title: Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages.
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.
authors: TNO, Zeist, The Netherlands, UK.
authors: M L H
authors: ML
authors: Vlaming
authors: TNO, Zeist, The Netherlands, UK.
authors: E
authors: E
authors: van Duijn
authors: Centre for Human Drug Research, Leiden, The Netherlands, UK.
authors: M R
authors: MR
authors: Dillingh
authors: AMRIF BV, Wageningen, The Netherlands, UK.
authors: R
authors: R
authors: Brands
authors: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands, UK.
authors: A D
authors: AD
authors: Windhorst
authors: Department of Pharmacy and Clinical Pharmacology, VU University Medical Center, Amsterdam, The Netherlands, UK.
authors: N H
authors: NH
authors: Hendrikse
authors: TNO, Zeist, The Netherlands, UK.
authors: S
authors: S
authors: Bosgra
authors: Centre for Human Drug Research, Leiden, The Netherlands, UK.
authors: J
authors: J
authors: Burggraaf
authors: TNO, Zeist, The Netherlands, UK.
authors: M C
authors: MC
authors: de Koning
authors: TNO, Zeist, The Netherlands, UK.
authors: A
authors: A
authors: Fidder
authors: TNO, Zeist, The Netherlands, UK.
authors: J A J
authors: JA
authors: Mocking
authors: TNO, Zeist, The Netherlands, UK.
authors: H
authors: H
authors: Sandman
authors: TNO, Zeist, The Netherlands, UK.
authors: R A F
authors: RA
authors: de Ligt
authors: TNO, Zeist, The Netherlands, UK.
authors: B O
authors: BO
authors: Fabriek
authors: TNO, Zeist, The Netherlands, UK.
authors: W J
authors: WJ
authors: Pasman
authors: AMRIF BV, Wageningen, The Netherlands, UK.|Utrecht University, Utrecht, The Netherlands, UK.
authors: W
authors: W
authors: Seinen
authors: GenIBET/IBET, Oeiras, Portugal.
authors: T
authors: T
authors: Alves
authors: GenIBET/IBET, Oeiras, Portugal.
authors: M
authors: M
authors: Carrondo
authors: GenIBET/IBET, Oeiras, Portugal.
authors: C
authors: C
authors: Peixoto
authors: Centre for Human Drug Research, Leiden, The Netherlands, UK.
authors: P A M
authors: PA
authors: Peeters
authors: TNO, Zeist, The Netherlands, UK.
authors: W H J
authors: WH
authors: Vaes
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002250:Carbon Radioisotopes; D004311:Double-Blind Method; D054796:Drug Dosage Calculations; D058851:GPI-Linked Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007527:Isoenzymes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009426:Netherlands; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D058851:GPI-Linked Proteins; D007527:Isoenzymes; D011994:Recombinant Proteins; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental