Dihydroergotamine (DHE) — a Toxicological and Pharmacokinetic Study in Cynomolgus Monkeys Following Administration by the Intra-Nasal Route
A new formulation of dihydroergotamine (DHE) intended for treatment of migraine by the intra-nasal route was evaluated in Cynomolgus monkeys (Macaca fascicularis). This species was selected because its upper respiratory tract is similar to that of man and its size allowed use of a human applicator. Three groups of animals (each 3 males and 3 females) received daily either 1, 3, or 8 metered doses, each containing 0.5 mg DHE in 0.12 ml, corresponding to dose levels of 0.2, 0.6, and 1.6 mg/kg/day. A fourth group received 8 metered doses of vehicle daily and acted as controls.
There were no deaths and food intake and bodyweight gain were unaffected. There were no ocular abnormalities, no electrocardiographic changes, no hematological, blood chemistry or urine composition changes, no effects on organ weights and no necropsy nor histological findings that could be related to treatment. The only adverse effects were superficial mucosal ulceration of the nasal mucosa and slight epistaxis, both of which regressed during the course of the study.
A pharmacokinetic study validated the animal model in relation to man. Unchanged drug (DHE) and metabolites were dosed in plasma and urine by radioimmunology using two kits differing in their specificity. As in man, absorption was rapid and the α elimination half life was approximately 6 h. The nasal route avoiding the hepatic first pass effect, DHE represent 65–85% of total DHE + metabolites in plasma as in urine. Bioavailability however, was lower than in man.
Local tolerance was assessed by an electron microscopy study of the mucosa. 70 to 83% of the mucosal surface area of all groups was unaltered or showed only slight alteration considered to be reversible. This degree of change is considered unlikely to cause marked and enduring impairment of mucociliary clearance.
In conclusion, DHE administered for 13 weeks at doses 6 to 50 times those proposed for man, elicited no systemic and no local adverse effects.