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.
Subject(s)
Alkaline Phosphatase/administration & dosage , Alkaline Phosphatase/pharmacokinetics , Carbon Radioisotopes , Isoenzymes/administration & dosage , Isoenzymes/pharmacokinetics , Administration, Intravenous , Adolescent , Adult , Alkaline Phosphatase/adverse effects , Area Under Curve , Double-Blind Method , Drug Dosage Calculations , GPI-Linked Proteins/administration & dosage , GPI-Linked Proteins/adverse effects , GPI-Linked Proteins/pharmacokinetics , Half-Life , Healthy Volunteers , Humans , Isoenzymes/adverse effects , Linear Models , Male , Mass Spectrometry/methods , Metabolic Clearance Rate , Models, Biological , Netherlands , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacokinetics , Young AdultABSTRACT
A conceptually novel approach to the design of reactivators of nerve agent-inhibited acetylcholinesterase (AChE) is presented. The concept comprises the linkage of a peripheral site ligand via a spacer to a reactivating moiety with the eventual goal to develop non-ionic reactivators with sufficient affinity for AChE to induce reactivation and potentially improved blood-brain barrier penetration. Herein, the first step towards that goal-the synthesis and biological evaluation of a peripheral site ligand conjugated to a charged pyridinium oxime is discussed. It was found, that the introduction of the peripheral site ligand not only increased affinity of the construct for AChE but also enhanced reactivation of nerve agent-inhibited AChE.
