Thalidomide dose proportionality assessment following single doses to healthy subjects

Thalidomide is approved in the United States for treating erythema nodosum leprosum, a complication of leprosy; The present study determined the single-dose oral pharmacokinetics and dose proportionality from 50 to 400 mg of Celgene's commercial Thalomid (R) thalidomide formulation in an open-label, single-dose, three-way crossover study. Fifteen healthy subjects were given 50, 200, and 400 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using noncompartmental methods, and dose proportionality was assessed by linear regression of dose-normalized C-max and AUC(0-infinity). No serious or unexpected adverse events occurred. The most common adverse events were dizziness, somnolence, headache, and nausea. One patient was discontinued because of pharyngitis. There was a significant deviation from proportionality for C-max with increases being less than proportionally than changes in dose normalized C,, creases being less than proportional than changes in dose. AUC(0-infinity) increased proportionally with dose, suggesting that the overall amount of thalidomide absorbed, as well as ifs clearance, is independent of dose over the range used. V/F was found 50 increase with dose. This was most likely due to the terminal rate constant, which is used to calculate V/F, actually representing the absorption process rather than elimination (i.e., flip-flop phenomenon). The terminal rate constant (absorption rate constant) for She highest dose was 50% less than for the other two lower doses. The less than proportional increases in C-max were most likely due to thalidomide's low aqueous solubility. Thalidomide shows reasonable dose proportionality with respect to AUC from 50 to 400 mg.