Variability of oral sumatriptan pharmacokinetics in migraine patients

Sumatriptan was the first selective serotonin (5-HT) 1B/1D agonist for the acute treatment of migraine attacks. It is thought to relieve migraine attacks by several mechanisms including cranial vasoconstriction and peripheral and central neural inhibition. Sumatriptan has proved to be effective and generally well tolerated in the absence of cardiovascular disease . Nevertheless, its use by migraine sufferers is still limited, approximately 40% of patients using only one prescription of this drug. Reason for terminating use after only one prescription is inefficacy and/or side effects in the majority (78%) of patients . Objectives: To evaluate oral bioavailability and pharmacokinetic profiles of sumatriptan in migraine patients. Methods: We studied 10 migraine patients (8 F, 3 M; mean age 45.3+8.1 years, range 34-60 years) twice, after oral (100 mg) and after subcutaneous (6 mg) administration of sumatriptan. A 1-week washout period was allowed between the administration of the two formulations. Patients were studied in headache free intervals. Blood samples were taken at baseline, at 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min. after oral administration, and at baseline, at 5, 10, 15, 20, 25, 30, 60, 90, 120 and 180 min. after subcutaneous injection. Sumatriptan concentrations were determined by HPLC with electrochemical detection. Pharmacokinetic parameters were calculated by means of the P K Solutions 2.0 program. The value of AUC obtained after subcutaneous administration was assumed correspond to 100% of bioavailability and relative oral bioavailability was calculated referred to this value. Results: Following administration of an oral dose of 100 mg, plasma concentrations of sumatriptan showed large differences among patients and two subjects had multiple peaks. In particular (Fig. 1), 5 patients (these subjects will be referred to as group A hereinafter) absorbed the drug faster (Tmax <120 min.), and achieved plasma levels significantly higher (soon after 45 minutes and up to 90 minutes) than the other 5 patients (hence forth, these last patients with Tmax >180 min will be referred to as group B). Notably, the systemic exposure to sumatriptan in the first 2 hours (which are the most important for rapid onset of action and for the antimigraine efficacy) was significantly greater in group A than in group B, as shown by AUC0-2 value in group A (3.174.2+1186 ng/min/ml) which is double the value in group B (1530.9+256 ng/min/ml). On the other hand, after subcutaneous administration of 6 mg of sumatriptan, the profile of the curves was similar in all patients, and there were no differences in pharmacokinetics between group A and group B. Conclusions: Since Tmax is a key variable in migraine response, and migraine relief is related to the systemic exposure to the drug in the first 2 hours after dosing, patients with slow rate and low extent of absorption of the drug in this interval of time could have poor benefit after oral sumatriptan administration. These patients could instead obtain more migraine relief using injection formulation of the drug, since there are no significant differences in pharmacokinetics after subcutaneous administration of sumatriptan. Our findings have the limitation of having been obtained in a small number of patients; however, they could explain the variability of outcomes observed with the different formulations of sumatriptan. Indeed, almost one third of patients in clinical trials fail to have headache relief after oral administration, while only one sixth of patients fail to have headache relief after subcutaneous administration. It is precisely the marked variability in the rate and extent of sumatriptan absorption after oral administration that we observed in clinical practice which could have an impact on sumatriptan response and, as a consequence, in some patients’ disaffection with this drug.