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

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Author: Vlaming, M.L. · Duijn, E. van · Dillingh, M.R. · Brands, R. · Windhorst, A.D. · Hendrikse, N.H. · Bosgra, S. · Burggraaf, J. · Koning, M.C. de · Fidder, A. · Mocking, J.A. · Sandman, H. · Ligt, R.A. de · Fabriek, B.O. · Pasman, W.J. · Seinen, W. · Alves, T. · Carrondo, M. · Peixoto, C. · Peeters, P.A. · Vaes, W.H.
Type:article
Date:2015
Source:Clinical pharmacology and therapeutics, 2, 98, 196-204
Identifier: 528630
doi: doi:10.1002/cpt.131
Keywords: Biology · Alkaline phosphatase, placental · Carbon · Glycosylphosphatidylinositol anchored protein · Isoenzyme · Recombinant protein · Area under the curve · Biological model · Clinical trial · Controlled study · Dose calculation · Double blind procedure · Half life time · Intravenous drug administration · Phase 1 clinical trial · Procedures · Randomized controlled trial · Statistical model · Administration, Intravenous · Adolescent · Adult · Alkaline Phosphatase · Area Under Curve · Carbon Radioisotopes · Double-Blind Method · Drug Dosage Calculations · GPI-Linked Proteins · Half-Life · Healthy Volunteers · Humans · Isoenzymes · Linear Models · Male · Mass Spectrometry · Metabolic Clearance Rate · Models, Biological · Netherlands · Recombinant Proteins · Young Adult · Biomedical Innovation · Healthy Living · Life Triskelion BV · MSB - Microbiology and Systems Biology ARPC - Analytical Research (Pharm & Chemistry) · ELSS - Earth, Life and Social Sciences TNO Bedrijven

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