Thalidomide in Oncology: the Peril and the Promise

Abstract

Questions relating to drug use, dosing, and related issues in oncology are presented in this regular feature. Pharmacokinetics Due to poor aqueous solubility, the absolute bioavailability of thalidomide is unknown. Time to maximal concentration (T max) ranged from 2.9 to 5.7 hours in patients with Hansen's disease and healthy volunteers. 3 A similar range of 2 to 7.1 hours was seen in elderly prostate cancer patients. 32 The volume of distribution in prostate cancer patients varied by dose level: 66.93 ± 34.27 L (200 mg/day) and 165.81 ± 84.18 L (1,200 mg/day). 32 The extent of plasma protein binding is unknown. 3 Significant hepatic metabolism has not yet been identified 3 ; however, the presence of an antiangiogenic active metabolite is anticipated. 30 Thalidomide does not induce or inhibit its own metabolism. 3 Renal elimination is minor, with 0.7% of the dose excreted unchanged in the urine. 3 The major route of elimination appears to be non-enzymatic hydrolysis. 3 The elimination half-life is reported to be 5 to 7 hours, based on Hansen's disease patients who rarely receive more than 400 mg/day. 3 Half-life was shown to be dose-related in prostate cancer patients: 6.52 ± 3.81 hours (200 mg/day) and 18.25 ± 14.08 hours (1,200 mg/day). 32 However, overall clearance was comparable between the two groups (7.41 ± 2.05 L/h and 7.21 ± 2.89 L/h, respectively). 32 Renal dysfunction would be expected to have minimal effects on thalidomide's pharmacokinetics. Hepatic dysfunction may not produce a major effect on the elimination of thalidomide itself, but it could affect the production of the presumed antiangiogenic metabolite. Contraindications and Precautions Several side effects, particularly severe human teratogenicity, are associated with thalidomide therapy and thus have limited its use in specific populations. Some of the adverse effects are listed in Table 1, and a summary of the indications and contraindications of thalidomide use are presented in Table 2. Chemical structure of thalidomide.

Thalidomide: A Banned Drug Resurged into Future Anticancer Drug

“…contains both left-and right-handed optical isomers in equal amounts. It has been reported that teratogenicity and sedative properties are associated with S-and Renantiomers, respectively [34]. The enantiomers can interconvert (racemize) in vivo.…”

Targeted therapy in melanoma

“…However, thalidomide and its analogues (lenalidomide, CC-4047) have immunomodulatory, antiangiogenic, antiproliferative, and proapoptotic properties, which are responsible for antitumor action. Thalidomide also inhibits the inflammatory response by decreasing cyclooxygenase-2 activity 59,60. Thalidomide is a potent inhibitor of TNF-α by inducing TNF-α mRNA degradation,61 and thereby decreasing the density of TNF-α-induced adhesion molecules such as ICAM-I and VCAM-I 62.…”

Talidomida no tratamento do eritema nodoso hansênico: revisão sistemática dos ensaios clínicos e perspectivas de novas investigações

“…However, these trials conducted in the 1960's and 1970's were fundamental in the process of reutilization of thalidomide as a beneficial drug, and in fact preceding the description of its immunomodulating action, in the 1990's. 25 Several reviews about thalidomide have been published in various fields, including (a) immunology, biology and molecular genetics, 31,[58][59][60][61][62][63][64][65][66] (b) fpharmacology, [67][68][69] (c) clinical aspects, therapy, [70][71][72][73][74] [75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92] (e) teratogenicity 93,94,74 and (f) analogous drugs. 24 The discussion of these articles is not in the scope of this study.…”