Clinical Pharmacokinetics of Thalidomide

Abstract

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions is being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200 mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (C(max)) of 1-2 mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUC( infinity )) of 18 mg. h/L, apparent elimination half-life of 6 hours and apparent systemic clearance of 10 L/h. Thalidomide pharmacokinetics are best described by a one-compartment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacokinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than its absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state C(max) (C(ss)(max)) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accumulation, with C(ss)(max) of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400 mg. Because of the low solubility of thalidomide, C(max) is less than proportional to dose, and t(max) is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokinetics are not expected to change in patients with impaired liver or kidney function.

The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model

“…24 However, after a single oral dose of 200 mg of thalidomide (as the US-approved capsule formulation) in healthy volunteers, absorption was found to be slow, and this resulted in a peak serum concentration (C max ) of 1-2 mg/l at 3-4 h after administration, an absorption lag time of 30 min, an apparent elimination half-life of 6 h, and an apparent systemic clearance of 10 l/h. 60 Therefore, in the present study, we injected thalidomide i.p. 3 h before ischemic insult, in view of its elimination half-life and the fact that absorption is faster by the i.p.…”

The Pharmacokinetics of Low-Dose Thalidomide in Japanese Patients with Refractory Multiple Myeloma

“…Piscitelli et al 11) demonstrated that the averages of Vd/F , CL/F and T 1/2 were 87.8 l, 9.2 l/h and 6.5 h, respectively, after 100 mg dosing to human immunodeficiency virus-infected patients. Thalidomide pharmacokinetics are evaluated to be similar between healthy and patient populations, 12) and we speculated that the smaller Vd/F and CL/F may result from differences other than diseases, for example, lower body weight or higher bioavailability in Japanese patients. Consequently, AUC 0-∞ was 22.6Ϯ10.9 and 21.0Ϯ8.58 mg · h/ml after the first and second 100 mg administration, respectively (Table 1).…”

“…The cutoff AUC 0-∞ value for adverse events was determined by drawing the ROC curve. Correlations between AUC 0-∞ and plasma concentration at each time point (1,2,4,6,8,12, 24 h) after the first and second administration were evaluated by simple linear regression analysis. Pharmacokinetics The plasma concentration-time profiles after the first and second administration at a dose of 100 mg were well fitted to the simulation curves (Fig.…”

Preparation, Characterization, and In Vitro Intestinal Permeability Evaluation of Thalidomide–Hydroxypropyl-β-Cyclodextrin Complexes

“…The molecule contains a glutarimide moiety with a single chiral center and undergoes spontaneous hydrolysis in aqueous solutions at pH 7.4 (6). In addition to the chemical instability, thalidomide exhibits diverse polymorphs (7) and absorption rate-limited pharmacokinetics.…”