RESUMO
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.
Assuntos
Fosfatase Alcalina/administração & dosagem , Fosfatase Alcalina/farmacocinética , Radioisótopos de Carbono , Isoenzimas/administração & dosagem , Isoenzimas/farmacocinética , Administração Intravenosa , Adolescente , Adulto , Fosfatase Alcalina/efeitos adversos , Área Sob a Curva , Método Duplo-Cego , Cálculos da Dosagem de Medicamento , Proteínas Ligadas por GPI/administração & dosagem , Proteínas Ligadas por GPI/efeitos adversos , Proteínas Ligadas por GPI/farmacocinética , Meia-Vida , Voluntários Saudáveis , Humanos , Isoenzimas/efeitos adversos , Modelos Lineares , Masculino , Espectrometria de Massas/métodos , Taxa de Depuração Metabólica , Modelos Biológicos , Países Baixos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Adulto JovemRESUMO
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.