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

Objectives: This double-blind, randomized, two-way crossover study in 12 he althy male subjects investigated the influence of caprylocaproyl macrogolgl ycerides on the pharmacokinetics of IS-159 (serotonin-carboxylmethyleneoxy- L-tyrosylglycinamide) , a peptide serotonin 1B/1D-receptor agonist, after i ntranasal administration. Methods: A dose of 4 mg IS-159 was administered in a volume of 200 mu L, on ce in the presence and once in the absence of 2% caprylocaproyl macrogolgly cerides. Plasma concentrations of IS-159 were measured over a period of 12 hours for determination of pharmacokinetic parameters. Systemic and local t olerability were assessed at regular time points, the latter by rhinoscopy and visual analog scales, Results: Caprylocaproyl macrogolglycerides significantly increased the maxi mum 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) an d the elimination half-life (2.0 to 2.3 hours) were not different between t he two treatments, Rhinoscopic examination revealed no differences between treatments, but in the presence of caprylocaproyl macrogolglycerides subjec ts 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 abso rption of IS-159 through the nasal mucosa and elicited only mild irritant e ffects.