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Clinical pharmacology of thalidomide

Eriksson, Tommy LU ; Björkman, Sven and Höglund, Peter LU (2001) In European Journal of Clinical Pharmacology 57(5). p.365-376
Abstract
Background: Thalidomide has a chiral centre, and the racemate of (R)- and (S)-thalidomide was introduced as a sedative drug in the late 1950s. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide due to its unique anti-inflammatory and immunomodulatory effects. Objective: To critically review pharmacokinetic studies and briefly review pharmacodynamic effects and studies of thalidomide in consideration of its chemical and stereochemical properties and metabolism. Methods: Literature search and computer simulations of pharmacokinetics. Results: Rational use of thalidomide is problematic due to lack of basic knowledge of its mechanism of action, effects of the separate... (More)
Background: Thalidomide has a chiral centre, and the racemate of (R)- and (S)-thalidomide was introduced as a sedative drug in the late 1950s. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide due to its unique anti-inflammatory and immunomodulatory effects. Objective: To critically review pharmacokinetic studies and briefly review pharmacodynamic effects and studies of thalidomide in consideration of its chemical and stereochemical properties and metabolism. Methods: Literature search and computer simulations of pharmacokinetics. Results: Rational use of thalidomide is problematic due to lack of basic knowledge of its mechanism of action, effects of the separate enantiomers and metabolites and dose- and concentration-effect relationships. Due to its inhibition of tumour necrosis factor-a and angiogenesis, racemic thalidomide has been tested with good effect in a variety of skin and mucous membrane disorders, Crohn's disease, graft-versus-host disease, complications to human immunodeficiency virus and, recently, in multiple myeloma. Adverse reactions are often related to the sedative effects. Irreversible toxic peripheral neuropathy and foetal malformations are serious complications that can be prevented. The results of several published pharmacokinetic studies can be questioned due to poor methodology and the use of non-stereospecific assays. The enantiomers of thalidomide undergo spontaneous hydrolysis and fast chiral interconversion at physiological pH. The oral bioavailability of thalidomide has not been unequivocally determined, but available data suggest that it is high. Absorption is slow, with a time to maximum plasma concentration of at least 2 h, and may also be dose-dependent; however, that of the separate enantiomers may be faster due to higher aqueous solubility. Estimation of the volume of distribution is complicated by probable hydrolysis and chiral inversion also in peripheral compartments. A value of around I 1/kg is however plausible. Plasma protein binding is low with little difference between the enantiomers. Elimination of thalidomide is mainly by pH-dependent spontaneous hydrolysis in all body fluids with an apparent mean clearance of 10 l/h for the (R)- and 21 l/h for the (S)enantiomer in adult subjects. Blood concentrations of the (R)-enantiomer are consequently higher than those of the (S)-enantiomer at pseudoequilibrium. The mean elimination half-life of both enantiomers is 5 h. One hydroxylated metabolite has been found in low concentrations in the blood. Since both enzymatic metabolism and renal excretion play minor roles in the elimination of thalidomide, the risk of drug interactions seems to be low. Conclusions: The interest in and use of thalidomide is increasing due to its potential as an immunomodulating and antiangiogenic agent. The inter-individual variability in distribution and elimination is low. Apart from this, its use is complicated by the lack of knowledge of dose- or concentration-effect relationships, possible dose-dependent oral absorption and of course by its well-known serious adverse effects. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Thalidomide, Stereoisomers, Pharmacokinetics
in
European Journal of Clinical Pharmacology
volume
57
issue
5
pages
365 - 376
publisher
Springer
external identifiers
  • wos:000171266700003
  • scopus:0035431717
ISSN
1432-1041
DOI
10.1007/s002280100320
language
English
LU publication?
yes
id
1f5aaa59-c56b-404c-a108-28f5887d00ec (old id 1118879)
date added to LUP
2008-06-27 09:29:29
date last changed
2018-01-21 03:51:29
@article{1f5aaa59-c56b-404c-a108-28f5887d00ec,
  abstract     = {Background: Thalidomide has a chiral centre, and the racemate of (R)- and (S)-thalidomide was introduced as a sedative drug in the late 1950s. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide due to its unique anti-inflammatory and immunomodulatory effects. Objective: To critically review pharmacokinetic studies and briefly review pharmacodynamic effects and studies of thalidomide in consideration of its chemical and stereochemical properties and metabolism. Methods: Literature search and computer simulations of pharmacokinetics. Results: Rational use of thalidomide is problematic due to lack of basic knowledge of its mechanism of action, effects of the separate enantiomers and metabolites and dose- and concentration-effect relationships. Due to its inhibition of tumour necrosis factor-a and angiogenesis, racemic thalidomide has been tested with good effect in a variety of skin and mucous membrane disorders, Crohn's disease, graft-versus-host disease, complications to human immunodeficiency virus and, recently, in multiple myeloma. Adverse reactions are often related to the sedative effects. Irreversible toxic peripheral neuropathy and foetal malformations are serious complications that can be prevented. The results of several published pharmacokinetic studies can be questioned due to poor methodology and the use of non-stereospecific assays. The enantiomers of thalidomide undergo spontaneous hydrolysis and fast chiral interconversion at physiological pH. The oral bioavailability of thalidomide has not been unequivocally determined, but available data suggest that it is high. Absorption is slow, with a time to maximum plasma concentration of at least 2 h, and may also be dose-dependent; however, that of the separate enantiomers may be faster due to higher aqueous solubility. Estimation of the volume of distribution is complicated by probable hydrolysis and chiral inversion also in peripheral compartments. A value of around I 1/kg is however plausible. Plasma protein binding is low with little difference between the enantiomers. Elimination of thalidomide is mainly by pH-dependent spontaneous hydrolysis in all body fluids with an apparent mean clearance of 10 l/h for the (R)- and 21 l/h for the (S)enantiomer in adult subjects. Blood concentrations of the (R)-enantiomer are consequently higher than those of the (S)-enantiomer at pseudoequilibrium. The mean elimination half-life of both enantiomers is 5 h. One hydroxylated metabolite has been found in low concentrations in the blood. Since both enzymatic metabolism and renal excretion play minor roles in the elimination of thalidomide, the risk of drug interactions seems to be low. Conclusions: The interest in and use of thalidomide is increasing due to its potential as an immunomodulating and antiangiogenic agent. The inter-individual variability in distribution and elimination is low. Apart from this, its use is complicated by the lack of knowledge of dose- or concentration-effect relationships, possible dose-dependent oral absorption and of course by its well-known serious adverse effects.},
  author       = {Eriksson, Tommy and Björkman, Sven and Höglund, Peter},
  issn         = {1432-1041},
  keyword      = {Thalidomide,Stereoisomers,Pharmacokinetics},
  language     = {eng},
  number       = {5},
  pages        = {365--376},
  publisher    = {Springer},
  series       = {European Journal of Clinical Pharmacology},
  title        = {Clinical pharmacology of thalidomide},
  url          = {http://dx.doi.org/10.1007/s002280100320},
  volume       = {57},
  year         = {2001},
}