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 BV
MSB - Microbiology and Systems Biology ARPC - Analytical Research (Pharm & Chemistry)
ELSS - Earth, Life and Social Sciences TNO Bedrijven
Biomedical Innovation
Biology
Healthy Living
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
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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