Pomalidomide

273.24

273.24

1592732-453-0

Solid yellow powder

L04AX06|L - Antineoplastic and immunomodulating agents

29251900

110

0.2

yellow

1.570±0.06 g/cm3(Predicted)

318.5 - 320.5°

582.9±45.0 °C(Predicted)

306.3±28.7 °C

1.691

DMSO: ≥14mg/mL

2-8°C

7.54X10-16 mm Hg at 25 deg C (est)

pKa1 = 1.56 (aromatic amine); pKa2 = 11.59 (secondary amide) (est)

Henry's Law contant = 4.56X10-20 atm-cu m/mol at 25 °C (est)

NONH for all modes of transport

3

NR3397905

Stable under recommended storage conditions.

P201, P202, P264, P270, P280, P281, P301+P310, P302+P352, P308+P313, P312, P321, P322, P330, P363, P405, P501

H301

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pomalidomide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H360 (42.86%): May damage fertility or the unborn child [Danger Reproductive toxicity]|P201, P202, P260, P281, P308+P313, P314, P405, and P501|Aggregated GHS information provided by 7 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Skin protection: Handle with gloves.|Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed.|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

Care should be exercised in handling of Pomalyst. Pomalyst capsules should not be opened or crushed. If powder from Pomalyst contacts the skin, wash the skin immediately and thoroughly with soap and water. If Pomalyst contacts the mucous membranes, flush thoroughly with water.|Appropriate engineering controls: General industrial hygiene practice.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Most common adverse reactions (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain and pyrexia.|IDENTIFICATION AND USE: Pomalidomide is a solid yellow powder. Pomalidomide, a thalidomide analog, is an immunomodulatory agent with antineoplastic and antiangiogenic activity. It is used in patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. HUMAN EXPOSURE AND TOXICITY: Pomalidomide may cause fetal toxicity; it is a structural analog of thalidomide, a known human teratogen. Therefore, pomalidomide is contraindicated during pregnancy. Acute myelogenous leukemia (AML) has been reported in patients receiving pomalidomide as investigational therapy for uses other than multiple myeloma. Serious venous thromboembolic events have also been reported in patients receiving pomalidomide. Pomalidomide did not induce chromosomal aberrations in human peripheral blood lymphocytes. ANIMAL STUDIES: Chronic administration of pomalidomide was well tolerated in rats at doses of 50, 250 and 1000 mg/kg/day for 6 months. However, monkeys exhibited greater sensitivity to pomalidomide in the studies reported. The primary toxicities observed in monkeys were associated with the hematopoietic/lymphoreticular systems. In the 9-month study in monkeys with doses of 0.05, 0.1, and 1 mg/kg/day, morbidity and early euthanasia of 6 animals were observed at the dose of 1 mg/kg/day and were attributed to immunosuppressive effects (staphylococcal infection, decreased peripheral blood lymphocytes, chronic inflammation of the large intestine, lymphoid depletion of lymphoid tissues, and lymphoid hypocellularity of bone marrow) at high exposures of pomalidomide. These immunosuppressive effects resulted in early euthanasia of 4 monkeys due to poor health condition (watery stool, inappetence, reduced food intake, and weight loss); histopathological evaluation of these animals showed chronic inflammation of the large intestine and villous atrophy of the small intestine. Staphylococcal infection was observed in 4 monkeys; 3 of these animals responded to antibiotic treatment and 1 died without treatment. In addition, findings consistent with acute myelogenous leukemia led to euthanasia of 1 monkey; clinical observations and clinical pathology and/or bone marrow alterations observed in this animal were consistent with immunosuppression. Minimal or mild bile duct proliferation with associated increases in ALP and GGT were also observed at 1 mg/kg/day. Evaluation of recovery animals indicated that all treatment-related findings were reversible after 8 weeks of dosing cessation, except for proliferation of intrahepatic bile ducts observed in 1 animal in the 1 mg/kg/day group. Pomalidomide was teratogenic in rabbits when administered during the period of major organogenesis. Doses ranging from 10 to 250 mg/kg produced embryo-fetal developmental malformations and variations. Increased cardiac anomalies and skeletal malformations were seen at all dose levels. At 100 and 250 mg/kg/day, there were slight increases in post-implantation loss and slight decreases in fetal body weights. At 100 and/or 250 mg/kg/day, fetal malformations also included limb anomalies and associated skeletal deformities, moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. Pomalidomide was also teratogenic in rats. Malformations such as the absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (central and/or neural arches) sometimes associated with discontinuous and misshapen ribs were observed at all dosage levels (25, 250, and 1000 mg/kg/day). In a fertility and early embryonic development study in rats, pomalidomide was administered to male and female rats at doses of 25, 250, and 1000 mg/kg/day before, during, and after mating with animals at the same dose level. Uterine examination on Gestation Day 13 showed a decrease in mean number of viable embryos and an increase in postimplantation loss at all dose levels. Pomalidomide was not mutagenic in bacterial and mammalian mutation Ames assays, and did not induce micronuclei formation in polychromatic erythrocytes in bone marrow of rats administered doses up to 2000 mg/kg/day.

Serum enzyme elevations occur in 1% to 2% of patients taking pomalidomide and are more frequent with higher doses. The enzyme abnormalities are usually mild and self-limited and rarely require drug discontinuation. In addition pomalidomide has been implicated in rare instances of clinically apparent, acute liver injury which can be severe and has been reported to lead to deaths from acute liver failure. However, few of these cases have been published and the clinical features, course and outcome of the typical case of liver injury from pomalidomide have not been defined. Both thalidomide and lenalidomide have been implicated in cases of clinically apparent acute liver injury and the presentation and course of injury is likely to be similar to that caused by pomalidomide. The latency to onset is usually within 1 to 6 weeks of starting the antineoplastic agent. The clinical features vary greatly and can be hepatocellular or cholestatic. Cases of acute liver failure as well as vanishing bile duct syndrome with rapid marked cholestasis and hepatic failure have been described with thalidomide and lenalidomide. Immunoallergic features may be prominent and instances of Stevens Johnson syndrome and toxic epidermal necrolysis with and without liver injury have also been linked to therapy with thalidomide and its derivatives. In most cases, the injury resolves rapidly after therapy is stopped. Monitoring of liver tests at monthly intervals is recommended when using thalidomide and its derivatives, and stopping therapy early may play an important role in preventing severe and fatal outcomes.|Serum enzyme elevations occur in 8% to 15% of patients taking thalidomide or lenalidomide and are more frequent with higher doses. The enzyme abnormalities are usually mild and self-limited, and only rarely require drug discontinuation. In addition, both thalidomide and lenalidomide have been implicated in rare instances of clinically apparent, acute liver injury which can be severe and has led to deaths from acute liver failure. The onset of injury is typically within 1 to 8 weeks of starting therapy. The pattern of serum enzyme elevation at the time of presentation can be either hepatocellular or cholestatic; however, the injury tends to be cholestatic and can be prolonged. Immunoallergic and autoimmune features are not common. Several instances of acute liver injury associated with thalidomide and lenalidomide therapy have occurred in patients with other apparent causes of liver disease or with preexisting chronic hepatitis B or C. If performed during the acute injury, liver biopsy shows hepatocellular necrosis and inflammatory cell infiltration, consistent with acute drug induced injury. In some instances there is bile duct injury and loss resulting in progressive cholestatic liver injury suggestive of vanishing bile duct syndrome.

Pomalidomide is a substrate of the efflux transporter P-glycoprotein (P-gp); potent inhibitors or inducers of this transport protein may potentially alter pomalidomide exposure. Concomitant use of pomalidomide with potent inhibitors or inducers of P-gp should be avoided.|Metabolism of pomalidomide is mediated primarily by cytochrome P-450 (CYP) isoenzymes 1A2 and 3A4. Concomitant use of pomalidomide with potent inhibitors of CYP1A2 or CYP3A (e.g., ketoconazole) may increase exposure to pomalidomide and should be avoided. Conversely, concomitant use of pomalidomide with potent inducers of CYP1A2 (e.g., cigarette smoking) or CYP3A (e.g., rifampin) may decrease exposure to pomalidomide and also should be avoided. When the weak CYP3A inducer dexamethasone (20-40 mg once daily) was administered concomitantly with pomalidomide (4 mg once daily) in patients with multiple myeloma, pharmacokinetics of pomalidomide were unchanged. Pomalidomide does not inhibit or induce CYP isoenzymes in vitro.|Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.|Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.

Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid Pomalyst in patients with a serum creatinine greater than 3.0 mg/dL.|Use of pomalidomide should be avoided in patients with serum aminotransferase (ALT and AST) concentrations exceeding 3 times the upper limit of normal (ULN) and bilirubin concentrations exceeding 2 mg/dL. Use of pomalidomide also should be avoided in patients with serum creatinine concentrations exceeding 3 mg/dL. Safety and efficacy have not been established in these patients.|Pomalidomide may cause fetal toxicity; pomalidomide is a structural analog of thalidomide, a known human teratogen, and teratogenic and other fetotoxic effects of pomalidomide (e.g., musculoskeletal anomalies and deformities; absence of internal organs, including bladder and thyroid; defects of internal organ systems, including cardiovascular, respiratory, renal, hepatic, and CNS abnormalities; increased fetal resorptions) have been demonstrated in animals. Therefore, pomalidomide is contraindicated in women who are pregnant.

12-44% protein bound. It is not concentration dependent.

EXPERIMENTAL: Following oral administration of pomalidomide to lactating rats, transfer into milk was observed, with milk to plasma ratios of 0.63 to 1.46.|EXPERIMENTAL: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats.

Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.|FDA Label|Imnovid in combination with bortezomib and dexamethasone is indicated in the treatment of adult patients with multiple myeloma who have received at least one prior treatment regimen including lenalidomide.Imnovid in combination with dexamethasone is indicated in the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy.|Treatment of post-essential thrombocythaemia myelofibrosis, Treatment of post-polycythaemia vera myelofibrosis|Drug: Pomalidomide

Pomalidomide is an immunomodulatory and antineoplastic agent that is used in the therapy of multiple myeloma. Pomalidomide, like the structurally related agents thalidomide and lenalidomide, is associated with a low rate of serum aminotransferase elevations during therapy and has been implicated in causing rare instances of clinically apparent liver injury which can be severe.|Thalidomide and its analogue lenalidomide are immunomodulatory and antineoplastic agents that are used in the therapy of multiple myeloma. Both agents are associated with a low rate of serum aminotransferase elevations during therapy and both have been implicated in causing rare instances of clinically apparent liver injury which can be severe.

Antineoplastic Agents

Angiogenesis Inhibitors; Immunologic Factors|Pomalyst is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified. /Included in US product label/|EXPL THER Pomalidomide /affected/ the regulation of fetal hemoglobin (HbF) making it a potential therapeutic agent for the treatment of non-malignant hematologic disorders such as sickle cell disease (SCD) and beta-thalassemia. In vitro pomalidomide was a more potent inducer of HbF than hydroxyurea (HU), the only treatment currently approved for SCD. Pomalidomide increased the expression of genes directing the production of HbF as well as gamma- and epsilon-globin gene transcription and expression during erythroid differentiation. In an in vivo knockout transgenic mouse model of SCD, pomalidomide (10 mg/kg; 5 QD/week x 8) stimulated erythropoiesis as indicated by bone marrow hyperplasia and increased extramedullary hematopoiesis, a trend toward higher reticulocytes and significantly higher red blood cell (RBC) levels. Pomalidomide significantly increased HbF expression with a trend toward higher gamma-globin chain A levels. The pomalidomide responder rate, defined as the percentage of animals that exceeded the maximum HbF and gamma-globin chain A levels in the vehicle group, reached 67% and 78% respectively. Among responders, pomalidomide induced a nearly 2-fold increase in HbF and the increase in gamma-globin chain A levels was significant and was similar to the approved HbF-inducing agent HU.

/BOXED WARNING/ WARNING: EMBRYO-FETAL TOXICITY. Embryo-Fetal Toxicity: Pomalyst is contraindicated in pregnancy. Pomalyst is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting Pomalyst treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping Pomalyst treatment. Pomalyst is only available through a restricted distribution program called Pomalyst REMS.|/BOXED WARNING/ WARNING: VENOUS THROMBOEMBOLISM. Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with Pomalyst. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient's underlying risk factors|Use of pomalidomide should be avoided in patients with serum aminotransferase (ALT and AST) concentrations exceeding 3 times the upper limit of normal (ULN) and bilirubin concentrations exceeding 2 mg/dL. Use of pomalidomide also should be avoided in patients with serum creatinine concentrations exceeding 3 mg/dL. Safety and efficacy have not been established in these patients.|Pomalidomide may cause fetal toxicity; pomalidomide is a structural analog of thalidomide, a known human teratogen, and teratogenic and other fetotoxic effects of pomalidomide (e.g., musculoskeletal anomalies and deformities; absence of internal organs, including bladder and thyroid; defects of internal organ systems, including cardiovascular, respiratory, renal, hepatic, and CNS abnormalities; increased fetal resorptions) have been demonstrated in animals. Therefore, pomalidomide is contraindicated in women who are pregnant.|For more Drug Warnings (Complete) data for Pomalidomide (21 total), please visit the HSDB record page.

Pomalidomide is more potent than thalidomide (100-times) and lenalidomide (10-times).

Agents and endogenous substances that antagonize or inhibit the development of new blood vessels. (See all compounds classified as Angiogenesis Inhibitors.)|Biologically active substances whose activities affect or play a role in the functioning of the immune system. (See all compounds classified as Immunologic Factors.)

Pomalidomide is generally well absorbed. The major circulating component is the parent compound. Tmax, single oral dose = 2 -3 hours. When 4 mg of promalidomide is given to patients with multiple myeloma, the steady-state pharmacokinetic parameters are as follows: AUC(T) = 400 ng.hr/mL; Cmax = 75 ng/mL. Promalidomide accumulates following multiple doses.|When a single oral dose (2mg) is given to healthy subjects, 73% of the dose was eliminated in urine. 15% of the dose was eliminated in feces. 2% and 8% of the dose eliminated unchanged as pomalidomide in urine and feces, respectively.|Mean apparent volume of distribution (Vd/F), steady-state = 62 - 138 L|Total body clearance = 7-10 L/hour|Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately 67% of plasma level at 4 hours post-dose (approximate Tmax) after 4 days of once-daily dosing at 2 mg. Human plasma protein binding ranges from 12% to 44% and is not concentration dependent. Pomalidomide is a substrate for P-glycoprotein (P-gp).|In patients with multiple myeloma who received Pomalyst 4 mg daily alone or in combination with dexamethasone, pomalidomide steady-state drug exposure was characterized by AUC(T) of 400 ng*h/mL and Cmax of 75 ng/mL. Following multiple doses, pomalidomide has an accumulation ratio of 27% to 31%.|Following a single oral administration of (14)C-pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and feces, respectively, with approximately 2% and 8% of the radiolabeled dose eliminated unchanged as pomalidomide in urine and feces.|Pomalidomide has a mean total body clearance (CL/F) of 7-10 L/hr.|For more Absorption, Distribution and Excretion (Complete) data for Pomalidomide (12 total), please visit the HSDB record page.

Promalidomide is hepatically metabolized by CYP1A2 and CYP3A4. The metabolites are 26-fold less active than the parent compound. Minor contributions from CYP2C19 and CYP2D6 have been observed in vitro.|In hepatocytes from rabbit and human, and in vivo in rat, monkey and human, pomalidomide was metabolized primarily 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). There were no unique or disproportionate metabolites observed in humans, compared to rats and monkeys.|Pomalidomide is primarily metabolized in the liver by CYP1A2 and CYP3A4. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6.

Healthy subjects = 9.4 hours; Multiple myeloma patients = 7.5 hours.|... the terminal half-lives of pomalidomide in animals ranged from mean values of 4 to 7 hours following an IV dose.|Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma.

Promalidomide is an immunomodulatory agent with antineoplastic activity. It is shown to inhibit the proliferation and induce apoptosis of various tumour cells. Furthermore, promalidomide enhances T cell and natural killer (NK) cell-mediated immunity and inhibited the production of pro-inflammatory cytokines, like TNF-alpha or IL-6, by monocytes. The primary target of promalidomide is thought to be the protein cereblon. It binds to this target and inhibits ubiquitin ligase activity. It is also a transcriptional inhibitor of COX2.|In vitro studies have identified a molecular mechanism for the pleiotropic effects of pomalidomide in multiple myeloma (MM) and in T cells. Specifically, pomalidomide bound to the protein cereblon (CRBN), part of an E3 ligase complex, and the expression levels of CRBN in myeloma cells was linked to both the efficacy of pomalidomide and to the acquisition of resistance to lenalidomide. Pomalidomide was claimed to have direct antiproliferative activity against B cell lines derived from MM and Burkitt's lymphoma patients. Pomalidomide in combination with dexamethasone increased this effect in a dose dependent manner.|Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-alpha (TNF-a) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance.|The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects.|In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ This phase 1, open label, dose-escalation study investigated the tolerated dose (recommended dose), safety, efficacy, and pharmacokinetics of pomalidomide alone or pomalidomide plus low-dose dexamethasone in Japanese patients with refractory or relapsed and refractory multiple myeloma. Twelve patients were enrolled. Patients received pomalidomide 2 mg (Cohort 1) or 4 mg (Cohort 2) orally on day 1 and days 3-21 of a 28-day cycle. The tolerated dose of pomalidomide was determined to be 4 mg administered on days 1-21 of a 28-day cycle. Efficacy outcomes with pomalidomide plus low-dose dexamethasone were consistent with those of previous studies. Responses (partial response or better) were achieved by 3 patients (25%; 1 [17%] in Cohort 1 and 2 [33%] in Cohort 2), and the median time to response was 6.4 months overall (9.0 months for Cohort 1 and 4.2 months for Cohort 2). The median progression-free survival was 5.5 months overall (5.1 months for Cohort 1 and not reached for Cohort 2). The most frequently occurring grade = 3 adverse events were neutropenia (67%), anemia (25%), lymphopenia (25%), and pneumonia (25%), consistent with previous studies of pomalidomide plus low-dose dexamethasone in refractory or relapsed and refractory multiple myeloma. Further investigation of pomalidomide is recommended for Japanese patients with refractory or relapsed and refractory multiple myeloma.|/SIGNS AND SYMPTOMS/ Acute myelogenous leukemia (AML) has been reported in patients receiving pomalidomide as investigational therapy for uses other than multiple myeloma.|/SIGNS AND SYMPTOMS/ Serious venous thromboembolic events have been reported in patients receiving pomalidomide. In the pivotal multiple myeloma trial, deep-vein thrombosis or pulmonary embolism occurred in 3% of patients receiving pomalidomide alone or in combination with low-dose dexamethasone. In this trial, all patients were required to receive an antithrombotic agent for prevention of venous thromboembolism; antithrombotic agents used for prophylaxis or treatment included aspirin (81% of patients), heparin (21%), warfarin (16%), and clopidogrel (3%). The manufacturer and some experts state that decisions regarding use of thromboprophylaxis and selection of an appropriate thromboprophylaxis regimen (e.g., aspirin, anticoagulant) should be based on careful assessment of the patient's risk factors for thromboembolism.|/SIGNS AND SYMPTOMS/ Pomalidomide may cause fetal toxicity; pomalidomide is a structural analog of thalidomide, a known human teratogen, and teratogenic and other fetotoxic effects of pomalidomide (e.g., musculoskeletal anomalies and deformities; absence of internal organs, including bladder and thyroid; defects of internal organ systems, including cardiovascular, respiratory, renal, hepatic, and CNS abnormalities; increased fetal resorptions) have been demonstrated in animals. Therefore, pomalidomide is contraindicated in women who are pregnant.|For more Human Toxicity Excerpts (Complete) data for Pomalidomide (10 total), please visit the HSDB record page.

actimid

Table: Pomalidomide Preparations [Table#8218]

Pomalidomide is a second generation IMiD (immunomodulatory agent) that has recently been granted approval by the Food and Drug Administration for treatment of relapsed multiple myeloma after prior treatment with two antimyeloma agents, including lenalidomide and bortezomib. A simple and robust HPLC assay with fluorescence detection for pomalidomide over the range of 1-500ng/mL has been developed for application to pharmacokinetic studies in ongoing clinical trials in various other malignancies. A liquid-liquid extraction from human plasma alone or pre-stabilized with 0.1% HCl was performed, using propyl paraben as the internal standard. From plasma either pre-stabilized with 0.1% HCl or not, the assay was shown to be selective, sensitive, accurate, precise, and have minimal matrix effects (<20%). Pomalidomide was stable in plasma through 4 freeze-thaw cycles (<12% change), in plasma at room temperature for up to 2 hr for samples not pre-stabilized with 0.1% HCl and up to 8 hr in samples pre-stabilized with 0.1% HCl, 24 hr post-preparation at 4 °C (<2% change), and showed excellent extraction recovery (approximately 90%). This is the first reported description of the freeze/thaw and plasma stability of pomalidomide in plasma either pre-stabilized with 0.1% HCl or not. The information presented in this manuscript is important when performing pharmacokinetic analyses. The method was used to analyze clinical pharmacokinetics samples obtained after a 5 mg oral dose of pomalidomide. This relatively simple HPLC-FL assay allows a broader range of laboratories to measure pomalidomide for application to clinical pharmacokinetics.|HPLC determination in plasma.

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