SAFETY, TOLERANCE, AND PHARMACOKINETICS OF ATEVIRDINE MESYLATE (U-87201E) IN ASYMPTOMATIC HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PATIENTS

Atevirdine mesylate (U-87201E) is a new nonnucleoside (bisheteroarylpi perazine) inhibitor of human immunodeficiency virus type 1 reverse tra nscriptase. In a double-blind, escalating single-dose study the safety , tolerance, and pharmacokinetics of atevirdine mesylate were investig ated in 24 asymptomatic human immunodeficiency virus-seropositive male patients, Each patient received one single oral dose of atevirdine me sylate and placebo separated by an interval of 1 to 3 weeks. For each dose level (400, 800, 1,200, and 1,600 mg) six patients received drug and placebo on separate occasions. Blood samples were collected before dosing and at intervals afterward for safety evaluation and estimatio n of atevirdine and metabolite levels. The concentrations of atevirdin e and its principal metabolite (U-89255) in serum were determined by h igh performance liquid chromatography. The results of the study showed that atevirdine mesylate is well tolerated at all dose levels, No cli nically significant effects on vital signs, electrocardiograms, or lab oratory tests were observed. Occasional headache and nausea were repor ted both in the drug group and in the placebo group, The times to peak values were relatively short (0.5 to 1.0 h), suggesting a rapid absor ption. The maximum concentrations of drug in serum were 1.4 mu M (400 mg), 4.2 mu M (800 mg), 7.3 mu M (1,200 mg), and 5.8 mu M (1,600 mg), The values of the pharmacokinetic parameters for atevirdine were found to have relatively large intersubject variabilities, and consequently , the study had little power to detect dose-dependent changes in the v alues of the pharmacokinetic parameters. The oral clearance of atevird ine tended to increase by 90% as the atevirdine mesylate doses increas ed from 400 to 1,600 mg, but this change in oral clearance was not sta tistically significant, The values of the pharmacokinetic parameters d etermined in the study were similar to those found in a previous singl e-dose study in healthy volunteers.