The 1MV multi-element AMS system for biomedical applications at the Netherlands Organization for Applied Scientific Research (TNO)

Klein, M.; Vaes, Whj; Fabriek, Babs O.; Sandman, H.; Mous, D.J.W.; Gottdang, A.

doi:10.1016/j.nimb.2012.06.024

Cited by 15 publications

(8 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A final CO 2 /helium mixture of 6% was directed to the AMS ion source, at a pressure of 1 bar and a flow of 60 µL/minute. A 1‐MV Tandetron AMS (High Voltage Engineering Europe B.V., Amersfoort, The Netherlands) 33 was used. To determine the true amount of radioactivity in each fraction, the measured [ 14 C]/[ 12 C] ratios were multiplied by the corresponding total carbon measurement of the elemental analyzer.…”

Section: Methodsmentioning

confidence: 99%

Proof of Concept: First Pediatric [¹⁴C]microtracer Study to Create Metabolite Profiles of Midazolam

Groen

Duijn²,

Vries³

et al. 2020

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Growth and development affect drug‐metabolizing enzyme activity thus could alter the metabolic profile of a drug. Traditional studies to create metabolite profiles and study the routes of excretion are unethical in children due to the high radioactive burden. To overcome this challenge, we aimed to show the feasibility of an absorption, distribution, metabolism, and excretion (ADME) study using a [14C]midazolam microtracer as proof of concept in children. Twelve stable, critically ill children received an oral [14C]midazolam microtracer (20 ng/kg; 60 Bq/kg) while receiving intravenous therapeutic midazolam. Blood was sampled up to 24 hours after dosing. A time‐averaged plasma pool per patient was prepared reflecting the mean area under the curve plasma level, and subsequently one pool for each age group (0–1 month, 1–6 months, 0.5–2 years, and 2–6 years). For each pool [14C]levels were quantified by accelerator mass spectrometry, and metabolites identified by high resolution mass spectrometry. Urine and feces (n = 4) were collected up to 72 hours. The approach resulted in sufficient sensitivity to quantify individual metabolites in chromatograms. [14C]1‐OH‐midazolam‐glucuronide was most abundant in all but one age group, followed by unchanged [14C]midazolam and [14C]1‐OH‐midazolam. The small proportion of unspecified metabolites most probably includes [14C]midazolam‐glucuronide and [14C]4‐OH‐midazolam. Excretion was mainly in urine; the total recovery in urine and feces was 77–94%. This first pediatric pilot study makes clear that using a [14C]midazolam microtracer is feasible and safe to generate metabolite profiles and study recovery in children. This approach is promising for first‐in‐child studies to delineate age‐related variation in drug metabolite profiles.

show abstract

Section: Methodsmentioning

confidence: 99%

Proof of Concept: First Pediatric [¹⁴C]microtracer Study to Create Metabolite Profiles of Midazolam

Groen

Duijn²,

Vries³

et al. 2020

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

show abstract

“…A final CO 2 /helium mixture of 6% was directed to the AMS ion source, at a pressure of 1 bar and a flow of 60 µL/min. A 1-MV Tandetron AMS (High Voltage Engineering Europe B.V., Amersfoort, The Netherlands) [ 27 ] was used. The lower limit of quantification (LLOQ) of the method was 0.58 Bq/L.…”

Section: Methodsmentioning

confidence: 99%

Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism

Mooij

Duijn²,

Knibbe

et al. 2017

Clin Pharmacokinet

View full text Add to dashboard Cite

BackgroundWe previously showed the practical and ethical feasibility of using [14C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [14C]paracetamol (AAP).MethodsInfants admitted to the intensive care unit received a single oral [14C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [14C]AAP pharmacokinetic parameters were estimated. [14C]AAP and metabolites were measured with accelerator mass spectrometry. The plasma area under the concentration-time curve from time zero to infinity and urinary recovery ratios were related to age as surrogate markers of metabolism.ResultsFifty children [median age 6 months (range 3 days–6.9 years)] received a microdose (3.3 [2.0–3.5] ng/kg; 64 [41–71] Bq/kg). Plasma [14C]AAP apparent total clearance was 0.4 (0.1–2.6) L/h/kg, apparent volume of distribution was 1.7 (0.9–8.2) L/kg, and the half-life was 2.8 (1–7) h. With increasing age, plasma and urinary AAP-glu/AAP and AAP-glu/AAP-sul ratios significantly increased by four fold, while the AAP-sul/AAP ratio significantly decreased.ConclusionUsing [14C]labeled microdosing, the effect of age on orally administered AAP metabolism was successfully elucidated in both plasma and urine. With minimal burden and risk, microdosing is attractive to study developmental changes in drug disposition in children.

show abstract

“…CO 2 was released by heating of the trap and transferred to a vacuum syringe using helium. The resulting 6% v/v gas mixture of CO 2 with helium was infused at a pressure of 1 bar at 60 μL/min into the titanium target in the SO110 ion source of a 1 MV Tandetron AMS (High Voltage Engineering Europe B.V., The Netherlands) . As the AMS solely counts [ 14 C] atoms, the analysis is universal.…”

Section: Methodsmentioning

confidence: 99%

“…The resulting 6% v/v gas mixture of CO 2 with helium was infused at a pressure of 1 bar at 60 lL/min into the titanium target in the SO110 ion source of a 1 MV Tandetron AMS (High Voltage Engineering Europe B.V., The Netherlands). 28,29 As the AMS solely counts [ 14 C] atoms, the analysis is universal. No study, matrix, or compound method development is required.…”

Section: Determination Of Enzymatic Activitymentioning

confidence: 99%

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Vlaming¹,

Duijn²,

Dillingh

et al. 2015

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 μg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.

show abstract

The 1MV multi-element AMS system for biomedical applications at the Netherlands Organization for Applied Scientific Research (TNO)

Cited by 15 publications

References 15 publications

Proof of Concept: First Pediatric [¹⁴C]microtracer Study to Create Metabolite Profiles of Midazolam

Proof of Concept: First Pediatric [¹⁴C]microtracer Study to Create Metabolite Profiles of Midazolam

Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Contact Info

Product

Resources

About

The 1MV multi-element AMS system for biomedical applications at the Netherlands Organization for Applied Scientific Research (TNO)

Cited by 15 publications

References 15 publications

Proof of Concept: First Pediatric [14C]microtracer Study to Create Metabolite Profiles of Midazolam

Proof of Concept: First Pediatric [14C]microtracer Study to Create Metabolite Profiles of Midazolam

Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism

Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Contact Info

Product

Resources

About

Proof of Concept: First Pediatric [¹⁴C]microtracer Study to Create Metabolite Profiles of Midazolam

Proof of Concept: First Pediatric [¹⁴C]microtracer Study to Create Metabolite Profiles of Midazolam