Human pharmacokinetics of dihydroergotamine administered by nasal spray

A nasal spray of dihydroergotamine was developed for the treatment of migraine headaches, and pharmacokinetic studies were scheduled to evaluate the bioavailability of dihydroergotamine by this new route of administration.

Nine studies were performed with dihydroergotamine administered by nasal spray to evaluate the bioavailability of the nasal route versus the intramuscular route, the linearity of the kinetics, the interindividual and intraindividual variations, and the influence of different factors.

Nasally administered dihydroergotamine (1 mg) becomes rapidly available to the systemic circulation, with peak plasma levels of 1 ng/ml achieved in 0.9 hour. The relative bioavailability versus intramuscular route is 38.4%. Dihydroergotamine administered by the nasal route exhibits linear dose proportionality (1 to 4 mg). Intraindividual variations of bioavailability evaluated for a 1-year period were higher (29%) than those found for the intramuscular route (20%) but comparable to the oral route. Interindividual variations for bioavailability were greater (25% versus 14% by the intramuscular route) but comparable to the oral route. Caffeine contained in the nasal solution (1%) had no effect on the absorption. Vasomotor phenomena, which could also affect the nasal mucosa during a migraine headache, do not modify the bioavailability. The constriction of the nasal mucosa by fenoxazoline leads to a slight decrease (-15%) in the bioavailability. The presence of acute viral rhinitis did not result in any change in dihydroergotamine nasal absorption compared with the normal state of the nasal mucosa. From a pharmacokinetic point of view, nasally administered dihydroergotamine can be given, without risk of overdose, to patients receiving long-term oral dihydroergotamine medication.

These results show the reliability and reproducibility of this route of dihydroergotamine administration adapted for the treatment of migraine headaches.