Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor n ecrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disor ders. 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, a nd were best described by a one-compartment model with first-order absorpti on and elimination processes. The drug was rapidly absorbed, with a mean ab sorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.3 33.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean C-max values were 1.15 +/- 0.24 mu g/ml (100 mg) and 1.92 +/- 0.47 mu g/ml (200 mg; p < 0.001), which were achieved (T-max) at 2.5 +/- 1.5 h and 3.3 +/- 1.4 hr, respectively, Plasma concentrations of thalidomide declined the reafter, 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 distribut ion (V-dss/F) were 69.9 +/- 15.6 liters (100 mg) and 82.7 +/- 34.9 liters ( 200 mg) while total body clearances (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 fre quently at the higher dose of thalidomide.