Print Email Facebook Twitter Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages Title Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages Author Vlaming, M.L. van Duijn, E. Dillingh, M.R. Brands, R. Windhorst, A.D. Hendrikse, N.H. Bosgra, S. Burggraaf, J. de Koning, M.C. Fidder, A. Mocking, J.A. Sandman, H. de Ligt, R.A. Fabriek, B.O. Pasman, W.J. Seinen, W. Alves, T. Carrondo, M. Peixoto, C. Peeters, P.A. Vaes, W.H. Publication year 2015 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. © 2015 American Society for Clinical Pharmacology and Therapeutics. Chemicals/CAS: alkaline phosphatase, 9001-78-9; carbon, 7440-44-0; Alkaline Phosphatase; alkaline phosphatase, placental; Carbon Radioisotopes; GPI-Linked Proteins; Isoenzymes; Recombinant Proteins Subject Life Triskelion BVMSB - Microbiology and Systems Biology ARPC - Analytical Research (Pharm & Chemistry)ELSS - Earth, Life and Social Sciences TNO BedrijvenBiomedical InnovationBiologyHealthy LivingAlkaline phosphatase, placentalCarbonGlycosylphosphatidylinositol anchored proteinIsoenzymeRecombinant proteinArea under the curveBiological modelClinical trialControlled studyDose calculationDouble blind procedureHalf life timeIntravenous drug administrationPhase 1 clinical trialProceduresRandomized controlled trialStatistical modelAdministration, IntravenousAdolescentAdultAlkaline PhosphataseArea Under CurveCarbon RadioisotopesDouble-Blind MethodDrug Dosage CalculationsGPI-Linked ProteinsHalf-LifeHealthy VolunteersHumansIsoenzymesLinear ModelsMaleMass SpectrometryMetabolic Clearance RateModels, BiologicalNetherlandsRecombinant ProteinsYoung Adult To reference this document use: http://resolver.tudelft.nl/uuid:de1d0c5d-f878-4f4a-ac97-74e0d45797a9 DOI https://doi.org/10.1002/cpt.131 TNO identifier 528630 ISSN 1532-6535 Source Clinical pharmacology and therapeutics, 98 (2), 196-204 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.