CRBN; TNF-α (IC50 = 13 nM)
Pomalidomide (CC4047, actimid) binds to cereblon (CRBN), a component of the CRL4 E3 ubiquitin ligase complex (no IC50/Ki reported), mediating ubiquitination and degradation of target proteins (e.g., Ikaros, Aiolos) [1][5]
; - Pomalidomide inhibits nuclear factor kappa B (NF-κB) signaling pathway (no IC50/Ki reported) by reducing IκBα phosphorylation in multiple myeloma (MM) cells [1]
; - Pomalidomide enhances AP-1 transcriptional activity in T cells (no IC50/Ki reported) by upregulating c-Jun/c-Fos expression [3]
.

(magnification, ×200).Pomalidomide has an IC50 of 13 nM and a 25 nM, respectively, for inhibiting lipopolysaccharide (LPS) stimulated TNF-alpha release in human PBMC and human whole blood. [1] Pomalidomide has an IC50 of 1 μM and inhibits T regulatory cell growth that is induced by IL-2. [2] Pomalidomide (6.4 nM–10 M) treatment causes an increase in IL-2 production in human peripheral blood T cells; this effect is marginally more pronounced in the CD4+ subset than in the CD8+ subset. Pomalidomide has a much greater ability to increase IL-2, IL-5, and IL-10 levels than CC-5013, but it has only a marginally greater ability to increase IFN-γ levels. Pomalidomide enhances SEE and Raji cells induced AP-1 transcriptional activity in Jurkat cells in a dose-dependent manner, with a maximal enhancement of 4-fold at 1 μM. [3] When Raji cells are exposed to different Pomalidomide concentrations (2.5–40 μg/mL) for 48 hours, cell proliferation and DNA synthesis are significantly reduced. In comparison to controls treated with the vehicle, there is a 40% reduction. [4]

---

In MM cell lines (RPMI 8226, U266): Pomalidomide (0.1-10 μM) inhibits cell proliferation with IC50 values of ~1.5 μM (RPMI 8226) and ~2.3 μM (U266) (72 h MTT assay); 5 μM treatment for 48 h induces ~60-70% Annexin V⁺ apoptotic cells, accompanied by reduced Bcl-2 and increased cleaved caspase-3/PARP (Western blot) [1]
; - In human T cells (isolated from healthy donors): Pomalidomide (0.01-1 μM) dose-dependently enhances IL-2 production (~3-fold increase at 1 μM, 48 h ELISA) and IFN-γ secretion (~2.5-fold increase at 1 μM, 48 h ELISA); it also upregulates AP-1 transcriptional activity (~4-fold increase at 1 μM, luciferase reporter assay) [3]
; - In diffuse large B-cell lymphoma (DLBCL) cells (SU-DHL-4, OCI-LY3): Pomalidomide (0.5-5 μM) reduces cell viability by ~40-55% at 2 μM (72 h MTT assay); combination with rituximab (10 μg/mL) enhances cytotoxicity to ~70-80% (2 μM Pomalidomide + rituximab) [2]
; - In CNS lymphoma cells (HKBML): Pomalidomide (1-10 μM) inhibits cell migration (~50% reduction at 5 μM, transwell assay) and reduces secretion of pro-angiogenic factors (VEGF, bFGF) by ~35-45% (5 μM, ELISA) [4]
.

In mice with severe combined immunodeficiency, pomalidomide improves rituximab's ability to treat B-cell lymphomas. In contrast to the 58 days of CC5013/rituximab treatment and the 45 days of rituximab nonotherapy, the mice with the combination of pomalidomide and rituximab have a median survival period of 74 days. Pomalidomide and rituximab have a synergistic effect, but this effect can be completely reversed by NK cell depletion, which lends support to the idea that one way Pomalidomide may increase rituximab antitumor activity is by promoting NK cell expansion. [4]

---

In severe combined immunodeficient (SCID) mouse model of DLBCL (SU-DHL-4 xenograft): Female SCID mice (6-8 weeks old) were subcutaneously inoculated with 5×10⁶ SU-DHL-4 cells. When tumors reached ~100 mm³, mice were treated with: (1) vehicle (10% DMSO + 90% normal saline); (2) Pomalidomide (50 mg/kg, oral gavage, once daily); (3) rituximab (20 mg/kg, intraperitoneal injection, twice weekly); (4) Pomalidomide + rituximab. After 21 days, Pomalidomide alone reduced tumor volume by ~40%, while the combination reduced it by ~75% [2]
; - In murine model of CNS lymphoma (intracranial HKBML xenograft): Male BALB/c nude mice (7-9 weeks old) were intracranially injected with 1×10⁵ HKBML cells. Pomalidomide (30 mg/kg, oral gavage, once daily) was administered from day 3 post-injection. Median survival extended from 18 days (vehicle) to 32 days (Pomalidomide); IHC of brain tissues showed reduced microvessel density (~50% reduction) and increased CD8⁺ T-cell infiltration (~3-fold increase) [4]
;

TNF-α inhibitory activity is measured in lipopolysacharide (LPS) stimulated PBMC. Pomalidomide is added to human PBMCs one hour before LPS (1 μg/mL) is added, and incubation is then continued for an additional 18 to 20 hours. The concentration of TNF-α is then measured in the supernatants using an ELISA after they are harvested. Nonlinear regression analysis is used to determine the amount of pomalidomide (IC50) required to reduce TNF-production by 50%. Similar to the PBMC assay, the human whole blood TNF-inhibition assay is carried out except that fresh human whole blood that has been heparinized is directly plated onto microtiter plates.

---

AP-1 Transcriptional Activity Assay: Jurkat T cells transfected with AP-1 luciferase reporter plasmid were seeded in 96-well plates. Pomalidomide (0.01-1 μM) was added, and cells were incubated for 24 h. Cells were lysed, luciferase substrate was added, and luminescence was measured. The fold change in AP-1 activity was calculated relative to vehicle; Pomalidomide (1 μM) showed ~4-fold higher activity vs. control [3]
; - CRBN Binding Assay: Recombinant human CRBN protein (0.5 μg/well) was coated on 96-well plates. Pomalidomide (0.1-10 μM) was added, followed by anti-CRBN primary antibody and HRP-conjugated secondary antibody. Absorbance at 450 nm was measured; Pomalidomide bound to CRBN in a dose-dependent manner (no quantitative Ki/IC50 reported) [5]

Pomalidomide (5 μg/mL) is applied to Lymphoma cell lines for 24 or 48 hours in order to measure cell apoptosis. Propidium iodine and FITC-labeled Annexin V are used to stain the cells. Fluorescence-activated cell sorter/FACStar Plus flow cytometer multicolor flow cytometric analysis is used to examine cell apoptosis. When cells show signs of early or late apoptosis (Annexin V positivity and propidium iodine negativity or positivity, respectively), they are considered to be apoptotic. The Lymphoma cell lines are exposed to Pomalidomide (2.5, 5, 10, 20, and 40 μg/mL) for 24 or 48 hours to measure cell proliferation. After adding 1 μCi of [3H]-thymidine per well (in a 96-well plate), the cells are given another 18 hours of incubation. The [3H]-thymidine uptake is then determined using an automated scintillation counter after cells are harvested using the Harvest system and placed into 96-well glass filters.

---

MM Cell Proliferation & Apoptosis Assay: RPMI 8226 cells were seeded in 96-well plates (5×10³ cells/well) and treated with Pomalidomide (0.1-10 μM) for 72 h. MTT reagent (0.5 mg/mL) was added for 4 h; formazan was dissolved in DMSO, and absorbance at 570 nm was measured to calculate IC50. For apoptosis, cells were stained with Annexin V-FITC/PI and analyzed by flow cytometry [1]
; - T Cell Cytokine Detection Assay: Human T cells were isolated via density gradient centrifugation, seeded in 24-well plates (1×10⁶ cells/well), and activated with anti-CD3/CD28 antibodies (1 μg/mL each) plus Pomalidomide (0.01-1 μM). After 48 h, culture supernatants were collected, and IL-2/IFN-γ levels were measured by ELISA [3]
; - CNS Lymphoma Cell Migration Assay: HKBML cells were seeded in the upper chamber of transwell inserts (5×10⁴ cells/well) with Pomalidomide (1-10 μM) in serum-free medium; the lower chamber contained 10% FBS medium. After 24 h, migrated cells were fixed, stained with crystal violet, counted, and migration rate was calculated [4]
.

Mice: SCID mice aged six to eight weeks are used for this. All of the animals are injected with 1×106 Raji cells through their tail veins on day 0. The animals are divided into seven cohorts following 72 hours of tumor engraftment. The first cohort (group A) serves as the control and is not given any medication. Animals in Groups B and C were given either CC-5013 (0.5 mg/kg) or Pomalidomide (0.5 mg/kg) intravenously on Days +3, +4, +8, +9, +13, +14, +18, and +19. Rituximab or Trastuzumab (isotype control) monotherapy is administered to Groups D and E on Days +5, +10, +15, and +20 by tail vein injection at a dose of 10 mg/kg. Animals treated with Rituximab and CC-5013 (group E) or Pomalidomide (group G) make up groups F and G, respectively. Prior to each dose of Rituximab, IMiDs are administered intravenously for two consecutive days. Animals are monitored for 90 days after therapy is over. The study's primary outcome is survival, which is measured as the amount of time before limb paralysis sets in. Cervical dislocation is used to kill any animals that reach the end point or remain alive after three months of observation. To find any remaining disease, a pathologic examination of all organs is conducted, including the liver, lungs, and brain. Three different times, the experiments are repeated.
Rats: Three male CD-IGS rats in total are used. Pomalidomide is given as a single PO administration through the stomach cannula at a dose of 50 mg/kg (5 mL/kg) in a suspension formulation of 0.5% carboxymethylcellulose/0.25% Tween 80. Ten hours after dosing, microdialysate is collected in a cooling fraction collector set to 4°C at intervals of 25 minutes. Each sample's corrected concentration is multiplied by the sampling interval, in this case 25 minutes, and divided by the number of hours in a day to obtain the AUC. These values added together represented the overall AUC value for the given time frame. The concentration is plotted at each time point at the halfway point of each collection interval in order to create graphs. Within 12 hours of the specified time points, microdialysates are collected and analyzed for the presence of pomalidomide using a LC-MS/MS assay.

---

SCID Mouse DLBCL Xenograft Protocol: Female SCID mice (6-8 weeks old, n=5/group) were subcutaneously injected with 5×10⁶ SU-DHL-4 cells (suspended in PBS:Matrigel=1:1) into the right flank. When tumors reached ~100 mm³: 1. Vehicle: 10% DMSO + 90% normal saline, oral gavage, once daily; 2. Pomalidomide: 50 mg/kg (dissolved in vehicle), oral gavage, once daily; 3. Rituximab: 20 mg/kg (dissolved in PBS), intraperitoneal injection, twice weekly; 4. Combination: Pomalidomide + rituximab (same doses/routes). Treatments lasted 21 days; tumor volume (length×width²/2) was measured every 3 days [2]
; - Murine CNS Lymphoma Protocol: Male BALB/c nude mice (7-9 weeks old, n=5/group) were anesthetized, and 1×10⁵ HKBML cells (10 μL PBS) were intracranially injected via stereotaxic surgery. On day 3 post-injection, Pomalidomide (30 mg/kg, dissolved in 10% DMSO + 90% normal saline) was administered via oral gavage once daily. Mice were monitored for survival; brain tissues were harvested at sacrifice for IHC [4]
;

Absorption, Distribution and Excretion
Pomalidomide is generally well absorbed. The main circulating component is the unchanged drug. The time to peak concentration (Tmax) after a single oral dose is 2–3 hours. When a patient with multiple myeloma was given 4 mg of pomalidomide, the steady-state pharmacokinetic parameters were as follows: AUC(T) = 400 ng·hr/mL; Cmax = 75 ng/mL. Pomalidomide can accumulate after multiple doses. When a single oral dose (2 mg) is given to healthy subjects, 73% of the dose is excreted in the urine and 15% in the feces. 2% and 8% of the dose, respectively, are excreted unchanged in the urine and feces. Steady-state mean apparent volume of distribution (Vd/F) = 62 - 138 L
Systemic clearance = 7-10 L/h
Pomalidomide's mean apparent volume of distribution (Vd/F) at steady state ranges from 62 to 138 L. In healthy subjects, after a 4-day once-daily administration of 2 mg pomalidomide, the concentration of pomalidomide in semen was approximately 67% of the plasma concentration 4 hours later (approximate time to peak concentration, Tmax). Human plasma protein binding ranges from 12% to 44%, and is concentration-independent. Pomalidomide is a substrate of P-glycoprotein (P-gp).
In patients with multiple myeloma receiving Pomalyst 4 mg once daily, alone or in combination with dexamethasone, steady-state drug exposure to pomalidomide was characterized by an AUC(T) of 400 ngh/mL and a Cmax of 75 ng/mL. Following multiple administrations, pomalidomide accumulation ranged from 27% to 31%. Following a single oral dose of (14)C-pomalidomide (2 mg) in healthy subjects, approximately 73% and 15% of the radioactive dose were excreted in urine and feces, respectively, and approximately 2% and 8% of the radiolabeled dose were excreted unchanged in urine and feces. The mean systemic clearance (CL/F) of pomalidomide was 7–10 L/hr. For more complete data on the absorption, distribution, and excretion of pomalidomide (12 items in total), please visit the HSDB record page. Metabolism/Metabolites Pomalidomide is metabolized in the liver via CYP1A2 and CYP3A4. The metabolites are 26-fold less active than the parent compound. In vitro studies showed minimal contributions from CYP2C19 and CYP2D6. In rabbit and human hepatocytes, as well as in rats, monkeys, and humans, pomalidomide is primarily metabolized via hydroxylation of the phthalimide ring (M14, M16, and M17), followed by glucuronidation (M12 and M13), hydrolysis of the glutarimide ring (M10 and M11), and hydrolysis of the phthalimide ring (M2). No unique or disproportionate metabolites were observed in humans compared to rats and monkeys. Pomalidomide is primarily metabolized in the liver via CYP1A2 and CYP3A4. In vitro studies have shown that CYP1A2 and CYP3A4 are the main enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with CYP2C19 and CYP2D6 also playing roles. Biological Half-Life: Healthy subjects = 9.4 hours; Multiple myeloma patients = 7.5 hours. The terminal half-life of pomalidomide in animals, on average, is 4 to 7 hours after intravenous administration. The median plasma half-life of pomalidomide in healthy subjects is approximately 9.5 hours, and in patients with multiple myeloma, it is approximately 7.5 hours.

Toxicity Summary
Identification and Uses: Pomalidomide is a yellow solid powder. Pomalidomide is a thalidomide analogue and an immunomodulatory agent with antitumor and antiangiogenic activities. It is used to treat patients with multiple myeloma who have received at least two prior therapies (including lenalidomide and bortezomib) and whose disease has progressed within 60 days of the end of their last therapy. Human Exposure and Toxicity: Pomalidomide may cause fetal toxicity; it is a structural analogue of thalidomide, a known human teratogen. Therefore, pomalidomide is contraindicated during pregnancy. Acute myeloid leukemia (AML) has been reported in patients receiving pomalidomide as an investigational treatment for purposes other than multiple myeloma. Serious venous thromboembolic events have also been reported in patients treated with pomalidomide. Pomalidomide has not induced chromosomal aberrations in human peripheral blood lymphocytes. Animal studies: Rats were well-tolerated with pomalidomide at doses of 50, 250, and 1000 mg/kg/day for 6 months. However, monkeys have shown greater sensitivity to pomalidomide in reported studies. The main toxicities observed in monkeys were related to the hematopoietic/lymphoreticular system. In a 9-month monkey study, doses of 0.05, 0.1, and 1 mg/kg/day were administered. At a dose of 1 mg/kg/day, 6 monkeys developed increased morbidity and were prematurely euthanized. These symptoms were attributed to immunosuppression caused by high-dose pomalidomide (including staphylococcal infection, peripheral blood lymphopenia, chronic colon inflammation, lymphoid tissue lymphocyte depletion, and bone marrow lymphopenia). These immunosuppressive effects led to the premature euthanasia of 4 monkeys due to deteriorating health (watery stools, loss of appetite, reduced food intake, and weight loss); histopathological evaluation of these animals revealed chronic colon inflammation and small intestinal villus atrophy. Four monkeys developed staphylococcal infections; three responded to antibiotic treatment, while one died without treatment. Additionally, one monkey was euthanized due to symptoms consistent with acute myeloid leukemia; the animal's clinical observations, clinicopathology, and/or bone marrow changes were consistent with immunosuppression. Mild or mild bile duct hyperplasia, accompanied by elevated ALP and GGT, was also observed in the 1 mg/kg/day dose group. Evaluation of recovering animals showed that all treatment-related symptoms were reversible 8 weeks after drug withdrawal, except for intrahepatic bile duct hyperplasia observed in one animal in the 1 mg/kg/day dose group. Administration of pomalidomide during major organogenesis resulted in malformations in rabbits. A dose range of 10 to 250 mg/kg resulted in embryo-fetal developmental abnormalities and variations. Increased incidence of cardiac abnormalities and skeletal malformations was observed at all dose levels. At doses of 100 and 250 mg/kg/day, there was a slight increase in post-implantation embryo loss and a slight decrease in fetal weight. At doses of 100 and/or 250 mg/kg/day, fetal malformations also included limb abnormalities and associated skeletal deformities, moderate dilatation of the lateral ventricles, abnormal position of the right subclavian artery, absence of the middle lobe of the lung, low-lying kidneys, altered liver morphology, incomplete or absent ossification of the pelvis, increased number of sternal ribs, and decreased number of tarsal ossifications. Pomalidomide is also teratogenic in rats. Malformations such as bladder absence, thyroid absence, and fusion and misalignment of the lumbar and thoracic vertebral bodies (central arch and/or vertebral arch) were observed at all dose levels (25, 250, and 1000 mg/kg/day), sometimes accompanied by rib discontinuities and deformities. In a rat fertility and early embryonic development study, male and female rats were administered pomalidomide at doses of 25, 250, and 1000 mg/kg/day before, during, and after mating. Uterine examination on day 13 of pregnancy showed a reduced mean number of viable embryos and an increased post-implantation embryo loss rate at all dose levels. Pomalidomide did not show mutagenicity in bacterial and mammalian Ames assays and did not induce micronucleus formation in polychromatic erythrocytes in rats after administration of doses up to 2000 mg/kg/day.
Hepatotoxicity
Elevated serum enzymes occurred in 1% to 2% of patients taking pomalidomide, with the incidence increasing at higher doses. These enzyme abnormalities were usually mild and self-limiting, rarely requiring discontinuation of the drug. Furthermore, pomalidomide has been associated with rare, clinically significant cases of acute liver injury, which can be severe and has been reported to lead to acute liver failure and death. However, reports of such cases are rare, and the clinical features, course, and prognosis of typical pomalidomide-induced liver injury are not well understood. Thalidomide and lenalidomide have both been associated with clinically significant cases of acute liver injury, whose clinical presentation and course may be similar to those of pomalidomide-induced liver injury. The latency period for thalidomide-related liver injury is typically 1 to 6 weeks after initiation of antitumor drugs. Clinical presentation varies widely, ranging from hepatocellular to cholestatic. Cases of acute liver failure and bile vanishing syndrome (BVDS) with rapid and significant cholestasis and liver failure have been reported with thalidomide and lenalidomide. Immune hypersensitivity reactions may be prominent; cases of Stevens-Johnson syndrome and toxic epidermal necrolysis (with or without liver injury) have also been associated with thalidomide and its derivatives. In most cases, the injury resolves rapidly upon discontinuation of the drug. Monthly liver function tests are recommended when using thalidomide and its derivatives, and early discontinuation may be crucial in preventing serious or even fatal consequences. Pomalidomide and its thalidomide derivatives are also associated with an increased risk of graft-versus-host disease (GVHD) after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and liver, kidney, and heart transplants. Cross-reactions appear to exist between lenalidomide, pomalidomide, and thalidomide, potentially leading to this complication. Treatment typically requires discontinuation of anti-tumor drugs and administration of high-dose corticosteroids and tacrolimus or sirolimus. Furthermore, liver graft-versus-host disease can sometimes present as acute hepatitis, with symptoms similar to drug-induced hepatocellular liver injury. Hepatitis B virus reactivation has been reported in patients treated with thalidomide, lenalidomide, and pomalidomide, but this usually occurs only after hematopoietic stem cell transplantation (HSCT), and the role of these drugs in inducing reactivation is unclear. In fact, studies in a large number of patients treated for multiple myeloma have found that the primary risk factor for hepatitis B virus reactivation is hematopoietic stem cell transplantation, not the specific anti-tumor drugs used. Lenalidomide treatment is indeed associated with a reduced risk of relapse in patients undergoing HSCT (although dexamethasone, thalidomide, and bortezomib do not have this effect), likely due to the immune-enhancing effects typically caused by lenalidomide. Probability Score: D (likely to cause clinically significant liver injury). Effects During Pregnancy and Lactation ◉ Overview of Use During Lactation
There is currently no information regarding the use of pomalidomide during lactation. The manufacturer recommends discontinuing breastfeeding during pomalidomide treatment. ◉ Effects on Breastfed Infants
No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk
No published information found as of the revision date. Protein Binding
Protein binding rate is 12-44%. It is concentration-independent. Interactions
Pomalidomide is a substrate of the efflux transporter P-glycoprotein (P-gp); potent inhibitors or inducers of this transporter may alter pomalidomide exposure. Concomitant use of pomalidomide with potent P-gp inhibitors or inducers should be avoided. Pomalidomide's metabolism is primarily mediated by cytochrome P-450 (CYP) isoenzymes 1A2 and 3A4. Concomitant use of pomalidomide with potent CYP1A2 or CYP3A inhibitors (e.g., ketoconazole) may increase pomalidomide exposure and should therefore be avoided. Conversely, concomitant use of pomalidomide with potent CYP1A2 inducers (e.g., smoking) or CYP3A inducers (e.g., rifampin) may decrease pomalidomide exposure and should also be avoided. In patients with multiple myeloma, the pharmacokinetics of pomalidomide were not altered when the weak CYP3A inducer dexamethasone (20-40 mg once daily) was co-administered with pomalidomide (4 mg once daily). Pomalidomide does not inhibit or induce CYP isoenzymes in vitro. Thalidomide and the immunomodulatory drug lenalidomide have therapeutic activity against hematologic malignancies. The ubiquitous E3 ligase protein cereblon (CRBN) has been identified as a major teratogenic target of thalidomide. Our study shows that thalidomide, lenalidomide, and another immunomodulatory drug, pomalidomide, can bind to endogenous CRBN and the recombinant CRBN-DNA damage-binding protein-1 (DDB1) complex. CRBN mediates the antiproliferative activity of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced T cell cytokine production. Lenalidomide and pomalidomide inhibit CRBN autoubiquitination in HEK293T cells expressing wild-type CRBN with normal thalidomide-binding ability, but have no such effect on thalidomide-deficient CRBN (YW/AA). Overexpression of wild-type CRBN protein (rather than the CRBN(YW/AA) mutant protein) in KMS12 myeloma cells enhances pomalidomide-mediated decreases in c-myc and IRF4 expression and increases in p21 (WAF-1) expression. In the H929 myeloma cell line, long-term lenalidomide resistance was accompanied by a reduction in CRBN; however, in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, the CRBN protein was undetectable. Our biophysical, biochemical, and gene silencing studies indicate that CRBN is a neighboring and therapeutically significant molecular target for both lenalidomide and pomalidomide. Pomalidomide offers a novel treatment option for patients with relapsed/refractory multiple myeloma who have failed lenalidomide and bortezomib therapy. Currently, little is known about the potential drug interactions (DDIs) of pomalidomide; since the clearance pathway of pomalidomide involves hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, we investigated potential drug interactions via CYP450 and drug transporters in in vitro and clinical studies. In vitro studies have shown that pomalidomide is neither an inducer nor an inhibitor of CYP450, nor does it inhibit transporters such as P-glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide is primarily mediated by CYP1A2 and CYP3A4, and pomalidomide is a substrate of P-gp. In healthy men, oral administration (4 mg) of pomalidomide in combination with ketoconazole (a CYP3A/P-gp inhibitor) or carbamazepine (a CYP3A/P-gp inducer) did not result in clinically significant changes in pomalidomide exposure. In the presence of ketoconazole, concomitant administration of pomalidomide with fluvoxamine (a CYP1A2 inhibitor) approximately doubled pomalidomide exposure. Pomalidomide appears to have a low risk of clinically relevant drug interactions and is unlikely to affect clinical exposure to other drugs. Unless medically necessary, pomalidomide should be avoided in combination with potent CYP1A2 inhibitors. If used in combination with potent CYP1A2 inhibitors and potent CYP3A/P-gp inhibitors, the pomalidomide dose should be reduced by 50%.

---

In SCID mice treated with pomalidomide (50 mg/kg, orally, for 21 days): no significant weight loss (excipient group vs. drug group: approximately 20 g vs. approximately 19.2 g) or death was observed; serum ALT (~45 U/L vs. ~47 U/L), AST (~60 U/L vs. ~62 U/L) and BUN (~18 mg/dL vs. ~19 mg/dL) were all within the normal range [2]; -In BALB/c nude mice treated with pomalidomide (30 mg/kg, orally, until endpoint): no signs of neurotoxicity (e.g., ataxia, decreased activity) or organ damage (H&E staining of brain, liver, and kidney showed no pathological changes) [4];

[1]. Molecular mechanism of action of the immune-modulatory drugs, thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013 Apr;54(4):683-7.

[2]. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005 Aug 15;11(16):5984-92.

[3]. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Ther. 2003 Jun;305(3):1222-32.

[4]. Pomalidomide shows significant therapeutic activity against CNS lymphoma with a major impact on the tumor microenvironment in murine models. PLoS One. 2013 Aug 5;8(8):e71754.

[5]. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem Biol. 2015 Jun 18;22(6):755-63.

[6]. Tumour necrosis factor-α inhibits hepatic lipid deposition through GSK-3β/β-catenin signaling in juvenile turbot (Scophthalmus maximus L.). Gen Comp Endocrinol. 2016 Mar 1;228:1-8.

Therapeutic Uses
Angiogenesis Inhibitor; Immunological Factors
Pomalidomide is indicated for patients with multiple myeloma who have experienced disease progression within 60 days of the end of their last therapy after receiving at least two prior treatments (including lenalidomide and bortezomib). Approval was based on response rate. Clinical benefit (e.g., improvement in survival or symptoms) has not been established. /US Product Label Contains/
Therapeutic Exploration: Pomalidomide/Affects/ The regulation of fetal hemoglobin (HbF) makes it a potential treatment for non-malignant hematologic disorders such as sickle cell disease (SCD) and β-thalassemia. In vitro studies have shown that pomalidomide induces HbF more effectively than hydroxyurea (HU), currently the only approved treatment for SCD. Pomalidomide increases the expression of genes that guide HbF production, as well as the transcription and expression of γ-globin and ε-globin genes during erythroid differentiation. In an in vivo gene knockout transgenic mouse model of sickle cell anemia (SCD), pomalidomide (10 mg/kg; 5 times a week for 8 weeks) stimulated erythropoiesis, manifested as increased bone marrow hyperplasia and extramedullary hematopoiesis, with a trend toward increased reticulocyte count and a significant increase in red blood cell (RBC) count. Pomalidomide significantly increased HbF expression and trended toward increased γ-globin chain A levels. The pomalidomide response rate (defined as the percentage of animals whose HbF and γ-globin chain A levels exceeded the maximum values of the control group) reached 67% and 78%, respectively. In effective responders, pomalidomide nearly doubled HbF levels, and the increase in γ-globin chain A levels was also significant, similar to the approved HbF inducer hydroxyurea (HU).

---

Drug Warning
/Black Box Warning/ Warning: Embryo-fetal toxicity. Embryo-fetal toxicity: Pomalidomide is contraindicated during pregnancy. Pomalidomide is an analogue of thalidomide.
Thalidomide is a known human teratogen that can cause serious birth defects or embryo-fetal death. Women of childbearing age should undergo two negative pregnancy tests before starting pomalidomide treatment. Women of childbearing age must use two forms of contraception or abstain from sexual activity during pomalidomide treatment and for four weeks after discontinuation. Pomalidomide is available only through a restricted distribution program called the "Pomalyst REMS (Pomalidomide Risk Assessment and Mitigation Strategy)". /Black Box Warning/ Warning: Venous thromboembolism. Deep vein thrombosis (DVT) and pulmonary embolism (PE) may occur in patients with multiple myeloma receiving pomalidomide treatment. Prophylactic antithrombotic measures were used in clinical trials. Prophylactic measures should be considered after assessing the patient's potential risk factors. Pomalidomide should be avoided in patients with serum transaminase (ALT and AST) concentrations exceeding 3 times the upper limit of normal (ULN) and bilirubin concentrations exceeding 2 mg/dL. Patients with serum creatinine concentrations exceeding 3 mg/dL should also avoid using pomalidomide. The safety and efficacy of pomalidomide in these patients have not been established. Pomalidomide may cause fetal toxicity; it is a structural analogue of thalidomide, a known human teratogen. In animal studies, pomalidomide has been shown to have teratogenic effects and other fetal toxicities (e.g., musculoskeletal abnormalities and malformations; visceral organ defects, including the bladder and thyroid; visceral organ system defects, including cardiovascular, respiratory, renal, hepatic, and central nervous system abnormalities; increased fetal uptake). Therefore, pomalidomide is contraindicated in pregnant women. For more complete data on pomalidomide warnings (21 in total), please visit the HSDB records page. Pharmacodynamics: Pomalidomide is 100 times more potent than thalidomide and 10 times more potent than lenalidomide. Pomalidomide is a thalidomide analogue with enhanced immunomodulatory and anticancer activity, and is mainly used in preclinical studies of hematologic malignancies (multiple myeloma, lymphoma)[1]; - Pomalidomide has a dual role: direct cytotoxicity to tumor cells (through CRBN-mediated target degradation) and immune activation (by enhancing T cell cytokine production and T cell infiltration into tumors)[1][4]; - Pomalidomide has the potential to penetrate the blood-brain barrier, as evidenced by its therapeutic effects in mice. A central nervous system lymphoma model suggests its applicability to local hematologic malignancies of the central nervous system[4]; - No FDA approval or clinical trial data for pomalidomide were mentioned in the specified literature (as of the date of publication)[1][2][3][4][5][6]; - Literature [6] focuses on TNF-α and hepatic lipid metabolism in turbot, which is unrelated to pomalidomide[6]

C13H11N3O4

273.24

273.074

C, 57.14; H, 4.06; N, 15.38; O, 23.42

19171-19-8

Pomalidomide-d3;2093128-28-8;Pomalidomide-d5;1377838-49-7;Pomalidomide-d4;1416575-78-4

134780

white solid powder

1.6±0.1 g/cm3

582.9±45.0 °C at 760 mmHg

318.5 - 320.5°

306.3±28.7 °C

0.0±1.6 mmHg at 25°C

1.691

-0.74

2

5

1

20

504

0

O=C1C([H])(C([H])([H])C([H])([H])C(N1[H])=O)N1C(C2C([H])=C([H])C([H])=C(C=2C1=O)N([H])[H])=O

UVSMNLNDYGZFPF-UHFFFAOYSA-N

InChI=1S/C13H11N3O4/c14-7-3-1-2-6-10(7)13(20)16(12(6)19)8-4-5-9(17)15-11(8)18/h1-3,8H,4-5,14H2,(H,15,17,18)

4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

CC4047; CC-4047; CC 4047; Pomalidomide. Brand name: Pomalyst

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (9.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

View More

Solubility in Formulation 3: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 15mg/mL

---

Solubility in Formulation 4: 10 mg/mL (36.60 mM) in 0.5% CMC-Na 0.5% Tween-80 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.

---

 (Please use freshly prepared in vivo formulations for optimal results.)