Clinical pharmacokinetics of thalidomide

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Clinical Pharmacology

Background:

• Thalidomide, a glutamic acid derivative, is approved for erythema nodosum leprosum and investigated for inflammatory and oncologic conditions.
• It exists as (R)- and (S)-enantiomers, interconverting in plasma with varying protein binding.
• Over 90% of thalidomide is excreted in urine and feces within 48 hours, with minimal hepatic metabolism.

Purpose of the Study:

• To characterize the pharmacokinetic profile of thalidomide following oral administration.
• To evaluate the impact of single and multiple dosing on thalidomide pharmacokinetics.
• To assess the influence of dose, patient factors, and potential drug interactions on thalidomide's behavior in the body.

Main Methods:

• Single oral dose of 200 mg thalidomide in healthy volunteers.
• Multiple dose studies (200 mg/day for 21 days) and simulations at higher doses (400 and 800 mg/day).
• Pharmacokinetic parameters including C(max), T(max), AUC, half-life, and clearance were determined.

Main Results:

• Single dose: Slow absorption (lag time 30 min, T(max) 3-4 hours), extensive absorption (AUC 18 mg.h/L), apparent half-life 6 hours, clearance 10 L/h.
• Absorption rate-limited pharmacokinetics ('flip-flop') due to low solubility; the 6-hour half-life reflects absorption, not elimination.
• Multiple dosing and higher doses showed no accumulation; dose-proportional AUC increase from 50-400 mg, but less than proportional C(max) and prolonged T(max) at higher doses.

Conclusions:

• Thalidomide exhibits absorption rate-limited pharmacokinetics, with its elimination faster than absorption.
• No significant drug accumulation occurs with multiple dosing or increased doses.
• Pharmacokinetics are unaffected by age, sex, smoking, food, and are unlikely to be altered in patients with impaired renal or hepatic function.