Thalidomide does not alter estrogen-progesterone hormone single dose pharmacokinetics.

OBJECTIVES: To determine the single- and multiple-dose pharmacokinetics of oral thalidomide (200 mg/day, administered for 21 days) and to assess the effects of steady-state plasma concentrations of thalidomide on the single-dose pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: A randomized, 2-period crossover study was performed in 10 healthy premenopausal female volunteers. The pharmacokinetic profiles of plasma concentrations of thalidomide were evaluated with both noncompartmental and compartmental methods, whereas those of ethinyl estradiol and norethindrone were calculated with noncompartmental methods. The effects of steady-state plasma thalidomide concentrations on the pharmacokinetics of ethinyl estradiol and norethindrone were determined with use of an ANOVA model that included treatment sequence, subject within sequence, period, and treatment as factors. RESULTS: Thalidomide plasma concentrations were best predicted by a 1-compartment model with first-order absorption and elimination and an absorption time-lag. There were no significant differences between pharmacokinetic parameters for thalidomide after 1 dose and those after 18 consecutive doses. Except for a minor decrease of the elimination rate constant (k(e)) for ethinyl estradiol, coadministration of thalidomide had no significant effects on the pharmacokinetic profiles for either ethinyl estradiol or norethindrone. The change in k(e) for ethinyl estradiol during thalidomide administration was not associated with any alteration in the clearance or elimination half-life for this hormone. CONCLUSIONS: Multiple-dose pharmacokinetics of thalidomide is similar to the single-dose profile. This study did not investigate the efficacy of the 21-day fixed ethinyl estradiol-norethindrone regimen, but the results suggest that thalidomide is unlikely to affect the pharmacokinetics of orally administered hormonal contraceptives.

Thalidomide for the treatment of AIDS-associated wasting.

A double-blind, placebo-controlled trial of efficacy and safety of thalidomide in AIDS-associated wasting was carried out. Ninety-nine of 103 male patients had at least one on-study measurement (intent-to-treat [ITT] cohort). Patients were randomized to thalidomide at 100 mg/day (T100) or 200 mg/day (T200), or placebo for 8 weeks. By ITT analysis, the mean change in body weight of the placebo, T100, and T200 treatment groups was 0.3 kg (0.4%), 2.0 kg (3.0%), and 0.9 kg (1.4%), respectively (p = 0.021 for T100 versus placebo; p = 0.53 for T200 versus placebo). Of the 64 patients who completed the 8 weeks of study treatment, significant weight gain was observed in both the T100 group (2.2 kg, [33%]; p = 0.008 versus placebo) and the T200 group (1.5 kg [2.5%]; p = 0.019 versus placebo). Approximately half the weight gain was fat-free mass (bioimpedance analysis). Patients in the T100 or T200 groups had no significant change in CD4+ cell counts, neutrophil counts, or TNF-alpha levels, compared with placebo. HIV viral load measured as log10 copies/ml decreased by a median of 0.07 in the placebo group, and increased by a median of 0.29 (T100 group) and 0.23 (T200 group) (p = 0.024 andp = 0.018 versus placebo, respectively). Thalidomide therapy was associated with mild to moderate rashes and fevers, but not peripheral neuropathy. Although the anabolic benefits of high-dose thalidomide are limited by drug intolerance, 8 weeks of low-dose thalidomide results in significant weight gain in patients with AIDS-associated wasting.

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.

Accuracy and safety of a priori lithium loading.

A 30 mg/kg loading dose of slow-release lithium carbonate (Lithobid) was given in three divided doses to 38 patients to evaluate the accuracy and safety of achieving a therapeutic level in 12 hours. No patient experienced any adverse effects during the loading procedure or in the 12 hours after loading was completed. Prediction error (actual minus predicted level) for males was -0.11 mEq/L +/- 0.03 (SEM) with a mean absolute error of 0.16 mEq/L +/- 0.09 (SEM). Prediction error for females was -0.04 mEq/L +/- 0.07 (SEM) with a mean absolute error of 0.28 mEq/L +/- 0.14 (SEM). Lithium loading is safe and slightly overestimates the level actually achieved, except in obese females.

Repeated swim-stress reduces GABAA receptor alpha subunit mRNAs in the mouse hippocampus.

The effects of brief repeated swim stress on the expression of GABAA receptor alpha 1 subunit mRNAs was investigated in the mouse. Adult male mice were exposed to repeated brief (10 min) swim-stress once daily for 7 or 14 days and the levels of GABAA receptor alpha subunit mRNAs were quantified in the hippocampus 24 h after the last session by Northern analysis. Repeated swim stress for 14 days resulted in a 47.3% +/- 6.5 and 39.8% +/- 7.6 decrease in the levels of the 4.8 kb and 4.4 kb GABAA receptor alpha 1 subunit mRNAs, respectively. While there was a trend toward a reduction in the level of GABAA receptor alpha 1 subunit mRNAs following 7 days of repeated swim stress, the latter did not reach statistical significance. In contrast, no significant alterations in the levels of glutamic acid decarboxylase or beta-actin mRNAs were observed at either time point. The reduction in GABAA receptor alpha 1 subunit mRNAs following repeated swim stress may underlie similar alteration(s) in hippocampal GABAA receptor density previously observed following repeated swim stress.

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 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 Cmax and AUC0-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 Cmax with increases being less than proportional than changes in dose. AUC0-infinity increased proportionally with dose, suggesting that the overall amount of thalidomide absorbed, as well as its clearance, is independent of dose over the range used. V/F was found to 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 the highest dose was 50% less than for the other two lower doses. The less than proportional increases in Cmax were most likely due to thalidomide's low aqueous solubility. Thalidomide shows reasonable dose proportionality with respect to AUC from 50 to 400 mg.

Adrenalectomy prevents the stress-induced decrease in in vivo [3H]Ro15-1788 binding to GABAA benzodiazepine receptors in the mouse.

The effect of a single or repeated swim stress on in vivo benzodiazepine receptor binding to various brain regions in adrenalectomized and sham-operated (control) mice was assessed using the benzodiazepine receptor antagonist, [3H]Ro15-1788. In sham-operated mice the binding of [3H]Ro15-1788 to benzodiazepine receptors was reduced in the hippocampus and hypothalamus (single or repeated stress) and cerebral cortex (repeated swim stress) compared to non-stressed mice. In contrast, no alterations in [3H]Ro15-1788 binding were observed in any brain region in adrenalectomized mice after either single or repeated swim stress. These data suggest that an intact hypothalamic-pituitary-adrenal axis is required for the stress-induced decrease in benzodiazepine receptor occupancy measured using the in vivo binding method.

Repeated swim stress alters brain benzodiazepine receptors measured in vivo.

The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of [3H]Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in [14C]iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress [an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures], although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results.

Metabolism of thalidomide in human microsomes, cloned human cytochrome P-450 isozymes, and Hansen's disease patients.

Previous in vitro studies in rat microsomal preparations suggested that thalidomide is metabolized by the cytochrome P450 system (CYP). In this study, we examined the extent of thalidomide metabolism by preparations of pooled human microsomes, microsomes containing cloned human CYP isozymes (CYPIA2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), and Hansen's disease patients. Results indicated that thalidomide was a poor substrate for CYP isozymes. Alteration of incubation buffer, pH, incubation time, and microsome and thalidomide concentrations did not increase the production of any metabolites. Thalidomide also did not inhibit metabolism of CYP-specific substrates and therefore any interactions with other drugs that are metabolized by the same enzyme system are unlikely. Hansen's patients were given a single oral dose of thalidomide (400 mg), and their blood and urine were collected at time points up to 72 hours, processed, and analyzed by tandem mass spectrometry. Although thalidomide was present in the plasma and urine, no metabolites were found in the plasma and very low amounts of the 5-OH thalidomide metabolite were present in the urine. These results suggest that thalidomide does not undergo significant metabolism by human CYP and that clinically important interactions between thalidomide and drugs that are also metabolized by this enzyme system are unlikely. The major route of thalidomide breakdown in humans and animals is through spontaneous hydrolysis with subsequent elimination in the urine.

Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women.

The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.