Clinical Pharmacokinetics

, Volume 43, Issue 5, pp 311–327

Clinical Pharmacokinetics of Thalidomide

  • Steve K. Teo
  • Wayne A. Colburn
  • William G. Tracewell
  • Karin A. Kook
  • David I. Stirling
  • Markian S. Jaworsky
  • Michael A. Scheffler
  • Steve D. Thomas
  • Oscar L. Laskin
Review Article

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 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.

References

  1. 1.
    Koch H. Thalidomide and congeners as anti-inflammatory agents. Prog Med Chem 1995; 22: 165–242CrossRefGoogle Scholar
  2. 2.
    Somers GF. Pharmacological properties of thalidomide (α-phthalidimo glutarimide), a new sedative hypnotic drug. Br J Pharmacol 1960; 15: 111–6Google Scholar
  3. 3.
    Neuhaus G, Ibe K. Survival following suicide attempt with 14 × 100mg of thalidomide. Dis Nerv Syst 1961; 22: 52–3PubMedGoogle Scholar
  4. 4.
    Mellin GW, Katzenstein M. The saga of thalidomide: neuropathy to embryopathy, with case reports and congenital abnormalities. N Engl J Med 1963; 267: 1184–93CrossRefGoogle Scholar
  5. 5.
    Schumacher H, Blake D, Gurian J, et al. A comparison of the teratogenic activity of thalidomide in rabbits and rats. J Pharmacol Exp Ther 1968; 160: 189–99PubMedGoogle Scholar
  6. 6.
    Szabo K, Steelman R. Effects of maternal thalidomide treatment on pregnancy, fetal development and mortality of the offspring in random-bred mice. Am J Vet Res 1967; 28: 1823–8PubMedGoogle Scholar
  7. 7.
    Kelsey F. Thalidomide update: regulatory aspects. Teratology 1988; 38: 221–6CrossRefPubMedGoogle Scholar
  8. 8.
    Sheskin J. Thalidomide in the treatment of lepra reaction. Clin Pharmacol Ther 1965; 6: 303–6PubMedGoogle Scholar
  9. 9.
    Calabrese L, Fleischer A. Thalidomide: current and potential clinical applications. Am J Med 2000; 108: 487–95CrossRefPubMedGoogle Scholar
  10. 10.
    Teo S, Resztak K, Scheffler M, et al. Thalidomide in the treatment of leprosy. Microbes Infect 2002; 4: 1193–202CrossRefPubMedGoogle Scholar
  11. 11.
    Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71CrossRefPubMedGoogle Scholar
  12. 12.
    Srinavas S, Guardino A. Randomized phase II trial of high and low dose thalidomide in metastatic renal cell carcinoma [abstract]. Proc Am Soc Clin Oncol 2002; 38: 2403Google Scholar
  13. 13.
    Marx G, Pavlakis N, McCowatt S, et al. Phase II study of thalidomide in the treatment of recurrent glioblastoma multiforme. J Neurooncol 2001; 54: 31–8CrossRefPubMedGoogle Scholar
  14. 14.
    Govindarajan R, Heaton K, Broadwater R, et al. Effect of thalidomide on gastrointestinal toxic effects of irinotecan. Lancet 2000; 356: 566–7CrossRefPubMedGoogle Scholar
  15. 15.
    Moreira A, Sampaio E, Zmuidzinas A, et al. Thalidomide exerts its inhibitory action on TNF-α by enhancing mRNA degradation. J Exp Med 1993; 177: 1675–80CrossRefPubMedGoogle Scholar
  16. 16.
    D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994; 91: 4082–5CrossRefPubMedGoogle Scholar
  17. 17.
    Chen T-L, Vogelsang G, Petty B, et al. Plasma pharmacokinetics and urinary excretion of thalidomide after oral dosing in healthy male volunteers. Drug Metab Dispos 1989; 17: 402–5PubMedGoogle Scholar
  18. 18.
    Trapnell CB, Donahue SR, Collins JM, et al. Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone. Clin Pharmacol Ther 1998; 64: 597–602CrossRefPubMedGoogle Scholar
  19. 19.
    Teo SK, Colburn WA, Thomas SD. Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers. J Clin Pharmacol 1999; 39: 1162–8PubMedGoogle Scholar
  20. 20.
    Scheffler M, Colburn W, Kook K, et al. Thalidomide does not alter estrogen-progesterone hormone single-dose pharmacokinetics. Clin Pharmacol Ther 2000; 65: 483–90CrossRefGoogle Scholar
  21. 21.
    Teo S, Scheffler M, Kook K, et al. Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women. Biopharm Drug Dispos 2000; 21: 33–40CrossRefPubMedGoogle Scholar
  22. 22.
    Teo S, Scheffler M, Kook K, et al. Thalidomide single-dose proportionality assessment in healthy subjects. J Clin Pharmacol 2001; 41: 662–7CrossRefPubMedGoogle Scholar
  23. 23.
    Piscitelli SC, Figg WD, Hahn B, et al. Single-dose pharmacokinetics of thalidomide in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1997; 41: 2797–9PubMedGoogle Scholar
  24. 24.
    Figg WD, Raje S, Bauer KS, et al. Pharmacokinetics of thalidomide in an elderly prostate cancer population. J Pharm Sci 1999; 88: 121–5CrossRefPubMedGoogle Scholar
  25. 25.
    Noormohamed FH, Youle MS, Higgs CJ, et al. Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects. AIDS Res Hum Retroviruses 1999; 15: 1047–52CrossRefPubMedGoogle Scholar
  26. 26.
    Baidas S, Winer E, Fleming G, et al. Phase II evaluation of thalidomide in patients with metastatic breast cancer. J Clin Oncol 2000; 18: 2710–7PubMedGoogle Scholar
  27. 27.
    Fine H, Figg W, Jaeckle K, et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000; 18: 708–15PubMedGoogle Scholar
  28. 28.
    Eriksson T, Bjorkman S, Hoglund P. Clinical pharmacology of thalidomide. Eur J Pharmacol 2001; 57: 365–76CrossRefGoogle Scholar
  29. 29.
    Teo S, Chandula R, Harden J, et al. Sensitive and rapid method for the determination of thalidomide in human plasma and semen using solid-phase extraction and liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 767: 145–51CrossRefPubMedGoogle Scholar
  30. 30.
    Eriksson T, Bjorkman S, Fyge A. Determination of thalidomide in plasma and blood by high-performance liquid chromatography: avoiding hydrolytic degradation. J Chromatogr 1992; 582: 211–6CrossRefPubMedGoogle Scholar
  31. 31.
    Kenyon B, Browne F, D’Amato R. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997; 64: 971–8CrossRefPubMedGoogle Scholar
  32. 32.
    Reist M, Carrupt P-A, Francotte E, et al. Chiral inversion and hydrolysis of thalidomide mechanisms and catalysis by bases and serum albumin and chiral stability of teratogenic metabolites. Chem Res Toxicol 1998; 11: 1521–8CrossRefPubMedGoogle Scholar
  33. 33.
    Hoglund P, Eriksson T, Bjorkman S. A double-blind study of the sedative effects of the thalidomide enantiomers in humans. J Pharmacokinet Biopharm 1998; 26: 363–83PubMedGoogle Scholar
  34. 34.
    Eriksson T, Bjorkman S, Roth B, et al. Enantiomers of thalidomide: blood distribution and the influence of serum albumin on chiral inversion and hydrolysis. Chirality 1998; 10: 223–8CrossRefPubMedGoogle Scholar
  35. 35.
    Eriksson T, Bjorkman S, Roth B, et al. Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality 1995; 7: 44–52CrossRefPubMedGoogle Scholar
  36. 36.
    Wnendt S, Finkam M, Winter W, et al. Enantioselective inhibition of TNF-α release by thalidomide and thalidomide-analogues. Chirality 1996; 8: 390–6CrossRefPubMedGoogle Scholar
  37. 37.
    Turk B, Jiang H, Liu J. Binding of thalidomide to α1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor α production. Proc Natl Acad Sci U S A 1996; 93: 7552–6CrossRefPubMedGoogle Scholar
  38. 38.
    Iyer C, Languillon J, Ramanujan K, et al. WHO coordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. Bull World Health Organ 1971; 45: 719–32PubMedGoogle Scholar
  39. 39.
    Ehrenpreis E, Kane S, Cohen L, et al. Thalidomide therapy for patients with refractory Crohn’s disease: an open label trial. Gastroenterology 1999; 117: 1271–7CrossRefPubMedGoogle Scholar
  40. 40.
    Braun A, Harding F, Weinreb S. Teratogen metabolism of thalidomide activation is mediated by cytochrome P-450. Toxicol Appl Pharmacol 1986; 82: 175–9CrossRefPubMedGoogle Scholar
  41. 41.
    Tsambaos D, Bolsen K, Georgiou S, et al. Effects of oral thalidomide on rat liver and skin microsomal P450 isozyme activities on urinary porphyrin excretion: interaction with oral hexachlorobenzene. Arch Dermatol Res 1994; 286: 347H–9HCrossRefGoogle Scholar
  42. 42.
    Teo S, Trigg N, Shaw M, et al. Subchronic toxicity of thalidomide in rodents after 13 weeks of oral administration. Int J Toxicol 1999; 18: 337–52CrossRefGoogle Scholar
  43. 43.
    Knoche B, Blaschke G. Stereoselectivity of the in vitro metabolism of thalidomide. Chirality 1994; 6: 221–4CrossRefGoogle Scholar
  44. 44.
    Ando Y, Fuse E, Figg W. Thalidomide metabolism by the CYP2C family. Clin Cancer Res 2002, 73Google Scholar
  45. 45.
    Eriksson T, Bjorkman S, Roth B, et al. Hydroxylated metabolites of thalidomide: formation in vitro and in vivo in man. J Pharm Pharmacol 1998; 50: 1409–16CrossRefPubMedGoogle Scholar
  46. 46.
    Teo S, Sabourin P, O’Brien K, et al. Metabolism of thalidomide in human microsomes, cloned human cytochrome P-450 isozymes and Hansen’s disease patients. J Biochem Mol Toxicol 2000; 14: 140–7CrossRefPubMedGoogle Scholar
  47. 47.
    Schumacher H, Smith R, Williams R. The metabolism of thalidomide: the fate of thalidomide and some of its hydrolysis products in various species. Br J Pharmacol 1965; 25: 338–51Google Scholar
  48. 48.
    Schumacher H, Blake D, Gillette G. Disposition of thalidomide in rabbits and rats. J Pharmacol Exp Ther 1968; 160: 201–11PubMedGoogle Scholar
  49. 49.
    Schumacher H, Wilson J, Terapane J, et al. Thalidomide: disposition in rhesus monkeys and studies of its hydrolysis in tissues of this and other species. J Pharmacol Exp Ther 1970; 173: 265–9PubMedGoogle Scholar
  50. 50.
    Eriksson T, Bjorkman S, Roth B, et al. Intravenous formulations of the enantiomers of thalidomide: pharmacokinetic and initial pharmacodynamic characterization in man. J Pharm Pharmacol 2000; 52: 807–17CrossRefPubMedGoogle Scholar
  51. 51.
    Francis J, Biggerstaff J, Amirkhorsravi A. Hemostatis and malignancy. Semin Thromb Hemost 1998; 24: 93–109CrossRefPubMedGoogle Scholar
  52. 52.
    Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001; 98: 1614–5CrossRefPubMedGoogle Scholar
  53. 53.
    Teo S, Harden J, Burke A, et al. Thalidomide is distributed into human semen after oral dosing. Drug Metab Dispos 2001; 29: 1355–7PubMedGoogle Scholar
  54. 54.
    Zeldis J, Williams B, Thomas S, et al. STEPS: a comprehensive program for controlling and monitoring access to thalidomide. Clin Ther 1999; 21: 319–30CrossRefPubMedGoogle Scholar
  55. 55.
    Rosenfeld W, Doose D, Walker S, et al. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997; 38: 317–23CrossRefPubMedGoogle Scholar
  56. 56.
    Saano V, Glue P, Banfield C, et al. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther 1995; 58: 523–32CrossRefPubMedGoogle Scholar
  57. 57.
    Shenfield G. Oral contraceptives: are drug interactions of clinical significance?. Drug Saf 1993; 9(1): 21–37CrossRefPubMedGoogle Scholar
  58. 58.
    Guengerich F. Inhibition of oral contraceptives steroid-metabolizing enzymes by steroids and drugs. Am J Obstet Gynecol 1990; 163: 2159–63PubMedGoogle Scholar
  59. 59.
    Lacy C, Armstrong L, Ingrim N, Lance L, editors. Drug information handbook. Cleveland: Lexi-Comp Inc, 1997–98Google Scholar
  60. 60.
    Barlogie B, Zangari M, Spencer T, et al. Thalidomide in the management of multiple myeloma. Semin Hematol 2001; 38: 250–9CrossRefPubMedGoogle Scholar
  61. 61.
    Kosa T, Maruyama T, Otagiri M. Species difference of serum albumins: I. drug binding sites. Pharm Res 1997; 14: 1607–13CrossRefPubMedGoogle Scholar
  62. 62.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–23PubMedGoogle Scholar
  63. 63.
    Lown K, Bailey D, Fontana R, et al. Grapefruit increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99: 2545–53CrossRefPubMedGoogle Scholar
  64. 64.
    Hess C, Hunziker T, Kupfer A, et al. Thalidomide-induced peripheral neuropathy: a prospective clinical, neurophysiological and pharmacogenetic evaluation. J Neurol 1986; 233: 83–9CrossRefPubMedGoogle Scholar
  65. 65.
    Eriksson T, Hoglund P, Turesson I, et al. Pharmacokinetics of thalidomide in patients with impaired renal function and while on and off dialysis. J Pharm Pharmacol 2003; 55: 1701–6CrossRefPubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Steve K. Teo
    • 1
  • Wayne A. Colburn
    • 2
  • William G. Tracewell
    • 3
  • Karin A. Kook
    • 4
  • David I. Stirling
    • 1
  • Markian S. Jaworsky
    • 1
  • Michael A. Scheffler
    • 1
  • Steve D. Thomas
    • 1
  • Oscar L. Laskin
    • 1
  1. 1.Celgene CorporationWarrenUSA
  2. 2.MDS Pharma ServicesPhoenixUSA
  3. 3.MDS Pharma ServicesLincolnUSA
  4. 4.Salamandra LLCChevy ChaseUSA

Personalised recommendations