Pharmacokinetics, pharmacodynamics, and safety of the 5-HT(1B/1D) agonist eletriptan following intravenous and oral administration.
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.
Milton
K Ashley
KA
Clinical Sciences, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom.
Scott
Nicholas R
NR
Allen
Michael J
MJ
Abel
Samantha
S
Jenkins
Vivienne C
VC
James
Gerry C
GC
Rance
David J
DJ
Eve
Malcolm D
MD
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D014018:Tissue Distribution; D014363:Tryptamines
D007211:Indoles; D011759:Pyrrolidines; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C115647:eletriptan