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 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1–2 mg/L at 3–4 hours after administration, absorption lag time of 30 minutes, total exposure (AUC∞) 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 Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accumulation, with Cssmax 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 400mg. Because of the low solubility of thalidomide, Cmax is less than proportional to dose, and tmax 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.
Human Serum Albumin Thalidomide Ethinylestradiol Capsule Formulation Norethindrone
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This review is dedicated to the memory of Wayne Colburn PhD who passed away on February 2, 2003. Wayne will be remembered for his leadership and passion in advancing the profession of Clinical Pharmacology and for his enormous contribution to this discipline. This review was sponsored by Celgene Corporation. Doctors Teo, Stirling, Jaworsky, Scheffler, Thomas and Laskin are employees of Celgene Corporation.
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