Pharmacokinetics and Hemodynamic Effects of Single Oral Doses of Thalidomide in Asymptomatic Human Immunodeficiency Virus-Infected Subjects

Abstract

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15 +/- 0.24 mug/ml (100 mg) and 1.92 +/- 0.47 mug/ml (200 mg; p < 0.001), which were achieved (Tmax) at 2.5 +/- 1.5 h and 3.3 +/- 1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6 +/- 1.2 hr (100 mg) and 5.3 +/- 2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9 +/- 15.6 liters (100 mg) and 82.7 +/- 34.9 liters (200 mg) while total body cleardss ances (Cl/F) were 10.4 +/- 2.1 and 10.8 +/- 1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.