A microdose study of 14C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung

Lappin, Graham; Boyce, Malcolm; Matzow, Torkjel; Lociuro, Sergio; Seymour, Mark; Warrington, Steve

doi:10.1007/s00228-013-1528-2

Cited by 17 publications

(27 citation statements)

References 28 publications

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“…To evaluate the pharmacokinetics of GP-4 in rodents at a microdose and a pharmacological dose, rats (n ϭ 3) were administered a single intravenous dose of 0.01 mg/kg of body weight or 3.0 mg/kg 14 C-labeled GP-4 (specific activities, 353 Ci/mmol and 1.26 Ci/mmol, respectively) formulated in 20% Captisol in 0.05 M methanesulfonic acid, pH 3.5. The use of one microdose concentration and one therapeutic concentration for this study is in accordance with the characteristics of previous microdosing studies as well as with the guidelines set forth by the U.S. Food and Drug Administration (FDA) for microdosing studies (5,7,18,19). Following dose administration, whole-blood samples (approximately 0.3 ml) were collected from each animal via the jugular vein at 0, 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h postdose and placed into Microtainer tubes coated with lithium heparin (Becton Dickinson, Franklin Lakes, NJ), and the tubes were placed on ice.…”

Section: Chemicals and Reagentsmentioning

confidence: 84%

“…Microdosing is used to downselect among multiple new chemical entities, to obtain preliminary human pharmacokinetic information for investigational new drugs early in the development process, and to confirm in vitro or in silico metabolic pathways in vivo (4)(5)(6)(7). It should be noted that microdosing provides no data on the efficacy or safety of the drug candidate.…”

mentioning

confidence: 99%

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Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

Malfatti

Lao

Ramos

et al. 2014

Antimicrob Agents Chemother

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Determining the pharmacokinetics (PKs) of drug candidates is essential for understanding their biological fate. The ability to obtain human PK information early in the drug development process can help determine if future development is warranted. Microdosing was developed to assess human PKs, at ultra-low doses, early in the drug development process. Microdosing has also been used in animals to confirm PK linearity across subpharmacological and pharmacological dose ranges. The current study assessed the PKs of a novel antimicrobial preclinical drug candidate (GP-4) in rats as a step toward human microdosing studies. Dose proportionality was determined at 3 proposed therapeutic doses (3, 10, and 30 mg/kg of body weight), and PK linearity between a microdose and a pharmacological dose was assessed in Sprague-Dawley rats. Plasma PKs over the 3 pharmacological doses were proportional. Over the 10-fold dose range, the maximum concentration in plasma and area under the curve (AUC) increased 9.5-and 15.8-fold, respectively. PKs from rats dosed with a 14 C-labeled microdose versus a 14 C-labeled pharmacological dose displayed dose linearity. In the animals receiving a microdose and the therapeutically dosed animals, the AUCs from time zero to infinity were 2.6 ng · h/ml and 1,336 ng · h/ml, respectively, and the terminal half-lives were 5.6 h and 1.4 h, respectively. When the AUC values were normalized to a dose of 1.0 mg/kg, the AUC values were 277.5 ng · h/ml for the microdose and 418.2 ng · h/ml for the pharmacological dose. This 1.5-fold difference in AUC following a 300-fold difference in dose is considered linear across the dose range. On the basis of the results, the PKs from the microdosed animals were considered to be predictive of the PKs from the therapeutically dosed animals.T he development of new drugs is a long and costly process, often taking more than 10 years and over $1 billion to get one drug to market (1). The huge cost of new drugs is a consequence of the high failure rate of potential candidates prior to approval. One of the factors contributing to the high attrition rate during development is poor pharmacokinetics (PKs). Poor PK parameters are responsible for up to 40% of drug candidates failing to make it past the first studies in humans (2, 3). The ability to predict complete biodistribution profiles, which include PKs, tissue distribution, and route of elimination, early in the drug development process would provide critical data for decisions about the continued development of a drug lead. These data are also useful for the optimization of dosage regimes, potentiation of therapeutic efficacy, tailoring of drug delivery systems, and evaluation of safety. Early evaluation of these factors in humans would determine if further development is warranted before the initiation of costlier clinical trials.Microdosing is a technique used to assess a compound's in vivo biological fate through the administration of subpharmacological doses of a 14 C-labeled drug candidate that produce virtually no adver...

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Section: Chemicals and Reagentsmentioning

confidence: 84%

mentioning

confidence: 99%

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

Malfatti

Lao

Ramos

et al. 2014

Antimicrob Agents Chemother

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“…In Figure 11.2b, drug concentrations in bronchial mucosa biopsy samples and plasma are shown from a microdose study of drug being developed to treat respiratory infections. 53 In the same study bronchoalveolar lavage samples were obtained. Extracts of these were analysed by HPLC followed by AMS analysis.…”

Section: Microdosing and Drug Targetingmentioning

confidence: 99%

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

Garner¹

2014

Human-Based Systems for Translational Research

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There is an urgent need to accelerate the development of new drugs to treat unmet medical needs both in the developed and underdeveloped parts of the world. There is also an urgent need to improve the efficiency of drug development through time and cost reduction because development costs hinder the introduction of new therapies. There are many life-threatening human diseases that still require better therapies including cancer, bacterial and viral infection and lifestyle-associated diseases. The costs of bringing a drug to market are so high that there are very few organisations able to afford to discover, develop and introduce drugs on their own. Estimates of drug development costs vary between US$1.2 and 12.0 billion dollars, making the costs of newly approved drugs very high in order that companies can recover the costs of all the failed drugs in their pipelines. 1,2 It has been estimated that only three out of 10 drugs make a return on their investment and that over 99% of molecules researched by a pharmaceutical company are likely to fail at some point during the development process. 3 Even when a drug enters into RSC Drug Discovery Series No. 41 Human-based Systems for Translational Research Edited by Robert Coleman

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“…Individual stool samples are collected predose and throughout the cohort study period, and postdose faeces samples are subsequently pooled into 24‐h collection periods. Collection of other samples, such as cerebrospinal fluid and tissue biopsies, is also possible and may be included in order to address project‐specific questions such as whether the compound (and/or its metabolites) are present at the site of action (for example in lung tissues).…”

Section: Clinical Study Designmentioning

confidence: 99%

Adding value through accelerator mass spectrometry‐enabled first in human studies

Seymour

2016

Labelled Comp Radiopharmac

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Accelerator mass spectrometry (AMS) is an ultra-sensitive technique for the analysis of radiocarbon. It is applicable to bioanalysis of any C-labelled analyte and any sample type. The increasing body of data generated using LC+AMS indicates that the methodology is robust and reliable, and capable of meeting the same validation criteria as conventional bioanalytical techniques. Because it is a tracer technique, AMS is capable of discriminating between an administered radiolabelled dose and endogenous compound or non-radiolabelled compound administered separately. This paper discusses how it can be used to enhance the design of first in human (FIH) clinical studies and generate significant additional data, including: fundamental pharmacokinetics (CL and V), absolute bioavailability, mass balance, routes and rates of excretion, metabolic fate (including first-pass metabolism, identification of biliary metabolites and quantitative data to address metabolite safety testing issues), and tissue disposition of parent compound and metabolites. Because the C-labelled microtracer dose is administered at the same time as a pharmacologically relevant non-radiolabelled dose, there is no concern about dose-linearity. However the mass of the microtracer dose itself is negligible and therefore does not affect the outcome of the FIH study. The addition of microtracer doses to a FIH study typically requires little additional expense, apart from the AMS analytics, making the approach cost-effective. It can also save significant time, compared to conventional approaches, and, by providing reliable human in vivo data as early as possible, prevent unnecessary expenditure later in drug development.

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A microdose study of 14C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung

Cited by 17 publications

References 28 publications

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

Adding value through accelerator mass spectrometry‐enabled first in human studies

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