Pharmacokinetic profile of alniditan nasal spray during and outside migraine attacks

Abstract

Aims To compare the pharmacokinetic profile of intranasal alniditan during and outside migraine attacks, and to investigate the relationship between initial rise of alniditan plasma concentration, and headache improvement. Methods Twenty-seven migraine patients (age: 18-65 years) were randomized to receive alniditan 2 mg or 4 mg, and investigated both during and outside a migraine attack. Maximal plasma concentrations (C max ), time to C max (t max ), and the area under the curve over 2 h (AUC(0,2 h)), were calculated from the individual plasma concentration-time profile, obtained from 10 blood samples in each patient, during each of the two administrations. Results Alniditan was rapidly absorbed into the systemic circulation (t max =11min). All investigated pharmacokinetic parameters (C max , t max , AUC(0,2 h)) were similar during and outside migraine attacks, both in the 2 mg (n=13) and the 4 mg group (n=14). In the 4 mg group, during attacks, mean plasma alniditan concentration at 5 min after administration (C t=5 ) in responders (21±16 ng ml −1 ; n=10) was significantly higher than the C t=5 in nonresponders (3±3 ng ml −1 ; P=0.01; n=4). However, the C max and AUC(0,2 h) in responders (33±18 ng ml −1 and 12±6 ng ml −1 h) were also significantly higher than the C max and AUC(0,2 h) in nonresponders (13±9 ng ml −1 ; P=0.048 and 5±3 ng ml −1 h; P=0.03).Conclusions Absorption of alniditan nasal spray was not affected by migraine attacks, although 95% confidence intervals were wide. Early rise of plasma concentrations and the amount of drug in the circulation were related to headache improvement in the higher dose group.Keywords: 5-HT 1B/1D receptor agonist, alniditan, migraine, nasal spray, pharmacokinetics showed similar clinical efficacy to that of orally adminisIntroduction trated sumatriptan [9][10][11]. The absence of superiority of the nasal route could be caused by lack of nasal absorption During attacks most migraine patients suffer from gastrointestinal symptoms such as nausea, vomiting and either because most of the drug is swallowed or because of a possible influence of migraine attacks on the nasal diarrhoea [1]. In addition, gastric stasis delays and impairs the gastro-intestinal absorption of drugs [2], making oral mucosa resulting in decreased absorption. The magnitude of headache relief of 5-HT 1B/1D treatment of migraine sometimes unsatisfactory [3,4]. Subcutaneously administrated antimigraine drugs are an receptor agonists appears to be related to the initial rise of plasma levels of the drugs [8, 12, 13], rather than to alternative, but dislike of injections or an inability to selfadminister makes subcutaneous treatment unacceptable the total amount of drug in the circulation [14]. Rate of absorption (initial rise of plasma levels) can be measured to some patients. Absorption of drugs via the nasal mucosa circumvents the gastro-intestinal problems associby the concentration of drugs 5 min after administration. We hypothesized that patients without headache relief ated with migraine attacks an...

Multiple-dose pharmacokinetics of intranasally administered IS-159 in healthy subjects

“…This finding is in agreement with a previous study in which a value of 15 min was reported [13] and is consistent with absorption through the nasal mucosa [17]. The pharmacokinetics of alnitidan [18], an investigational5-HT 1BIl D receptor agonist, and sumatriptan [19,20] were also investigated after intranasal administration. As for 15-159, the absorption of alnitidan was fast (median t max of 11 min).…”

State of the Art Review: Current Status of Topical Nasal Antimicrobial Agents

“…Most of our present knowledge on systemic absorption of intranasally administered agents is obtained from studies involving non‐antimicrobial drugs. 21–23 In a randomized, crossover study involving healthy volunteers, Thorsson et al 21 showed that systemic absorption of budesonide, when administered intranasally, was more rapid and complete via aqueous pump spray and powder form than from pressurized aerosol. A study on the bioavailability of intranasally administered dihydroergotmaine 22 (developed for the treatment of migraine headaches) showed that the peak plasma concentration could be reached at 0.9 hours.…”

Chitosan

“…Roon et al 32 (Table 2 Study #H4) investigated the pharmacokinetic profile of alniditan-chitosan nasal spray both during and Table 2 Study #H5) published details of a twostage study undertaken in 187 post-bunionectomy patients. In the first stage, patients were randomized to 5 groups for an initial single-dose: intranasal morphine-chitosan at 3 dose levels; intravenous (IV) morphine or placebo; in the second stage, patients were randomized to 2 dose levels of intranasal morphine-chitosan and received up to 6 doses over 24 h. Local adverse events associated with intranasal administration (primarily nasal congestion, rhinorrea, sneezing, throat irritation, and taste disturbance) were mostly mild and transient even during the multiple-dose stage.…”

“…With respect to the safety issues raised above, a substantial amount of preclinical and clinical safety data has been generated on chitosan and its safe use for intranasal drug delivery and as a vaccine adjuvant has been widely reported in the literature. [22][23][24][25][26][27][28][29][30][31][32][33] …”