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 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 microg/ml (100 mg) and 1.92+/-0.47 microg/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 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 frequently at the higher dose of thalidomide.
Noormohamed
F H
FH
Section of Clinical Pharmacology, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, UK. f.noormohamed@ic.ac.uk
Youle
M S
MS
Higgs
C J
CJ
Kook
K A
KA
Hawkins
D A
DA
Lant
A F
AF
Thomas
S D
SD
D000284:Administration, Oral; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D013792:Thalidomide / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
D013792:Thalidomide