A Combined Accelerator Mass Spectrometry-Positron Emission Tomography Human Microdose Study with 14C- and 11C-Labelled Verapamil

Wagner, Cláudia; Simpson, Marie; Zeitlinger, Markus; Bauer, Martin; Karch, Rudolf; Abrahim, Aiman; Feurstein, Thomas; Schütz, Matthias; Kletter, Kurt; Müller, Markus; Lappin, Graham; Langer, Oliver

doi:10.2165/11537250-000000000-00000

Cited by 33 publications

(22 citation statements)

References 40 publications

(45 reference statements)

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“…The on-going plans are to label the drug molecule of interest with both 11 C and 14 C. The study would then involve the measurements of the drug pharmacodynamics on a short scale using PET (Positron Emission Tomography), providing spatial information on the accumulation site of the drug in the human body [16]. As 11 C has a half-life of about 20 min, within one hour after the administration of the drug the PET signal will be too weak to detect after which AMS can take over and measure the pharmacokinetic properties.…”

Section: Mechanism Studies Of the Blood Brain Barriermentioning

confidence: 99%

Accelerator mass spectrometry of ultra-small samples with applications in the biosciences

Salehpour¹,

Håkansson²,

Possnert³

2013

Nuclear Instruments and Methods in Physics Research Section B:

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Section: Mechanism Studies Of the Blood Brain Barriermentioning

confidence: 99%

Accelerator mass spectrometry of ultra-small samples with applications in the biosciences

Salehpour¹,

Håkansson²,

Possnert³

2013

Nuclear Instruments and Methods in Physics Research Section B:

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“…Furthermore, the inherent high sensitivity of the technique allows for studies where high specific activities of radiolabeled compounds are not possible. AMS has been utilized for both rodent and human studies including: nanoparticle dosimetry (Malfatti et al, 2012) and pharmacokinetic and metabolic evaluation of therapeutics and environmental contaminants (Henderson and Pan 2010; Wagner et al, 2011; Malfatti et al, 2014; Madeen et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Malfatti

Enright

et al. 2017

Chemico-Biological Interactions

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Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ∼1 hr. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The Cmax in the brain ranged between 0.03-0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.

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“…PET has been used with microdosing studies [16], and indeed in one case, traditional concentration-time pharmacokinetic data were acquired alongside PET images [17]. PET human microdose studies are, however, outside of the current review and the reader is referred to other publications in this respect [18,19].…”

Section: Introductionmentioning

confidence: 99%

Microdosing and drug development: past, present and future

Lappin

Noveck²,

Burt

2013

Expert Opinion on Drug Metabolism & Toxicology

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115

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Introduction Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date. Areas covered The authors define and distinguish the concept of microdosing from similar approaches. The authors review the ability of microdosing to provide exploratory pharmacokinetics (concentration-time data) but exclude microdosing using positron emission tomography. The article provides a comprehensive review of data within the peer-reviewed literature as well as the latest applications and a look into the future, towards where microdosing may be headed. Expert opinion Evidence so far suggests that microdosing may be a better predictive tool of human pharmacokinetics than alternative methods and combination with physiologically based modelling may lead to much more reliable predictions in the future. The concept has also been applied to drug-drug interactions, polymorphism and assessing drug concentrations over time at its site of action. Microdosing may yet have more to offer in unanticipated directions and provide benefits that have not been fully realised to date.

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A Combined Accelerator Mass Spectrometry-Positron Emission Tomography Human Microdose Study with 14C- and 11C-Labelled Verapamil

Abstract: Combining AMS and PET microdosing allows long-term pharmacokinetic data along with information on drug tissue distribution to be acquired in the same subjects thus making it a promising approach to maximize data output from a single clinical study.

Cited by 33 publications

References 40 publications

Accelerator mass spectrometry of ultra-small samples with applications in the biosciences

Accelerator mass spectrometry of ultra-small samples with applications in the biosciences

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Microdosing and drug development: past, present and future

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