Document Detail

Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men.
MedLine Citation:
PMID:  15176647     Owner:  NLM     Status:  MEDLINE    
AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose. CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.
A R van Troostenburg; D Lee; T R Jones; J A Dyck-Jones; M H Silverman; G N Lam; S J Warrington
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Publication Detail:
Type:  Clinical Trial; Clinical Trial, Phase I; Controlled Clinical Trial; Journal Article    
Journal Detail:
Title:  International journal of clinical pharmacology and therapeutics     Volume:  42     ISSN:  0946-1965     ISO Abbreviation:  Int J Clin Pharmacol Ther     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-06-04     Completed Date:  2004-09-09     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9423309     Medline TA:  Int J Clin Pharmacol Ther     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  253-9     Citation Subset:  IM    
HMR, Central Middlesex Hospital, London, UK.
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MeSH Terms
Angiogenesis Inhibitors / adverse effects,  blood,  pharmacokinetics*,  urine
Area Under Curve
Double-Blind Method
Injections, Subcutaneous
Middle Aged
Oligopeptides / adverse effects,  blood,  pharmacokinetics*,  urine
Peptide Fragments / adverse effects,  blood,  pharmacokinetics*,  urine
Urokinase-Type Plasminogen Activator / adverse effects,  blood,  pharmacokinetics*,  urine
Reg. No./Substance:
0/Angiogenesis Inhibitors; 0/Oligopeptides; 0/Peptide Fragments; 0/acetyl-lysyl-prolyl-seryl-seryl-prolyl-prolyl-glutamyl-glutamic acid amide; EC Plasminogen Activator

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