In the present study human recombinant placental alkaline phosphatase (hRESCAP) will be investigated. Alkaline Phosphatase is naturally present in the body and reported to use lipopolysaccharde (LPS, bacterial endotoxins) and extracellular nucleotides leaking from damaged and ischemic cells as physiological substrates. The LPS-substrate prevalence makes alkaline phosphatase an interesting novel therapeutic agent in the treatment of LPS-mediated diseases. A bovine homologue of this protein (bovine intestinal alkaline phosphatase, BIAP) has previously been investigated for treatment of acute inflammatory responses such as sepsis, and was shown to be safe in humans. hRESCAP, which will be investigated in the current study, is expected to have a longer half-life in humans than the previously investigated BIAP, due to the fact that it is more sialylated. The possibility to increase the t1/2 to days instead of minutes enables treatment of chronic diseases.
In the current study the peak plasma concentration (pharmacokinetics/elimination) of \[14C\]-labelled hRESCAP in healthy volunteers will be investigated at increasing single doses (up to anticipated therapeutic dose), with a microdose (≤30 nmol) as a safe starting dose. * Part 1: To assess the peak plasma concentration of a single microdose (≤30 nmol) of a recombinant human protein (hRESCAP), administered intravenously, as a suitable technique to predict the pharmacokinetics in humans at pharmacologically relevant doses; * Part 2: To determine the safety and tolerability of single dose of hRESCAP up to 5300 µg in healthy male volunteers administered intravenously; * To determine the peak plasma concentration of hRESCAP in healthy male volunteers within a pharmacologically relevant dose-range and compare this with BIAP pharmacokinetics with emphasis on half-life (t1/2).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
DIAGNOSTIC
Masking
QUADRUPLE
Enrollment
4
Centre for Human Drug Research
Leiden, South Holland, Netherlands
Evaluate the peak plasma concentration of hRESCAP after microdose administration of hRESCAP
After administration of hRESCAP intravenously, blood will be withdrawn of the subjects frequently for in total 35 days (five times the anticipated half-life period of one week).
Time frame: 35 days
In the ascending dose study increased dosages of of hRESCAP will be supplied till finally the therapeutic dose.
In three subjects a low, medium and high dose of hRESCAP will be administered and a control saline administration in one subject. The peak plasma concentration of hRESCAP response of different dosages will be useful for treatment evaluation. The administration of the different dosages supplied is one week apart for safety reasons.
Time frame: Two weeks (based upon time phrame of micodose section of the study)
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