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Thalidomide | CAS No: 50-35-1 | GMP-certified suppliers
A medication that provides immunomodulatory and anti-inflammatory benefits for acute treatment and maintenance of moderate to severe erythema nodosum leprosum (ENL) in leprosy patients.
Therapeutic categories
Primary indications
- Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL)
Product Snapshot
- Thalidomide is available in oral capsule and tablet formulations, including film-coated and coated tablets
- It is primarily indicated for the treatment and maintenance therapy of erythema nodosum leprosum (ENL)
- The product holds approval or investigational status in key regulatory markets including the EU, US, and Canada, with some withdrawals noted
Clinical Overview
Pharmacodynamically, thalidomide exhibits immunomodulatory, anti-inflammatory, and anti-angiogenic activities. It modulates inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Moreover, thalidomide inhibits basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), pathways pertinent to angiogenesis and tumor progression. The molecule is racemic; the (+)R enantiomer has sedative properties, whereas the (–)S enantiomer is responsible for teratogenicity. Enantiomers interconvert in vivo, precluding the use of a single enantiomer to mitigate teratogenic risks.
The mechanism of action involves binding to cereblon, a component of the E3 ubiquitin ligase complex, facilitating the selective degradation of transcription factors IKZF1 and IKZF3, essential for the proliferation of malignant myeloma cells. Thalidomide also downregulates TNF-α production by inhibiting myeloid differentiation factor 88 (MyD88) expression and nuclear factor kappa B (NF-κB) activation, in part through modulation of alpha-1 acid glycoprotein (AGP). These effects contribute to its immunosuppressive and anti-angiogenic profile.
Key ADME parameters for thalidomide demonstrate that it undergoes extensive racemization in vivo, leading to challenges in enantiomer-specific pharmacokinetics. As a substrate and modulator of multiple cytochrome P450 enzymes, thalidomide may participate in various drug-drug interactions.
Safety considerations are paramount due to its potent teratogenic potential. Strict exclusion of pregnancy prior to treatment initiation is mandatory, and adherence to risk management programs, including contraception, is required. Additional adverse effects include possible myelosuppression, peripheral neuropathy, and photosensitivity, necessitating careful patient monitoring.
Thalidomide is marketed globally under various brand names for approved indications, with usage predominantly confined to controlled clinical environments. Procurement of thalidomide API demands rigorous quality control to ensure stereochemical purity, appropriate polymorphic form, and absence of impurities linked to its teratogenicity. Compliance with Good Manufacturing Practice (GMP) standards and experience in handling substances with strict regulatory controls is critical for sourcing.
Identification & chemistry
| Generic name | Thalidomide |
|---|---|
| Molecule type | Small molecule |
| CAS | 50-35-1 |
| UNII | 4Z8R6ORS6L |
| DrugBank ID | DB01041 |
Pharmacology
| Summary | Thalidomide acts primarily as an immunomodulatory agent targeting cereblon within the E3 ubiquitin ligase complex to induce degradation of transcription factors IKZF1 and IKZF3, which are critical for malignant myeloma cell survival. It also modulates inflammatory pathways by inhibiting MyD88 and NF-kB signaling, leading to reduced production of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Additionally, thalidomide exhibits anti-angiogenic effects through suppression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). |
|---|---|
| Mechanism of action | The mechanism of action of thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha . The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. |
| Pharmacodynamics | Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans . |
Targets
| Target | Organism | Actions |
|---|---|---|
| Protein cereblon | Humans | inhibitor |
| DNA | Humans | intercalation |
| alpha1-acid glycoprotein | Humans | binder |
ADME / PK
| Absorption | The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T<sub>max</sub>) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t<sub>lag</sub> of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c<sub>max</sub> and AUC<sub>∞</sub> were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively. |
|---|---|
| Half-life | The half-life of thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 h. |
| Protein binding | The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. |
| Metabolism | Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as _in vitro_ studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of [omeprazole], a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human. |
| Route of elimination | Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. |
| Volume of distribution | The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. |
| Clearance | The oral clearance of thalidomide is 10.50 ± 2.10 L/h. |
Formulation & handling
- Thalidomide is a small molecule compound administered exclusively via oral dosage forms such as capsules and tablets.
- Formulations should consider the slight water solubility and near-neutral LogP, facilitating oral absorption with minimal formulation complexity.
- Handling precautions include advising administration after meals and avoiding alcohol to mitigate increased sedation effects.
Regulatory status
| Lifecycle | The API has reached market maturity in the United States with key patent protections expired between 2013 and 2020, while in Canada, patents have expired or are expiring as recently as 2023. The product is established in the EU, US, and Canadian markets. |
|---|
| Markets | EU, US, Canada |
|---|
Supply Chain
| Supply chain summary | The manufacturing and supply landscape for Thalidomide includes multiple originator companies involved in packaging and distribution across key markets such as the US, EU, and Canada. Branded products are established globally, with several brand names present in these regions. Patent expiration dates extending into the 2020s indicate both existing and potential upcoming generic competition in major markets. |
|---|
Safety
| Toxicity | The oral LD<sub>50</sub> in rats is 113 mg/kg and 2 g/kg in mouse. Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. |
|---|
- Oral LD50 values indicate moderate acute toxicity (113 mg/kg in rats
- 2 g/kg in mice)
- Two-year carcinogenicity studies in rodents showed no compound-related tumorigenic effects at doses up to 75-fold the maximum human daily dose based on body surface area
Thalidomide is a type of Immunomodulators
Immunomodulators, a category of pharmaceutical active pharmaceutical ingredients (APIs), are substances that help regulate and modify the immune response of an individual. These compounds play a crucial role in treating various immune-related disorders and diseases. Immunomodulators work by either enhancing or suppressing the immune system, depending on the specific condition being treated.
Immunomodulators are used in the treatment of autoimmune disorders, such as rheumatoid arthritis, multiple sclerosis, and psoriasis. By suppressing the immune system, these APIs help reduce the overactive immune response associated with these conditions, thereby alleviating symptoms and preventing further damage to the body's tissues.
On the other hand, immunomodulators are also employed to boost the immune system in cases of immunodeficiency disorders. These APIs stimulate the immune response, enabling the body to better fight off infections and diseases. Additionally, immunomodulators are utilized in the prevention and treatment of organ transplant rejection, where they help modulate the immune system to accept the transplanted organ.
The development and production of immunomodulators require rigorous testing and quality control to ensure their safety and efficacy. Pharmaceutical companies carefully formulate these APIs into various dosage forms, including tablets, capsules, injections, and topical preparations, to cater to different patient needs.
In summary, immunomodulators form a vital category of pharmaceutical APIs that regulate and modify the immune system. With their ability to modulate immune responses, these compounds contribute significantly to the management and treatment of various immune-related disorders and diseases, improving the quality of life for many patients.
Thalidomide API manufacturers & distributors
Compare qualified Thalidomide API suppliers worldwide. We currently have 10 companies offering Thalidomide API, with manufacturing taking place in 5 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Adley Formulations | Producer | India | India | CoA, GMP | 14 products |
| Chongqing Jooe Co., Ltd. | Producer | China | China | CoA, FDA, GMP, MSDS | 10 products |
| Flavine | Distributor | Germany | Unknown | CoA | 83 products |
| Hetero Labs | Producer | India | India | CoA, GMP, USDMF, WC | 90 products |
| Laurus Labs | Producer | India | India | CoA, GMP, USDMF, WC | 50 products |
| Mylan | Producer | India | India | CoA, USDMF | 201 products |
| Seratec | Producer | France | France | CoA, GMP | 5 products |
| Shilpa Medicare Ltd | Producer | India | India | BSE/TSE, CoA, EDMF/ASMF, GMP, ISO9001, MSDS, USDMF, WC | 54 products |
| Symed Labs | Producer | India | India | CoA, GMP, WC | 28 products |
| Triquim | Producer | Argentina | Argentina | CoA, GMP, ISO9001 | 16 products |
When sending a request, specify which Thalidomide API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
Use the list above to find high-quality Thalidomide API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
