Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

Mooij, Miriam G.; Duijn, Esther van; Knibbe, Catherijne A. J.; Windhorst, Albert D.; Hendrikse, N. Harry; Vaes, Wouter H. J.; Spaans, Edwin; Fabriek, Babs O.; Sandman, H.; Grossouw, Dimitri; Hanff, Lidwien M.; Janssen, Paul J. J. M.; Koch, Birgit C. P.; Tibboel, Dick; Wildt, Saskia N. de

doi:10.1007/s40262-014-0176-8

Cited by 29 publications

(72 citation statements)

References 31 publications

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“…Full metabolic profiles can be generated as an early indication of the drug's metabolism in humans or absolute bio-availability can be estimated [51,52]. More recently, the practice of microdosing has extended to other areas of drug development, including in vivo drug--drug interactions in human adults, but also explorative studies in special populations, including newborns [53][54][55]. This practice builds further on clinical experience with the use of stable isotopes in neonates to quantify carbohydrate, fat and amino acid metabolism or synthesis of specific peptides or proteins [56].…”

Section: Microdosing and Microtracersmentioning

confidence: 99%

“…The high sensitivity of the above-mentioned analytic technologies (AMS, LC/MS/ MS) facilitates PK studies by reduction of the sample volumes needed. To the very best of our knowledge, there are at present two compounds ( 14 C-ursodiol and paracetamol) to illustrate at least the feasibility to apply such study methodology (microdosing, microtracer) in neonates [53][54][55]. Gordi et al reported on the repeated administration of 14 C-ursodiol microdosing in 5 non-cholestatic and 3 cholestatic newborns, together with 40 mg/kg of non-labeled ursodiol [54].…”

Section: Microdosing and Microtracersmentioning

confidence: 99%

“…The authors hereby documented paracetamol disposition in their cohort. Using a similar approach, a multi-centre clinical study to evaluate the use of a microtrace dose of 14 C-labelled Paracetamol and AMS bio-analysis (PAMS study) as new tools in drug development to determine PK in 60 preterm and term neonates, infants and toddlers was recently finalized [53,55]. These studies also used 'microdoses' where the 14 C label was administered separately from a therapeutic dose.…”

Section: Microdosing and Microtracersmentioning

confidence: 99%

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Neonatal medicines research: challenges and opportunities

Samardžić

Turner

Bax³

et al. 2015

Expert Opinion on Drug Metabolism & Toxicology

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Section: Microdosing and Microtracersmentioning

confidence: 99%

Section: Microdosing and Microtracersmentioning

confidence: 99%

Section: Microdosing and Microtracersmentioning

confidence: 99%

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Neonatal medicines research: challenges and opportunities

Samardžić

Turner

Bax³

et al. 2015

Expert Opinion on Drug Metabolism & Toxicology

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“…Microdosing pharmacokinetic study with radioactive labeled drug [94] No potential benefit to patient despite safe radiation dose: 'gate-keeping' by physicians and/or nursing staff out of fear for radiation-related negative outcomes. Possible misunderstanding of minimal risks by parents …”

Section: Resultsmentioning

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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“…Microdosing is also used in cases where pharmacokinetics cannot confidently be predicted from preclinical animal species, or to investigate or confirm metabolic routes in humans. Furthermore, it enables investigation of pharmacokinetics in specific target populations (patients, children) that would not be admissible in high-dose phase I trials [10,11].…”

Section: Introductionmentioning

confidence: 99%

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

Bosgra¹,

Vlaming²,

Vaes³

2015

Clin Pharmacokinet

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Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non-linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non-linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose-proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates.

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Pediatric Microdose Study of [14C]Paracetamol to Study Drug Metabolism Using Accelerated Mass Spectrometry: Proof of Concept

Cited by 29 publications

References 31 publications

Neonatal medicines research: challenges and opportunities

Neonatal medicines research: challenges and opportunities

Ethics of Drug Research in the Pediatric Intensive Care Unit

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

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