Imatinib - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

In 2001, Imatinib, a small chemical kinase inhibitor, transformed cancer treatment, particularly for chronic myeloid leukemia. It was nicknamed a "miracle drug" because of its clinical success, with complete hematologic responses recorded in 53 of 54 patients given a daily dose of 300 mg (milligrams) or higher. This discovery gave rise to a new type of therapy known as "targeted therapy," which may be tailored to each patient's specific cancer genetics. Imatinib is a chemotherapy medication indicated for the treatment of leukemias (a type of blood cancer that develops in the bone marrow and produces a lot of abnormal blood cells), dermatofibrosarcoma protuberans (the rare skin cancer that develops slowly and originates in the connective tissue cells in the skin's middle layer.), myeloproliferative disease (rare blood disorders are characterized by an excess of red, white, or platelet blood cells due to an increase in bone marrow blood cell production.), systemic mastocytosis (a rare disorder characterized by an excessive number of mast cells in the body.), hypereosinophilic syndrome (a blood disorder is characterized by elevated eosinophil counts, which are essentially white blood cells in the body's immune system.), and gastrointestinal stromal tumors (rare cancer originating from interstitial cells of Cajal, which control the movement of the digestive tract). It was first licensed by the United States Food and Drug Administration (USFDA) in 2001 for use in treating Philadelphia chromosome-positive chronic myeloid leukemia (CML). The FDA approved it for treating advanced or metastatic gastrointestinal stromal tumors (GIST) in 2002. It received authorization in 2012 for usage following surgical excision of KIT-positive malignancies (cancers that exhibit the KIT gene, a cytokine receptor located on the surface of several cell types) to prevent recurrence.

Drug Group

Imatinib belongs to the group of drugs called tyrosine kinase inhibitors. Tyrosine kinases are proteins that living cells use to communicate with one another to grow. Imatinib works by inhibiting the function of the defective protein that urges cancer cells to grow, preventing cancer cell spread.

Indications:

Imatinib is a kinase inhibitor approved for the therapy of newly diagnosed adult patients with chronic Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). The observation period is limited to five years.

• Patients in blast crisis (BC), accelerated phase (AP), or chronic phase (CP) with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) after the failure of interferon-alpha therapy.

• Pediatric individuals who have Ph+ CML in the chronic phase have been recently diagnosed, relapsed after stem cell transplantation, or are resistant to interferon-alpha therapy. There are no controlled trials in pediatric patients that show a clinical benefit, such as a reduction in disease-related symptoms or an increase in survival.

• Relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults.

• Adults suffering from myelodysplastic or myeloproliferative disorders (MDS/MPD) with PDGFR (platelet-derived growth factor receptor) gene re-arrangements.

• Adults having aggressive systemic mastocytosis (ASM) who lack the D816V c-Kit mutation or whose status of cKit mutation is uncertain.

• Adults having hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) who possess the FIP1L1-PDGFR fusion kinase (mutational evaluation or FISH evidence of CHIC2 allele deletion), as well as those with HES and CEL who possess the FIP1L1-PDGFR fusion kinase negative or unknown.

• Adults with unresectable, recurring, or metastatic dermatofibrosarcoma protuberans (DFSP).

• Kit (CD117) positive patients with unresectable, recurrent, or metastatic malignant gastrointestinal stromal tumors (GIST).

Contraindications:

None.

Dosage Forms and Available Strengths:

Imatinib is available in 100mg (milligrams) and 400mg tablets.

Warnings and Precautions

• When given to a pregnant woman, fetal damage can occur. Women should be told about potential hazards to the unborn child.

• There has been edema (excess fluid accumulating in the body's tissues) and considerable fluid retention. Weigh patients regularly and handle unanticipated rapid weight gain with medication cessation and diuretics.

• Anemia, neutropenia, and thrombocytopenia are the most common cytopenias. Manage with dose decrease or interruption, and in unusual circumstances, medication termination. Complete blood counts should be done weekly for the first month, biweekly for the second month, and regularly after that.

• There have been reports of severe congestive heart failure and left ventricular dysfunction (swelling), particularly in patients with comorbidities and risk factors. Patients having heart disease or risk factors for heart failure should be closely examined and treated.

• Severe hepatotoxicity is possible. Before starting therapy and every month after that, or as clinically required, check liver function. When used with chemotherapy known to cause liver damage, monitor liver function.

• Clinical trials have found grade three or four bleeding in newly diagnosed CML and GIST patients. GI tumor areas could be the origin of bleeding from the gastrointestinal tract in GIST.

• There have been reports of gastrointestinal perforations, some of which have been fatal.

• Imatinib treatment has been connected to cardiogenic shock or left ventricular failure for those with high eosinophil levels (for example, HES, MDS/MPD, and ASM).

• Bullous dermatologic reactions (such as erythema multiforme and Stevens-Johnson syndrome) have been documented in association with Imatinib therapy.

• Thyroidectomy patients receiving Levothyroxine replacement have been reported to have hypothyroidism. TSH (Thyroid Stimulating Hormone) levels should be constantly tracked for these patients.

• Consider potential side effects, particularly liver, renal, and heart damage, as well as immunosuppression from long-term use.

For Patients

What Is Cancer?

Cancer is a disease in which damaged or atypical cells multiply uncontrollably and spread to other body parts. It can begin anywhere in the human body and might be malignant or non-cancerous. Cancerous tumors have the ability to spread to the surrounding tissues and spread to distant locations, whereas benign tumors do not. When benign tumors are removed, benign tumors typically do not regrow, but these tumors might be huge and produce significant symptoms or be life-threatening especially brain tumors.

How Does Imatinib Work?

Imatinib mesylate is a protein-tyrosine kinase inhibitor that targets the BCR-ABL tyrosine kinase, a tyrosine kinase that is constitutively active in CML. It prevents downstream phosphorylation of the target protein by sticking to the ATP pocket. Imatinib also inhibits Platelet-Derived Growth Factor (PDGF) and Stem Cell Cactor (SCF) receptor tyrosine kinases, c-Kit, and cellular processes. It causes apoptosis in GIST cells in vitro.

What Are the Clinical Uses of Imatinib?

Imatinib is employed in treating a variety of diseases. Imatinib has the following clinical applications:

• Leukemias: Imatinib is used to treat some kinds of leukemia, a cancer that starts in white blood cells. This comprises Acute Lymphoblastic Leukemia (ALL) and Chronic Myelogenous Leukemia (CML).

• Myelodysplastic or Myeloproliferative Diseases (MDS/MPD): A group of diseases wherein the bone marrow produces an abnormally large number of white blood cells.

• Systemic Mastocytosis (SM): Systemic Mastocytosis (SM) is when excessive mast cells gather throughout the skin and/or internal organs such as the liver, spleen, bone marrow, and small intestine.

• Hypereosinophilic Syndrome (HES): Hypereosinophilic Syndrome (HES) is a condition characterized by excessive eosinophils, a white blood cell.

• Dermatofibrosarcoma Protuberans (DFSP): Dermatofibrosarcoma Protuberans (DFSP) is a rare malignancy that produces a tumor in the deeper layers of the skin.

• Gastrointestinal Stromal Tumors (GIST): Imatinib treats some forms of Gastrointestinal Stromal Tumors (GIST), which grow in the walls of the digestive tract and can spread to other body regions.

How Is Imatinib Administered?

Imatinib is a drug that is given orally once or twice a day with a meal and water. It is taken precisely as suggested, with no more or less. If swallowing the pills is difficult, place the tablets in a glass of water or apple juice, 50 milliliters (ml) for each 100 mg tablet and 200 milliliters for each 400 mg tablet. Because of the iron concentration in the tablet coating, two 400 mg tablets should be eaten instead of eight. During treatment, the doctor may change the dose, and discussing concerns with the doctor is critical. Even if patients feel fine, it is critical to continue taking Imatinib and not discontinue without visiting the doctor.

What Are the Side Effects of Imatinib?

Imatinib might trigger unwanted side effects. If any of the subsequent symptoms are severe or persistent, contact the doctor:

• Diarrhea.

• Nausea.

• Vomiting.

• Taste alterations.

• Oral ulcers or swelling within the mouth.

• Appetite loss.

• Loss of weight.

• Indigestion or heartburn.

• Headache.

• Dry tongue.

• Swelling or discomfort in the joints.

• Bone ache.

• Muscle discomfort.

• Tingling, scorching, or a prickling sensation on the skin.

• Difficulty getting or staying asleep.

• Sweating.

• Teary eyes.

• Flushing.

• Pink eyes.

• Itching.

• Rashes.

• Dry skin.

• Alterations to the nails.

• Hair thinning.

Some of the negative effects can be severe. If patients have any of the subsequent symptoms, patients should call the doctor straight away:

• Puffiness of the eyes.

• Hands, feet, ankles, or lower legs swelling.

• Unexpected weight gain.

• Shortness of breath.

• A heartbeat that is rapid, irregular, or hammering.

• Coughing up pink or bright red mucous.

• Excessive urination, particularly at night.

• Chest discomfort.

• Skin peeling, blistering, or shedding.

• Yellowish discoloration of the skin or eye.

• Blood in the feces.

• Bruising or bleeding (uncommon).

• Flu, sore throat, fever, chills, and other infection symptoms.

• Extreme exhaustion or weakness.

• Bloating or abdominal pain.

In children, Imatinib may decrease growth. The child's pediatrician will closely monitor the child's growth. Consult the child's doctor about the hazards of Imatinib administration.

Other adverse effects of Imatinib are possible. Contact the doctor if patients have any odd side effects while taking this medicine.

What Are the Things to Inform the Doctor Before Taking Imatinib?

• Tell the doctor and pharmacist if patients are sensitive to Imatinib, any other drugs, or any of the substances in Imatinib tablets before starting treatment. Request a list of the components from the pharmacist.

• Inform the doctor and pharmacist about any prescription and nonprescription drugs, vitamins, or nutritional supplements patients are taking or plan to use. Make sure patients include any of the following: Isradipine, Itraconazole, Ketoconazole, Lovastatin, Metoprolol, Nefazodone, Nelfinavir, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Oxcarbazepine, Phenobarbital, Phenytoin, Pimozide, Primidone, Quinidine, Rifabut, Rifampin, Ritonavir, Saquinavir, Simvastatin, Sirolimus, Tacrolimus, Telithromycin, Triazolam, Voriconazole, and warfarin. Many other medications may interact with Imatinib, so be sure to inform the doctor about anything patients are taking, even if it is not on this list. The doctor may need to adjust the amounts of medication or closely monitor for adverse effects.

• Inform the doctor about herbal supplements patients take, particularly St. John's wort.

• If patients are currently or previously experiencing heart, lung, thyroid, renal, or liver illness, tell the doctor about it.

• If the patient is pregnant or wants to become pregnant, inform the doctor. Before beginning treatment, patients must take a pregnancy test. Patients should not become pregnant while taking Imatinib or for 14 days following the last dosage. Consult the doctor about birth control techniques that a patient can take while undergoing therapy. If patients become pregnant while taking Imatinib, contact the doctor immediately. Imatinib has the potential to harm the fetus.

• If patients are breastfeeding, inform the doctor. Patients should not breastfeed while using Imatinib or for one month following the last dosage.

• Inform the dentist or physician that patients are taking Imatinib if patients are having surgery, including dental surgery.

• Patients should know that Imatinib may induce dizziness, drowsiness, or blurred vision. Do not drive or operate machinery until patients have determined how this drug affects people.

Dietary Considerations:

While using Imatinib, avoid eating or drinking grapefruit.

Missed Dose:

Patients should take the missed dose upon recall, skip the next dose, resume the usual dosing regimen, not duplicate the dose.

Overdose:

Call the poison control hotline if the patient suspects an overdose. If the person collapses, experiences a seizure, has difficulty breathing, or cannot be awakened, call emergency services immediately. Overdose symptoms may include nausea, vomiting, diarrhea, rash, swelling, extreme tiredness, muscle cramps, abdominal pain, headache, and loss of appetite.

Storage and Disposal:

To keep medication safe, store it safely in its original container, properly closed, and out of the reach of children. It should be stored at room temperature, free of heat and moisture, and not in the bathroom. Many containers are not child-resistant and can be easily opened by young kids. Store the medication in a secure location and secure the safety caps. Dispose of unused medicines in specific ways to keep pets, children, and others from eating the medicines. Dispose of medications through a drug take-back program, which patients may find by speaking with the pharmacist or the nearby garbage/recycling department.

For Doctors

Pharmacodynamics

Imatinib is a tyrosine kinase inhibitor that is a 2-phenylaminopyrimidine derivative neoplastic agent. Although Imatinib suppresses various tyrosine kinases, it is highly selective for the BCR-ABL fusion protein seen in many malignancies. The BCR-ABL pathway regulates multiple downstream pathways involved in neoplastic growth, including the Ras or MapK pathway for cellular proliferation, the Src or Pax or Fak or Rac pathway for cellular motility, and the PI or PI3K or AKT or BCL-2 pathway for apoptosis. As a result, the BCR-ABL pathway is an appealing target for cancer treatment. Although normal cells rely on these pathways for proliferation, they have redundant tyrosine kinases that allow them to function in Imatinib-induced ABL suppression. Cancer cells may always depend on BCR-ABL and are more sensitive to Imatinib.

Chemical Taxonomy

Imatinib is a cancer growth blocker that targets multiple tyrosine kinases, including CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Tyrosine kinases are proteins cells use to signal growth, and blocking these proteins stops cancer cells from growing. It is classified as a Tyrosine Kinase Inhibitor (TKI).

Mechanism of Action

Imatinib is a tyrosine kinase inhibitor that targets CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. It operates by attaching to the ATP binding site of BCR-ABL, trapping it in a closed or self-inhibited conformation, and semi-competitively decreasing the protein's enzymatic activity. Imatinib inhibits BCR-ABL tyrosine kinase, the Philadelphia chromosome's constitutive aberrant gene product in Chronic Myeloid Leukemia (CML). In BCR-ABL positive cell lines and fresh leukemic cells in CML, this inhibition inhibits proliferation and promotes apoptosis, delaying growth or resulting in programmed cell death of some types of cancer cells.

Pharmacokinetics

• Absorption: Imatinib is well absorbed following oral administration, with the Cmax occurring after two to four hours of dosing. The absolute bioavailability is 98 percent on average. Imatinib's mean area under the curve (AUC) increases proportionally as the dose increases from 25 mg to 1,000 mg. The pharmacokinetics of imatinib do not alter significantly with repeated dosage, and accumulation is 1.5 to 2.5 fold at steady state when Imatinib is given once daily.

• Distribution: The steady-state volume of distribution of Imatinib in adult CML patients was calculated to be 295.0 plus or minus 62.5 L based on population pharmacokinetics. The volume of distribution of Imatinib in children and adolescents was determined to be 167 plus or minus 84 L at a dose of 340 mg/m2 (milligram per square meter). Adherence to plasma proteins in vitro tests at clinically relevant doses of Imatinib is approximately 95 percent, primarily to albumin and alpha1-acid glycoprotein.

• Metabolism: The main enzyme responsible for Imatinib metabolism is CYP3A4. Other cytochrome P450 enzymes involved in its metabolism include CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The primary circulating active metabolite in humans is the N-demethylated piperazine derivative, which CYP3A4 primarily produces. It has in vitro potency comparable to Imatinib.

• Excretion: Imatinib is removed mainly in the feces, usually as metabolites. Based on the compound recovered following an oral 14C-labeled dose of Imatinib, roughly 81 percent of the dose was removed in feces (68 percent of the dose) and urine (13 percent) within seven days. The unchanged Imatinib made up 25 percent of the dosage (five percent urine, 20 percent feces), with the rest being metabolites. The elimination half-lives of Imatinib and its principal active metabolite, the N-desmethyl derivative, after oral administration in healthy volunteers are around 18 and 40 hours, respectively.

Toxicity

Imatinib use has been associated with a variety of side effects, including edema, nausea, vomiting, muscular cramps, musculoskeletal discomfort, diarrhea, rash, fatigue, and abdominal pain. Imatinib reduced longevity in men and females in a two-year rat carcinogenicity trial at 60 mg/kg/day dosages and greater than or equal to 30 mg/kg/day. On the other hand, Imatinib was not found to be genotoxic in vitro mammalian cell experiments. Imatinib mesylate did not affect fertility in a fertility trial. Animal studies indicate potential damage, such as liver, renal, and cardiac toxicity, as well as immunosuppression.

Drug Interactions

• CYP3A4 Inducers: Pretreatment with multiple doses of rifampin followed by a single dose of Imatinib increased oral-dose clearance by 3.8 fold, significantly decreasing mean Cmax and AUC, suggesting a dose adjustment if alternative treatment is unavailable.

• CYP3A4 Inhibitors: Imatinib, combined with ketoconazole, significantly increases Imatinib exposure in healthy subjects. Caution is advised when using Imatinib with strong CYP3A4 inhibitors, as grapefruit juice may increase Imatinib concentrations. Substances inhibiting CYP3A4 activity may decrease metabolism and increase Imatinib concentrations.

• CYP3A4 Substrates: Imatinib increases the Cmax and AUC of simvastatin, suggesting inhibition of CYP3A4. It is recommended to use CYP3A4 substrates with a narrow therapeutic window. Imatinib also increases the plasma concentration of other CYP3A4 metabolized drugs. Patients requiring anticoagulation should receive low-molecular weight or standard heparin instead of warfarin, as CYP2C9 and CYP3A4 metabolize warfarin.

• CYP2D6 Substrates: Imatinib inhibits CYP2D6 activity in vitro, affecting CYP3A4 activity. Increased systemic exposure to CYP2D6 substrates is expected, but no specific studies have been conducted.

• Acetaminophen: Imatinib inhibits Acetaminophen O-glucuronidation in vitro, increasing systemic exposure. No human studies have been conducted, so caution is advised.

Clinical Studies

1. Chronic Myeloid Leukemia

• Chronic Phase, Newly Diagnosed: Phase 3 research was done in patients with recently diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia (CML) in the chronic phase, assessing treatment with single-agent Imatinib versus a combination of IFN with cytarabine (Ara-C). The trial included 1,106 patients from 177 medical centers in 16 countries, with 553 in each arm. In the Imatinib and IFN arms, the median length of the initial therapy was 60 and 8 months, respectively. Progression-Free Survival (PFS) was the main efficacy outcome. In the ITT population, the median survival rate without progression at 60 months was 83.2 percent in the Imatinib arm and 64.1 percent in the IFN arm. In the Imatinib arm, the biological reaction rate for those with a full cytogenetic response was 59 percent at 12 months and 72 percent at 24 months.

• Late Chronic Phase CML and Advanced Stage CML: Three international phase 2 studies evaluated Imatinib's safety and efficacy in patients with Ph+ CML, with most patients aged 60 to 70.

• Chronic Phase, Prior Interferon-Alpha Treatment: A study of 532 individuals in the late chronic phase of a disease who had previously received interferon-alpha treatment discovered that the treatment was beneficial, lasting a median of 29 months, with a higher probability of substantial cytogenetic response for those with IFN intolerance and cytogenetic failure.

• Accelerated Phase: The therapy requirements were met by 235 individuals who have accelerated phase CML. Initial treatment was 400 mg, with 600 mg starting at 600 mg. Efficacy was evaluated based on hematologic response and cytogenetic responses.

• Myeloid Blast Crisis: Research involved 260 individuals with myeloid blast crisis, with 37 percent having previously received chemotherapy for either accelerated phase or blast crisis. The study's success was primarily based on the rate of hematologic and cytogenetic responses. The median duration of therapy was four months, with 21 percent receiving treatment for 12 months and 10 percent receiving treatment for 24 months. The hematological reaction rate was greater in untreated patients and the group receiving a 600 mg first dosage. The median period from diagnosis to hematologic response was one month. The study demonstrated comparable efficacy in men and women and individuals under and over 65.

2. Pediatric CML: 51 juvenile patients with persistent CML were enrolled in a multicenter, single-arm phase 2 experiment. Imatinib treatment produced an overall hematologic response in 78 percent of patients, a complete cytogenetic response in 65 percent, and only a partial cytogenetic response in sixteen percent. Patients having Ph+ chronic phase CML that was recurrent or resistant to interferon-alpha therapy showed cytogenetic responses.

3. Acute Lymphoblastic Leukemia: A study of 48 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia found hematologic and cytogenetic response rates of 3.4 and 2.3 months, respectively.

4. Myelodysplastic or Myeloproliferative Diseases: Imatinib was investigated in phase 2 clinical trials in individuals with life-threatening disorders related to ABL, Kit, or PDGFR protein tyrosine kinases. Imatinib 400 mg daily was given to seven patients with Myelodysplastic or Myeloproliferative Diseases (MDS or MPD). 45 percent of the 31 patients had a complete hematological response, and 39 percent had a substantial cytogenetic response.

5. Aggressive Systemic Mastocytosis: Aggressive Systemic Mastocytosis: A phase 2 study tested Imatinib in patients with Aggressive Systemic Mastocytosis (ASM) and found it effective in 29 percent of patients. Imatinib, on the other hand, was ineffective in less aggressive forms of ASM and should not be used in patients with cutaneous mastocytosis, indolent systemic mastocytosis, systemic mastocytosis with clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma, or extracutaneous mastocytoma.

6. Hypereosinophilic Syndrome or Chronic Eosinophilic Leukemia: Imatinib was examined in a multicenter research on patients ranging in age from 16 to 64 years with life-threatening disorders associated with ABL, Kit, or PDGFR protein tyrosine kinases.

7. Dermatofibrosarcoma Protuberans: A multicenter phase 2 study tested Imatinib in patients with cutaneous soft tissue sarcoma Protuberans (DFSP). The study involved 18 patients, eight of whom had advanced cancer. With an average duration of 6.2 months, the response rate was 67 percent. The study discovered that Imatinib could benefit individuals suffering from life-threatening disorders caused by ABL, Kit, or PDGFR protein tyrosine kinases.

8. Gastrointestinal Stromal Tumors: Two open-label, randomized, global Phase 3 trials were conducted on patients with unresectable or metastatic malignant Gastrointestinal Stromal Tumors (GIST). The research sought to compare progression-free survival, overall survival, and overall survival between dosage groups. The median duration of follow-up was 37.5 months, with no differences in overall survival found. The 400 mg group received 68.5 percent of the responses, whereas the 600 mg group received 67.6 percent.

Use in Specific Populations

• Pregnancy Category D: When Imatinib, a pregnancy drug, is delivered to pregnant women, it can cause fetal damage. Teratogenic effects include exencephaly, absent bones, and post-implantation loss. There are no well-controlled studies on Imatinib in pregnant women, and patients should be informed of potential risks.

• Breastfeeding: Imatinib mesylate and its metabolites are extensively excreted in milk in lactating female rats, potentially causing adverse reactions in nursing infants from Imatinib, requiring careful decision-making.

• Pediatric Use: Imatinib is safe and effective in children with Ph+ chronic phase CML, stem cell transplantation-refractory CML, or resistance to interferon-alpha therapy. Its rapid absorption and half-life in pediatric patients are similar to adult doses.

• Geriatric Use: Clinical studies show no significant differences in safety or efficacy profiles between patients older than 65 and younger with CML, with Imatinib efficacy remaining similar across all age groups.

• Renal Impairment: The researchers examined the effect of renal impairment on Imatinib pharmacokinetics in 59 cancer patients and discovered that dose reductions are required for individuals with moderate to severe renal impairment.

• Hepatic Impairment: Hepatic impairment affects imatinib and its metabolite in 84 cancer patients. Severe impairment leads to higher exposure, with Cmax/dose and AUC/dose increasing by 63 percent and 45 percent, respectively.