Four separate studies were conducted to examine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of eletriptan, a 5-HT(1B/1D) receptor agonist being developed for the treatment of migraines, after oral and intravenous administration. Fifty-five males received oral (1.5-30 mg or 30-120 mg) or intravenous (1.67-50 microg/kg or 50-102 microg/kg) eletriptan in four double- and single-blind, placebo-controlled, ascending-dose crossover studies. The maximum plasma concentration (Cmax) and area under the concentration curve (AUC) appeared linear over all dose ranges, with an apparent terminal half-life of 4 to 5 hours. Clearance and volume of distribution remained constant with dose. The time to first occurrence of Cmax (tmax) for oral eletriptan was approximately 1 hour and was unaffected by dose. Comparison of AUC values suggested an absolute bioavailability of approximately 50%. A linear PK/PD model, fitted to the data, predicted small, transient elevations in diastolic blood pressure following eletriptan doses > or = 60 mg. These effects were considered unlikely to be clinically significant. Eletriptan was well tolerated, and treatment-related adverse events were mild to moderate and transient. These PK properties should result in eletriptan having a rapid onset and sustained duration of action in terms of migraine efficacy.

The purpose of this study was to determine the pharmacokinetics and safety of eletriptan in different phases of the menstrual cycle. Female volunteers (n = 16) with a regular menstrual cycle (28 +/- 4 days) received a single oral dose of 80 mg eletriptan during each of the four cycle phases: phase 1 (menses), days 1 to 4; phase 2 (follicular), days 6 to 10; phase 3 (ovulatory), days 11 to 13; and phase 4 (luteal), days 21 to 24. Eletriptan plasma concentrations were determined from serial plasma samples taken during a 24-hourperiod after dosing. Blood pressure, pulse rate, and ECG measurements were performed at baseline, 1 and 24 hours after dosing. No significant differences between phases were observed for maximum plasma concentration (cmax, range of means = 188-234 ng/ml), time to maximum concentration (tmax, range of means = 1.8-2.5 h), or systemic exposure (area under the curve [AUC], range of means = 1194-1514 ng x h/ml). Although there was a statistically significant difference in the terminal phase elimination rate constant (kel) between phases 1 and2 (0.175/h vs. 0.158/h, p = 0.044), the corresponding difference in terminal phase half-life (t 1/2) (4.0 h vs. 4.4 h) was not considered to be clinicallyrelevant. No clinically relevant differences in blood pressure, pulse rate, or ECG were observed, and the incidence, nature, and severity of adverse events were similar in all phases. The different phases of the menstrual cycle had no clinically significant effect on the pharmacokinetics, safety, or tolerability of oral 80 mg eletriptan in healthy females.

The bioequivalence of encapsulated vs standard (commercial) sumatriptan was assessed before comparative eletriptan-sumatriptan efficacy studies in the acute treatment of migraine were conducted. Commercially acquired sumatriptan was encapsulated to ensure the double-blind nature of these studies.The pharmacokinetics of three single oral doses of sumatriptan 100 mg -the standard tablet, an encapsulated tablet, and a stressed encapsulated tablet -were compared in an open, randomized, three-way crossover study. Stressed capsules were produced by storing capsules for 12 weeks at 40 C/75% humidity; conditions chosen to accelerate any effects potentially induced by long-term storage under normal conditions. Blood samples were obtained from 22 males at baseline and at intervals over 24 h post-dose. Bioequivalence parameters were calculated as mean ratios and associated 90% confidence intervals, and between-drug differences were assessed using standard criteria. A prior in vitro dissolution study confirmed similar dissolution of the encapsulated and standard forms; though stressed tablets had decreased dissolution.For standard, encapsulated and stressed encapsulated sumatriptan, the area under the plasma concentration-time curve from 0 to infinity (AUC) values were 201.95, 199.74 and 203.98 ng h/ml, respectively. Maximum observed plasma concentration (C max ) values were 58.91, 56.09 and 52.56 ng/ml, respectively. The times to the first occurrence of C max (T max ) were 1.69, 1.83 and 1.98 h, respectively. All forms were bioequivalent using the standard range of 80-125%, with the exception of a 1% out of range C max for the stressed form. This parameter was within range using C max /AUC, a more sensitive absorption rate estimate.These results demonstrate that the encapsulated and stressed sumatriptan used in these studies are bioequivalent to commercial sumatriptan. The T max data suggest a similar rate of absorption.

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