Pharmacokinetics and pharmacodynamics of avitriptan during intravenous administration in healthy subjects

Avitriptan, a selective 5-HT1-like receptor agonist, is an effective compou nd for the treatment of migraine headaches with a prolonged duration of res ponse. A double-blind, placebo-controlled, parallel-group, ascending-dose s tudy in 24 healthy subjects was designed to assess the safety, tolerance, p harmacokinetics, and pharmacodynamics of avitriptan. This antimigraine drug was administered as two consecutive constant-rate IV infusions at three do se levels (12.7, 25.3, and 38.0 mg), which were targeted to produce plasma concentrations in and above the therapeutic range. The best fitting of the plasma concentration-time data was obtained by using a triexponential funct ion yielding a terminal t(1/2) of 8 hours. The areas under the plasma conce ntration versus time curves were proportional to dose, indicating linear ph armacokinetics. Moreover, the clearance and steady-state volume of distribu tion values were independent of the dose. The change in pulse rate and supi ne systolic and diastolic blood pressure was determined as pharmacodynamic effects of avitriptan. A "threshold log-linear" model, which accounts for t he linear increase in pharmacodynamic effect with the log of plasma concent rations when the latter was higher than a certain threshold value, adequate ly described the pharmacodynamic data. The threshold plasma drug concentrat ions for the pulse rate and the diastolic and systolic blood pressure were 14, 74, and 161 ng/ml, respectively. Overall, avitriptan has consistent, li near pharmacokinetics and increases systolic and diastolic blood pressure i n a predictable manner at a higher plasma concentration, However, this drug does not produce a significant change in pulse rate at the dose levels (12 .7-38 mg) evaluated in this study. (C) 1999 the American College of Clinica l Pharmacology.