Applications of Accelerator Ms in Pediatric Drug Evaluation

Vuong, LT; Blood, Arlin B.; Js, Vogel; Anderson, M. Eric; Goldstein, Burton J.

doi:10.4155/bio.12.173

Cited by 28 publications

(42 citation statements)

References 22 publications

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“…67 The results from the much more comprehensive PAMPER study will provide procedures and methods to microdose development drugs.…”

Section: Use In Paediatric Studiesmentioning

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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“…67 The results from the much more comprehensive PAMPER study will provide procedures and methods to microdose development drugs.…”

Section: Use In Paediatric Studiesmentioning

confidence: 99%

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

Garner¹

2014

Human-Based Systems for Translational Research

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“…Microdosing is an elegant new method to minimize burden and risk in PK studies in children [88]. It uses a sub-therapeutic, extremely low dose of drug, known as a microdose (e.g., 1/100th of the therapeutic dose) [89,90].…”

Section: Microdosing Studiesmentioning

confidence: 99%

Ethics of Drug Research in the Pediatric Intensive Care Unit

et al. 2014

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Critical illness and treatment modalities change pharmacokinetics and pharmacodynamics of medications used in critically ill children, in addition to age-related changes in drug disposition and effect. Hence, to ensure effective and safe drug therapy, research in this population is urgently needed. However, conducting research in the vulnerable population of the pediatric intensive care unit (PICU) presents with ethical challenges. This article addresses the main ethical issues specific to drug research in these critically ill children and proposes several solutions. The extraordinary environment of the PICU raises specific challenges to the design and conduct of research. The need for proxy consent of parents (or legal guardians) and the stress-inducing physical environment may threaten informed consent. The informed consent process is challenging because emergency research reduces or even eliminates the time to seek consent. Moreover, parental anxiety may impede adequate understanding and generate misconceptions. Alternative forms of consent have been developed taking into account the unpredictable reality of the acute critical care environment. As with any research in children, the burden and risk should be minimized. Recent developments in sample collection and analysis as well as pharmacokinetic analysis should be considered in the design of studies. Despite the difficulties inherent to drug research in critically ill children, methods are available to conduct ethically sound research resulting in relevant and generalizable data. This should motivate the PICU community to commit to drug research to ultimately provide the right drug at the right dose for every individual child.

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“…The increased availability and acceptance of AMS within the pharmaceutical industry (Smith 2011;Iyer et al, 2012;Lappin et al, 2012;Vuong et al, 2012;Bowers et al, 2013;Harrell et al, 2013) does facilitate replacing the traditional single-dose human radiolabeled study with a design using repeated therapeutic doses incorporating trace levels of radioactivity amenable to AMS detection, which in …”

Section: Following IV and Oral Administration Of [mentioning

confidence: 99%

Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

et al. 2013

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The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A 2 , was investigated in healthy male subjects using [14 C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%-6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acidcatalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%-53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.

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Applications of Accelerator Ms in Pediatric Drug Evaluation

Cited by 28 publications

References 22 publications

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

Human Microdosing/Phase 0 Studies to Accelerate Drug Development

Ethics of Drug Research in the Pediatric Intensive Care Unit

Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

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