Ångstrom News
Safety, Tolerability, And Pharmacokinetics Of Subcutaneous Å6, An 8-Amino Acid Peptide With Anti-Angiogenic Properties, In Healthy Men
A-R van Troostenburg, D Lee, T R Jones, J A Dyck-Jones, M H Silverman, G N Lam, S J Warrington
Aims: To assess the safety, tolerability and pharmacokinetics of subcutaneous Å6, 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 Å6 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 Å6 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 Å6 were assessed up to 24 h after single doses, for12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses.
Materials: Å6 for subcutaneous injection in phosphate buffer, pH 5.6 – 6.0. Phosphate-buffered saline was used as placebo.
Results: All dose regimens of Å6 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 – 10333 ng/mL and mean AUC(0-inf) from 1690 –43371 ng·h/mL after the 15 and 300 mg single doses, respectively. Terminal t1/2 was 1.4 –1.8h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged Å6 was 94.6 % (SD 20.7) after the 300 mg single dose (0 – 24 h collection), and78.4 % (SD 13.0) after the 150 mg repeated dose (0 – 12 h collection). Å6 did not trigger production ofanti-Å6 IgG antibodies within 14 days of the first dose.
Conclusion: Single doses of Å6 up to 300 mg, and repeated doses up to 150mg, were well tolerated and safe in healthy young men. Å6 was rapidly absorbed; it waseliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. Å6 did not trigger an early immunogenic response.