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Preclinical Species (preclinical + species)
Selected AbstractsSpecies-specific interaction of HIV protease inhibitors with accumulation of cholyl-glycylamido-fluorescein (CGamF) in sandwich-cultured hepatocytesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2010Zhi-wei Ye Abstract Using sandwich-cultured hepatocytes from rat, dog, pig, and human, we investigated the species-specificity of interaction of HIV protease inhibitors (PI) with in vitro hepatic accumulation of the bile salt analogue cholyl-glycylamido-fluorescein (CGamF). Extracellular sodium depletion or coincubation with the OATP/Oatp inhibitors rifampicin and digoxin revealed that about 35% of active CGamF accumulation was mediated by Ntcp/NTCP in rat and human hepatocytes, while the contribution of this sodium-dependent transporter reached 50,60% in dog and pig hepatocytes. One or more sodium-independent transporters, likely belonging to the Oatp/OATP family, constitute a major transport mechanism for CGamF accumulation. Various HIV PI (0.5, 5, 25,µM) exhibited pronounced species differences in their interaction with active CGamF accumulation (1,µM), although some similarity was observed between the dog and human interaction profiles when HIV PI were tested at 0.5,µM. Atazanavir, indinavir, and darunavir were the most potent inhibitors of CGamF accumulation in human hepatocytes. Potent inhibition of CGamF accumulation by ritonavir in rat hepatocytes contrasted with a weak effect in human hepatocytes. Thorough characterization of in vitro disposition of probe substrates in preclinical species compared to human hepatocytes will ultimately support a better insight in species-specific mechanisms underlying drug interactions and drug-mediated toxicity. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2886,2898, 2010 [source] Application of Genomics in Preclinical Drug Safety EvaluationBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2006Peter G. Lord Toxicologists have traditionally gathered pathological, morphological, chemical and biochemical information from in vivo studies of preclinical species in order to assess drug safety and to determine how new drugs can be safely administered to the human patient population. In recent years the emerging "-omics" technologies have been developed and integrated into preclinical studies in order to better assess drug safety by gaining information on the cellular and molecular events underlying adverse drug reactions. Genomics approaches in particular have become readily available and are being applied in several stages of drug development. The burgeoning literature on what has become known as "toxicogenomics" has for the most part highlighted successful applications of gene expression profiling in predictive toxicology, enabling decisions to be made on the developability of a compound early in the drug development process. It is also becoming apparent that toxicogenomic approaches are good starting points to develop experiments designed to gain a mechanistic insight into drug toxicities within and across species. Gene expression arrays permit the measurement of responses of essentially all the genes in the entire genome to be monitored, and knowledge of the function of the genes affected can identify the potential mechanisms to then be confirmed using conventional biochemical, toxicological and pathological approaches. As toxicologists put these technologies into practice they build up a knowledge base to better characterize toxicities at the molecular level and to make the search for much needed, novel biomarkers of toxicity more achievable. [source] Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisitedBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2010Weirong Wang Abstract In this report, the utility of a commonly used interspecies scaling method to predict the systemic clearance (CL) of therapeutic proteins in humans was evaluated. Based on analysis of a pharmacokinetic data set of 34 therapeutic proteins, including 12 monoclonal antibodies (mAbs) and Fc fusion proteins, human CL can generally be predicted reasonably well with simple allometric scaling and a fixed exponent of 0.8:,95% of the cases predicted values within 2-fold of the observed values when using CL data from multiple species, or,90% simply using CL from monkeys. Specific to mAbs/Fc fusion proteins, scaling from monkey CL using a fixed exponent of 0.8 gave an excellent prediction; all predicted CL values were within 2-fold of the corresponding observed values. Compared with the simple allometric scaling method that uses a fitted exponent from CL data of ,3 preclinical species, the fixed exponent approach with 1,2 preclinical species is simple, resource-saving and minimizes systematic bias. Together with its overall satisfactory prediction accuracy, especially in the absence of non-linear pharmacokinetics and species-specific clearance mechanisms, this fixed exponent method affords a viable alternative to other published allometric methods, including the Rule of Exponents (ROE). Copyright © 2010 John Wiley & Sons, Ltd. [source] Integrated strategies for assessment of metabolite exposure in humans during drug development: analytical challenges and clinical development considerationsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2009Mingshe Zhu Abstract Monitoring the exposure of a drug and its metabolites in humans and preclinical species during drug development is required to ensure that the safety of drug-related components in humans are adequately assessed in the standard toxicology studies. Recently published FDA guidance on metabolites in safety testing (MIST) has generated broad discussion from various perspectives. Most of the opinions and experiences shared among the scientific community are scientifically sound and practical. There are various approaches to assess the metabolite exposure margin between toxicology species and humans: either by direct or indirect comparison or by qualitative or quantitative comparison. The choice of when and how to pursuit metabolite assessment is based on the overall development strategy of the compound. Therefore, it is important to understand the utility and limitations of analytical instruments in order to apply an appropriate analytical tool to address specific questions posed at different stages of drug development. The urgency of metabolite monitoring depends on the intrinsic nature of the compound, therapeutic intent and objective of the clinical development. The strategy for assessing metabolite exposure in humans should be a holistic approach considering clinical situations and cumulative knowledge of the metabolism of the drug in order to appropriately address metabolite safety in humans. A one-size-fits-all approach is rarely the best use of resources. Copyright © 2009 John Wiley & Sons, Ltd. [source] Human radiolabeled mass balance studies: objectives, utilities and limitationsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2009Natalia Penner Abstract The determination of metabolic pathways of a drug candidate through the identification of circulating and excreted metabolites is vitally important to understanding its physical and biological effects. Knowledge of metabolite profiles of a drug candidate in animals and humans is essential to ensure that animal species used in toxicological evaluations of new drug candidates are appropriate models of humans. The recent FDA final guidance recommends that human oxidative metabolites whose exposure exceeds 10% of the parent AUC at steady-state should be assessed in at least one of the preclinical animal species used in toxicological assessment. Additional toxicological testing on metabolites that have higher exposure in humans than in preclinical species may be required. The metabolite profiles in laboratory animals and humans are generally accomplished by mass balance and excretion studies in which radiolabeled drugs are administered to these species. The biological fluids are collected, analysed for total radioactivity and evaluated for a quantitative profile of metabolites. Thus, these studies not only determine the rates and routes of excretion but also provide very critical information on the metabolic pathways of drugs in preclinical species and humans. In addition, these studies are required by regulatory agencies for the new drug approval process. Despite the usefulness of these radiolabeled mass balance studies, there is little concrete guidance on how to perform or assess these complex studies. This article examines the objectives, utilities and limitations of these studies and how these studies could be used for the determination of the metabolite exposure in animals and humans. Copyright © 2009 John Wiley & Sons, Ltd. [source] Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compoundsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2008Aberra Fura Abstract The oral pharmacokinetics (concentration-time profile) of four proprietary compounds in humans were predicted using the Cvss - MRT method. The first step was to demonstrate superposition of intravenous (i.v.) pharmacokinetic profiles of preclinical species following mathematical transformation of their respective concentration-time curves using the corresponding Cvss (where Cvss=dose/Vss; Vss is the volume of distribution at steady state) and mean residence time (MRT) values. The resultant profiles were then back-transformed to estimate human i.v. plasma concentration-time profiles using human Cvss and MRT values. Human Cvss and MRT values were estimated from projected human Vss and CL values. Projection of CL was based on scaled (in vitro) metabolic clearance, simple allometry with and without various correction factors and the unbound fraction corrected intercept method. Vss values were estimated by allometric scaling with and without correction for interspecies differences in plasma protein binding. The predicted human i.v. profiles, in combination with the estimated mean absorption rate constants and bioavailability, were then used to simulate the oral pharmacokinetics in human using one- or multi-compartment kinetic models. Overall, with this approach, key oral pharmacokinetic parameters such as AUC, Cmax, Cmin and oral plasma T½ were projected to be within two-fold of the actual values in humans. Copyright © 2008 John Wiley & Sons, Ltd. [source] Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine, a novel and selective p38, inhibitor: identification of an active metabolite in preclinical species and human liver microsomesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2006Amit S. Kalgutkar Abstract The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38,, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vdss) ranging from 0.4,1.3 l/kg (2.4,26 l/m2) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m2) and Sprague-Dawley rats (7.65±1.08 ml/min/kg, 45.9±6.48 ml/min/m2 in male rats and 3.15±0.27 ml/min/kg, 18.9±1.62 ml/min/m2 in female rats) and moderate in beagle dogs (12.3±5.1 ml/min/kg, 246±102 ml/min/m2) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30,65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38, in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (fu,0.1,0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC50>50 µM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent. Copyright © 2006 John Wiley & Sons, Ltd. [source] Pharmacokinetics of SB-247083, a potent and selective endothelinA receptor antagonist, in the rat, dog, and monkeyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2002Keith W. Ward Abstract The endothelins (ET) are among the most potent vasoconstrictors identified to date, and have been implicated in such diseases as renal failure, pulmonary hypertension, atherosclerosis, and congestive heart failure. There is currently interest in developing selective antagonists of the ET-A subtype receptor, and one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4-chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2-propionic acid). This investigation was conducted to evaluate the preclinical pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the rat and monkey, and high in the dog. Oral bioavailability of SB-247083 administered as a solid formulation of the free acid was 24% in the rat, but low in the dog (4%) and the monkey (2%). An extensive in vitro salt form and formulation screen resulted in the identification of a formulation containing the monoarginyl salt with improved dissolution properties. This formulation provided a 2- to 4-fold increase in oral bioavailability in each of the preclinical species. In the dog, this improvement was reversed by the pre-administration of 0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that SB-247083 may have suitable drug properties for progression in development. Copyright © 2002 John Wiley & Sons, Ltd. [source] | ||||||||||