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Clin Pharmacol Ther. 2015 Aug;98(2):196-204. doi: 10.1002/cpt.131. Epub 2015 May 19.

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

Author information

1
TNO, Zeist, The Netherlands, UK.
2
Centre for Human Drug Research, Leiden, The Netherlands, UK.
3
AMRIF BV, Wageningen, The Netherlands, UK.
4
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands, UK.
5
Department of Pharmacy and Clinical Pharmacology, VU University Medical Center, Amsterdam, The Netherlands, UK.
6
Utrecht University, Utrecht, The Netherlands, UK.
7
GenIBET/IBET, Oeiras, Portugal.

Abstract

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.

PMID:
25869840
DOI:
10.1002/cpt.131
[Indexed for MEDLINE]

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