Pronounced effect of caprylocaproyl macrogolglycerides on nasal absorption of IS‐159, a peptide serotonin 1B/1D‐receptor agonist

• Published in: Clinical pharmacology and therapeutics 2000-08, Vol.68 (2), p.114-121
• Main Authors: Dingemanse, Jasper, Soubrouillard, Catherine, Paris, Jérôme, Pisano, Pascale, Blin, Olivier
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Adult; Analysis of Variance; Biological and medical sciences; Cardiovascular system; Cross-Over Studies; Dipeptides - adverse effects; Dipeptides - pharmacokinetics; Double-Blind Method; Drug Interactions; Fatty Acids - pharmacology; Glycerides - pharmacology; Humans; Indoles - adverse effects; Indoles - pharmacokinetics; Male; Medical sciences; Pharmacology. Drug treatments; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin - metabolism; Serotonin Receptor Agonists - adverse effects; Serotonin Receptor Agonists - pharmacokinetics; Surface-Active Agents - pharmacology; Vasodilator agents. Cerebral vasodilators
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2000.108196

Objectives This double‐blind, randomized, two‐way crossover study in 12 healthy male subjects investigated the influence of caprylocaproyl macrogolglycerides on the pharmacokinetics of IS‐159 (serotonin‐carboxylmethyleneoxy‐L‐tyrosylglycinamide), a peptide serotonin 1B/1D‐receptor agonist, after intranasal administration. Methods A dose of 4 mg IS‐159 was administered in a volume of 200 μL, once in the presence and once in the absence of 2% caprylocaproyl macrogolglycerides. Plasma concentrations of IS‐159 were measured over a period of 12 hours for determination of pharmacokinetic parameters. Systemic and local tolerability were assessed at regular time points, the latter by rhinoscopy and visual analog scales. Results Caprylocaproyl macrogolglycerides significantly increased the maximum plasma concentration (from 4.7 ± 1.7 to 48 ± 17 ng/mL) and the area under the plasma concentration–time curve (from 12 ± 4.7 to 56 ± 22 ng · h/mL) of IS‐159. The time to maximum concentration (15 to 20 minutes) and the elimination half‐life (2.0 to 2.3 hours) were not different between the two treatments. Rhinoscopic examination revealed no differences between treatments, but in the presence of caprylocaproyl macrogolglycerides subjects reported more local and systemic adverse events and on the visual analog scales greater nasal obstruction and rhinorrhea. Conclusion 2% caprylocaproyl macrogolglyceride markedly increased the absorption of IS‐159 through the nasal mucosa and elicited only mild irritant effects. Clinical Pharmacology & Therapeutics (2000) 68, 114–121; doi: 10.1067/mcp.2000.108196