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Lappin G.,University of Lincoln | Boyce M.J.,Hammersmith Medicines Research | Matzow T.,Hammersmith Medicines Research | Seymour M.,Xceleron Inc. | Warrington S.J.,Hammersmith Medicines Research
European Journal of Clinical Pharmacology | Year: 2013

Purpose: To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection. Methods: Four healthy men each received two single, 100 μg microdoses of 14C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of 14C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 μg microdose of 14C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS. Results: After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8-12 h after IV dosing, 14C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, 14C was still mostly associated with AR-709 at 12 h after dosing. Conclusions: The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary. © 2013 Springer-Verlag Berlin Heidelberg.


Tse S.,Pfizer | Leung L.,Pfizer | Raje S.,Collegeville | Seymour M.,Xceleron Inc. | And 3 more authors.
Drug Metabolism and Disposition | Year: 2014

Cerlapirdine (SAM-531, PF-05212365) is a selective, potent, full antagonist of the 5-hydroxytryptamine 6 (5-HT6) receptor. Cerlapirdine and other 5-HT6 receptor antagonists have been in clinical development for the symptomatic treatment of Alzheimer's disease. A human absorption, distribution, metabolism, and excretion study was conducted to gain further understanding of the metabolism and disposition of cerlapirdine. Because of the low amount of radioactivity administered, total 14C content and metabolic profiles in plasma, urine, and feces were determined using accelerator mass spectrometry (AMS). After a single, oral 5-mg dose of [14C]cerlapirdine (177 nCi), recovery of total 14C was almost complete, with feces being the major route of elimination of the administered dose, whereas urinary excretion played a lesser role. The extent of absorption was estimated to be at least 70%. Metabolite profiling in pooled plasma samples showed that unchanged cerlapirdine was the major drug-related component in circulation, representing 51% of total 14C exposure in plasma. One metabolite (M1, desmethylcerlapirdine) was detected in plasma, and represented 9% of the total 14C exposure. In vitro cytochrome P450 reaction phenotyping studies showed that M1 was formed primarily by CYP2C8 and CYP3A4. In pooled urine samples, three major drug-related peaks were detected, corresponding to cerlapirdine-N-oxide (M3), cerlapirdine, and desmethylcerlapirdine. In feces, cerlapirdine was the major 14C component excreted, followed by desmethylcerlapirdine. The results of this study demonstrate that the use of the AMS technique enables comprehensive quantitative elucidation of the disposition and metabolic profiles of compounds administered at a low radioactive dose. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.


Lappin G.,Xceleron Ltd | Seymour M.,Xceleron Ltd | Young G.,Glaxosmithkline | Higton D.,Astrazeneca | Hill H.M.,Huntingdon Life science
Bioanalysis | Year: 2011

A technique has emerged in the past few years that has enabled a drug's intravenous pharmacokinetics to be readily obtained in humans without having to conduct extensive toxicology studies by this route of administration or expend protracted effort in formulation. The technique involves the intravenous administration of a low dose of 14C-labelled drug (termed a tracer dose) concomitantly with a non-labelled extravascular dose given at therapeutically levels. Ces collected over time are analysed to determine the total parent drug concentration by LC-MS (which essentially measures that arising from the oral dose) and by LC followed by accelerator mass spectrometry (AMS) to determine the 14C-drug concentration (i.e., that arising from the intravenous dose). There are currently no published accounts of how the principles of bioanalytical validation might be applied to intravenous studies using AMS as an analytical technique. The authors describe the primary elements of AMS when used with LC seperation and how this off-line technique differs from LC-MS. They then discuss how the principles of bioanalytical validation might be applied to determine selectivity, accuracy, precision and stability of methods involving LC followed by AMS analysis. © 2011 Future Science Ltd.


Higton D.,RedX Anti Infectives Ltd | Seymour M.,Xceleron Inc
Bioanalysis | Year: 2014

Since its introduction into the drug-development arena, accelerator mass spectrometry (coupled with liquid chromatography fractionation) has been used to support a variety of study types. The uses to which the technique has been put include parent and/or metabolite quantification in pharmacokinetic studies, total radioactivity measurement in adsorption, metabolism and excretion studies, and quantitative metabolite profiling. A tiered approach has been applied to the verification of accelerator mass spectrometry assays, dependant on in which type of study and at what stage of drug development they are used. As accelerator mass spectrometry is an absolute detector that can quantify without the use of analyte-related standards, the specific assay verification requirements differ from those for LC-MS/MS assays. This article describes when screening, qualified and validated assay verification procedures should be applied, and suggests what parameters should be assessed in each case. © 2014 Future Science Ltd.


Simpson M.,Xceleron Ltd | Lappin G.,Xceleron Inc. | Keely B.J.,University of York
Bioanalysis | Year: 2010

Background: A microdose study was performed where 50 μg R/S- 14C-verapamil was dosed intravenously to human volunteers. In order to quantify the individual R- and S-enantiomers in human plasma a 2D chiral HPLC method with subsequent analysis by accelerator mass spectrometry was verified. Results: R/S-verapamil was separated on a C18 column and the isolated fraction was applied to a chiral column where the verapamil enantiomers were separated. Experimental recovery (∼73% [coefficient of variation {CV} = 16%] and 66% [CV = 21%] for R- and S-verapamil, respectively) was accounted for by the use of internal standardization from the fluorescence response of nonlabeled R- and S-verapamil. The precision of the assay ranged from 4.1 to 15.9% CV and the limit of quantitation was 1.95-4.81 pg/ml for R-verapamil and 1.76-3.34 pg/ml for S-verapamil. Conclusion: This method was successfully applied to the analysis of R- and S-verapamil in human plasma. © 2010 Future Science Ltd.


Garner R.C.,Xceleron Ltd. | Garner R.C.,University of York
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2010

The enabling technology of accelerator mass spectrometry (AMS) permits ultrasensitive analysis of14C in the attogram to zeptogram range. As a result AMS analysis is being used in drug development to measure drug concentrations from human clinical studies conducted with very low amounts (nanoCuries) of administered radiolabel. The administered radiolabel can be at high specific radioactivity as in Phase 0 microdose studies or at much lower specific radioactivity as in metabolite profiling/mass balance and absolute bioavailability studies. Each of these study designs can give essential human ADME/PK information enabling drugs to be developed more effectively than using conventional approaches. Copyright © 2010 John Wiley & Sons, Ltd.


Croft M.,Xceleron Ltd. | Croft M.,University of York | Keely B.,University of York | Morris I.,University of York | And 2 more authors.
Clinical Pharmacokinetics | Year: 2012

Objective: The aim of this crossover human male volunteer study was to investigate the utility of microdosing in the investigation of drug-drug interactions. Methods: A mixture of midazolam, tolbutamide, caffeine and fexofenadine were administered as a microdose (25μg each) before and after administration of a combined pharmacological dose of ketoconazole (400 mg) and fluvoxamine (100 mg) to inhibit P-glycoprotein and metabolism by cytochrome P450 (CYP) 1A2, CYP3A4 and CYP2C9. Results: When administered alone, pharmacokinetics for all four microdosed compounds scaled well with those reported for therapeutic doses and with previously performed microdose studies. The pharmacokinetics of each compound administered as a microdose were significantly altered after the administration of ketoconazole and fluvoxamine, showing statistically significant (p<0.01) 12.8-, 8.1- and 3.2-fold increases in the area under the plasma concentration-time curve from time zero to infinity (AUC∞) for midazolam, caffeine and fexofenadine, respectively. A 1.8-fold increase (not statistically significant) in AUC∞ was observed for tolbutamide. The changes in pharmacokinetics mediated by ketoconazole and fluvoxamine were quantitatively consistent with previously reported, non-microdose, drug-drug interaction data from studies including the same compounds. Conclusion: The initial data reported here demonstrate the utility of microdosing to investigate the risk of development drugs being victims of drug-drug interactions. © 2012 Adis Data Information BV. All rights reserved.


The background to human microdosing or Phase 0 studies is reviewed, focusing particularly on the information that such studies can provide in the context of exploratory clinical development. Examples are provided of the microdose-validation studies known as the Consortium for Resourcing and Evaluating AMS Microdosing trial and EU Microdosing AMS Partnership Programme, which demonstrated that there was good dose proportionality between microdose and pharmacological dose pharmacokinetics. When microdosing was applied to ten development drugs, it was found that all ten molecules showed dose proportionality between the microdose and the pharmacological dose. The majority of microdose studies have used accelerator mass spectrometry (AMS) analysis and only these studies that are considered here; AMS provides information on all metabolites, even if these are minor. There is now sufficient scientific data to justify microdose studies being routinely conducted as part of the drug-development process. © 2010 Future Science Ltd.


Lappin G.,Xceleron Ltd | Seymour M.,Xceleron Ltd
Bioanalysis | Year: 2010

Active drug metabolites formed in humans but present in relatively low abundance in preclinical species can lead to unpredicted adverse effects during clinical use. The regulatory guidelines in recent years have therefore required that the metabolism of a drug be quantitatively compared between preclinical species and human at the earliest practicable stage of drug development. Amongst the variety of methods available, inclusion of low radioactive doses of 14C drug in first-in-man studies coupled to the sensitive analytical technology of accelerator MS (AMS) has found utility. Measurement of 14C by AMS allows for quantification of metabolites, even if their structures are unknown, and, when used in conjunction with LC-MS, can provide both quantitative and structural data. This review examines a typical approach to using AMS and associated analytical methods in addressing the regulatory guidelines and discusses a number of possible scenarios including the question of steady state. © 2010 Future Science Ltd.


Lappin G.,Xceleron Inc.
Bioanalysis | Year: 2010

The concept of microdosing has been around for approximately 10 years. In this time there have been an increasing number of drugs reported in the literature where the pharmacokinetics at a microdose have been compared with those observed at a therapeutic dose. Currently, approximately 80% of the microdose pharmacokinetics available in the public domain have been shown to scale to those observed at a therapeutic dose, within a twofold difference. Microdosing is now being extended into areas of drug development other than purely pharmacokinetic prediction. Microdosing has been applied to the study of drug-drug interactions by giving human volunteers a microdose of the candidate drug before and after the administration of a drug known to inhibit or induce certain enzymes, such as the cytochrome P450s. Early data on the metabolism of a drug candidate can be obtained by administering a 14C-drug to human volunteers and comparing the plasma concentration-time curves for total 14C and unchanged parent compound. Full metabolic profiles can be generated as an early indication of the drug's metabolism in humans, prior to Phase 1 clinical studies. Microdosing is also being applied to situations where the concentration of a drug in cell or tissue types is key to its efficacy. The application of microdosing as a tool in drug development is therefore widening into new and previously unforeseen fields. © 2010 Future Science Ltd.

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