physicochemistry of the receptor ligand. Aminergic ligands generally exhibit physicochemical properties (molecular weight, lipophilicity and hydrogen bonding potential) that are consistent with extensive oral absorption. In contrast, non-aminergic ligands generally exhibit physicochemical properties that are at odds with oral delivery. Thus, combining required potency versus the receptor, with oral delivery potential is a significant challenge, and drug discovery becomes a question of finding the exceptional compound that lies at the edge of ADME space.

Administration, Oral↗
PubMed2005

Keynote review: Is declining innovation in the pharmaceutical industry a myth?

Increasing the rate of innovation is a requirement to achieve much-needed advances in patient care, as well as to secure the future of the pharmaceutical industry. Currently, there is a perception in the external environment that pharmaceutical R&D is no longer innovative, fails to bring new drugs to market or, at best, produces a rising number of 'me-too' drugs with no advantage over existing treatments. In addition, the cost to discover and develop new medicines (i.e. cost per launch) has risen dramatically in recent years. The quoted development cost per medicine is a reality, and is not disputed here. However, data are provided that demonstrate that with regard to innovation rates, the current perception is wrong - although there have been, and continue to be, fluctuations in drug launches, there has been a steady increase in the number of new chemical entities launched, both in absolute numbers of FDA-approved medicines and in the proportion of priority reviews.

Cost-Benefit Analysis↗
PubMed2005

Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing.

Recent attention has been given to the potential roles that metabolites could play in safety evaluations of new drugs. In 2002, a proposal was published on "metabolites in safety testing" ("MIST"), which suggested some guidelines regarding when it is necessary to provide greater assessment of the safety of metabolites. However, this proposal was based on relative abundance values, i.e., the percentage that a metabolite comprises of total exposure to drug-related material. In the present commentary, we propose that absolute abundance criteria be used rather than relative abundance. The absolute abundance of a metabolite in circulation or excreta in humans should be combined with other information regarding the chemical structure of the metabolite (e.g., similarity to the parent drug, presence of chemically reactive substituents) and potential mechanisms of toxicity (e.g., suprapharmacological effects, secondary pharmacological effects, nonspecific effects). Decision trees are described that can be used to address human metabolites in safety testing.

Animals↗
PubMed2005

Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV.

UK-427,857 (4, 4-difluoro-N-[(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]cyclohexanecarboxamide) is a novel CCR5 antagonist undergoing investigation for use in the treatment of human immunodeficiency virus (HIV) infection. Pharmacokinetic and metabolism studies have been performed in mouse, rat, dog, and human after single and multiple administration by oral and intravenous routes. The compound has physicochemical properties that are borderline for good pharmacokinetics, being moderately lipophilic (log D(7.4) 2.1) and basic (pK(a) 7.3), possessing a number of H-bonding functionalities, and with a molecular weight of 514. The compound was incompletely absorbed in rat (approximately 20-30%) but well absorbed in dog (>70%). Based on in vitro studies in Caco-2 cells, UK-427,857 has relatively poor membrane permeability, and transcellular flux is enhanced in the presence of inhibitors of P-glycoprotein. Further evidence for the involvement of P-glycoprotein in restricting the oral absorption of UK-427,857 was obtained in P-glycoprotein null mice (mdr1a/mdr1b knockout). In these animals, AUC after oral administration was 3-fold higher than in control animals. In oral dose escalation studies in humans, the compound demonstrated nonlinear pharmacokinetics, with increased dose-normalized exposure with increased dose size, consistent with saturation of P-glycoprotein. The oral dose-exposure relationship of UK-427,857 in humans was not reflected in either rat or dog. In animal species and humans, UK-427,857 undergoes some metabolism, with parent compound the major component present in the systemic circulation and excreta. Elimination of radioactive dose was primarily via the feces. In rat, parent compound was secreted via bile and directly into the gastrointestinal tract. Metabolites were products of oxidative metabolism and showed a high degree of structural consistency across species.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios.

Glucuronidation is a listed clearance mechanism for 1 in 10 of the top 200 prescribed drugs. The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans. Spurred on by interest in developing potent and selective inhibitors for improved confidence around UGT reaction phenotyping, and the increased availability of recombinant forms of human UGTs, several recent studies have reported in vitro inhibition of UGT enzymes. In some cases, the observed potency of UGT inhibitors in vitro has been interpreted as having potential relevance in humans via pharmacokinetic drug-drug interactions. Although there are reported examples of clinically relevant drug-drug interactions for UGT substrates, exposure increases of the aglycone are rarely greater than 100% in the presence of an inhibitor relative to its absence (i.e., AUCi/AUC < or = 2). This small magnitude in change is in contrast to drugs primarily cleared by cytochrome P450 enzymes, where exposures have been reported to increase as much as 35-fold on coadministration with an inhibitor (e.g., ketoconazole inhibition of CYP3A4-catalyzed terfenadine metabolism). In this article the evidence for purported clinical relevance of potent in vitro inhibition of UGT enzymes will be assessed, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data on the pharmacokinetic drug-drug interactions of drugs primarily cleared by glucuronidation.

Animals↗
PubMed2004

Is pharmaceutical R&D just a game of chance or can strategy make a difference?

The pharmaceutical industry is currently experiencing turbulent, yet exciting times. Despite widely expressed negative sentiments regarding productivity there are now signs that innovation could yet win the day and bring a fresh wave of breakthrough drugs. Nowhere is this truer than for oncology, which previously was dominated by cytotoxic drugs. Today, however, this field shows exciting progress with the emergence of kinase inhibitors, as well as various antibody-based mechanistic approaches. Similarly, new drug mechanisms have transformed HIV therapy. Are these chance events, or have they come about through strategy? Here, we argue that a complex interplay of chance and strategy is at work in pharmaceutical R&D, separated in time by 10 years or more.

Anti-HIV Agents↗
PubMed2002

Discovery, innovation and the cyclical nature of the pharmaceutical business.

Unlike many recent articles, which paint the future of the pharmaceutical industry in gloomy colours, this article provides an optimistic outlook. It explores the foundations on which the pharmaceutical industry has based its outstanding successes. Case studies of important drug classes underpin the arguments made and provide the basis for the authors' argument that recent technological breakthroughs and the unravelling of the human genome will provide a new wave of high quality targets (substrate) on which the industry can build. The article suggests that in a conducive environment that understands the benefits that pharmaceuticals provide to healthcare, those players who can base their innovation on a sufficient scale and from a large capital base will reshape the industry.

Drug Design↗