1. Clinical pharmacology of exogenously administered alkaline phosphatase
- Author
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J.G. van der Hoeven, Ferdinand T F Snellen, M. Bulitta, Philippe G. Jorens, Jaap E. Tulleken, Peter Pickkers, R. Lins, S. Ramael, Peter Rogiers, J. Meulenbelt, Herbert Spapen, Jan Bakker, Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, Department of Intensive Care Medicine (551), Radboud University Medical Center [Nijmegen], Department of Anesthesiology, Isala Klinieken, Department of Intensive Care, Antwerp University Hospital [Edegem] (UZA), Erasmus Medical Centre, Department of Critical Care Medicine and Clinical Pharmacology, Division of Intensive Care Centre, University Medical Centre Utrecht, Institute for Risk Assessment Sciences, Utrecht University, ICU Department, University Hospital, Intensive and Respiratory Care Unit, University Medical Centre, Clinical Pharmacology Unit Antwerp, SGS Life Science Services (SGS), SGS (SGS)-SGS (SGS), and CRM Biometrics GmbH
- Subjects
Adult ,Male ,EXPRESSION ,medicine.medical_specialty ,Renal failure ,Time Factors ,Pharmacology ,Loading dose ,law.invention ,Sepsis ,Pharmacokinetics ,Double-Blind Method ,law ,PHOSPHODIESTERASE ACTIVITY ,Internal medicine ,Intensive care ,Alkaline phosphatase ,medicine ,Humans ,Pharmacology (medical) ,Infusions, Intravenous ,Volunteer ,ComputingMilieux_MISCELLANEOUS ,Aged ,Inflammation ,Clinical pharmacology ,SEPSIS ,business.industry ,Tumor Necrosis Factor-alpha ,Pharmacology. Therapy ,Interleukins ,SEPTIC SHOCK ,General Medicine ,Middle Aged ,medicine.disease ,ADENOSINE ,Endotoxemia ,Pathogenesis and modulation of inflammation [N4i 1] ,Clinical trial ,Endocrinology ,Pharmacodynamics ,Female ,business ,Half-Life - Abstract
Contains fulltext : 79632.pdf (Publisher’s version ) (Closed access) PURPOSE: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). METHODS: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg(-1) 24 h(-1)) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. RESULTS: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. CONCLUSIONS: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis.
- Published
- 2009