Pharmacological properties of the drug Bortezomib
Bortezomib has an antitumor effect. Reversibly inhibits the chymotrypsin-like activity of the 26S proteasome. The 26S proteasome is a large protein complex present in the nucleus and cytoplasm of all eukaryotic cells. This proteasome is a key component that catalyzes the breakdown of the main proteins involved in controlling the life cycle of cells and regulates their intracellular concentrations. In addition, proteasomes selectively destroy potentially harmful abnormal or unfolded proteins, which in cancer (especially multiple myeloma) may be produced in increased quantities. The so-called ubiquitin-proteasome pathway plays an important role in regulating the levels of specific proteins, thereby maintaining homeostasis within mammalian cells. By inhibiting the chymotrypsin-like action of the 26S proteasome, bortezomib causes inhibition of proteolysis, leading to a complex signaling cascade within the cell, disruption of normal cellular homeostasis and, possibly, apoptosis. Experimental results demonstrated that bortezomib is cytotoxic to a wide range of tumor cell types in vitro. It also induces tumor growth arrest in vivo in non-clinical tumor models, including multiple myeloma. Following an IV dose of 1.3 mg/m2, the maximum concentration of bortezomib was 509 ng/mL (109–1300 ng/mL) in patients with multiple myeloma and creatinine clearance in the range of 31–169 mL/min. The half-life of bortezomib after the first dose is 9–15 hours at doses of 1.45 to 2.0 mg/m2 in patients with advanced malignancies. Plasma protein binding is an average of 83% in the concentration range from 100 to 1000 ng/ml. In vitro studies using human liver microsomes showed that bortezomib is metabolized primarily by microsomal oxidation involving cytochrome P450 isoenzymes CYP 3A4, CYP 2D6, CYP 2C19, CYP 2C9 and CYP 1A2. The resulting metabolites are inactive against the 26S proteasome. In a pooled plasma sample obtained 10 and 30 minutes after administration, the level of metabolites was low compared with the level of the substance itself. The elimination pathway of bortezomib in humans has not yet been characterized.
Side effects of the drug Bortezomib
Based on the results of a study involving 228 patients with multiple myeloma who received bortezomib at a dose of 1.3 mg/m2 twice a week for 2 weeks with a 10-day break (treatment cycle duration - 21 days) for a maximum of no more than 8 cycles. The most common side effects were asthenic conditions, including fatigue, general weakness, malaise (65%), nausea (64%), diarrhea (51%), decreased appetite, including anorexia (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy, including peripheral sensory and exacerbation of peripheral neuropathy (37%), fever (36%), vomiting (36%), anemia (32%). At least 14% of patients experienced at least one episode of grade 4 toxicity, the most common being thrombocytopenia (3%) and neutropenia (3%). The most common serious side effects were fever (7%), pneumonia (7%), diarrhea (6%), vomiting (5%), dehydration (5%), nausea (4%). Side effects reported by investigators as being drug related and leading to treatment discontinuation were observed in 18% of patients. The reasons for stopping the drug were peripheral neuropathy (5%), thrombocytopenia (4%), diarrhea (2%), and increased fatigue (2%). Asthenic conditions (increased fatigue, general weakness, malaise). Asthenia was noted in 65% of patients, mainly of 1st and 2nd degree severity. Initially, increased fatigue was noted most often during the 1st and 2nd cycles of patient therapy. Treatment was stopped due to increased fatigue in 2% of patients. Gastrointestinal disorders observed in most patients include nausea, diarrhea, constipation, and vomiting. Vomiting and diarrhea were most often severe. Treatment was stopped due to gastrointestinal disorders in 5% of patients. Decreased appetite (anorexia) was reported as a side effect in 43% of patients. Thrombocytopenia during treatment with bortezomib was detected in 43% of patients, it was characterized by a dose-dependent decrease in platelet count during the period of bortezomib use (from 1 to 11 days) and returned to the initial level during the break period (days from 12 to 21) in every cycle. The platelet count decreased by 40% compared to baseline. Platelet count values were less than 50 thousand cells/μl and less than 10 thousand cells/μl in 27 and 3% of patients, respectively. Treatment was stopped due to thrombocytopenia, regardless of its severity, in 4% of patients. Peripheral sensory neuropathy. Neuropathy, including sensory and exacerbation of peripheral neuropathy, was observed in 37% of cases. Initial manifestations or exacerbation of pre-existing neuropathy were noted throughout the treatment cycle. Neuropathy was the reason for drug discontinuation in 6% of cases. More than 80% of patients in the study had signs and symptoms of peripheral neuropathy compared to baseline. The incidence of neuropathy was 5% in people without previous neuropathy. Symptoms improved or returned to baseline in some patients after discontinuation of the drug. A full assessment of the time course of this toxicity has not been performed. Fever (38°C) was reported as a side effect in 36% of patients. Neutropenia was determined in 26% of patients, while in 13% of cases it was moderate and severe in 3%. The incidence of febrile neutropenia was ≤1%. Hypotension (including reports of orthostatic hypotension) was observed in 12% of patients. Patients who had orthostatic hypotension did not have it at the beginning of the study; half of the patients had pre-existing hypertension, and 1/3 had peripheral neuropathy. Doses of antihypertensive medications may need to be adjusted in patients receiving bortezomib. In 4% of patients with hypotension, including orthostatic, syncope was observed simultaneously.
Bortezomib
Serious adverse reactions were observed infrequently during bortezomib therapy and included heart failure, tumor lysis syndrome, pulmonary hypertension, reversible posterior encephalopathy syndrome, and acute diffuse infiltrative pulmonary disease. In addition, autonomic neuropathy has been observed in rare cases. The most common adverse reactions observed during bortezomib therapy were: nausea, diarrhea, constipation, vomiting, fatigue, fever, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory), headache, paresthesia, decreased appetite, shortness of breath , rash, herpes zoster and myalgia.
The following side effects are listed as likely or possibly related to bortezomib.
Side effects are grouped by system-organ classes and frequency of occurrence. Frequency was defined as: very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%) , very rare (<0.01%, including isolated cases). Within each frequency group, adverse reactions are presented in order of decreasing severity.
Infections and infestations:
often - pneumonia, herpes simplex, herpes zoster (including disseminated and ophthalmic herpes), fungal infections;
uncommon - infection, bacterial, viral infections, sepsis (including septic shock), bronchopneumonia, herpes virus infection, herpetic meningoencephalitis, bacteremia (including staphylococcal), barley, influenza, inflammation of subcutaneous fatty tissue, infections associated with the use of medical devices , skin infections, ear infections, staph infections, dental infections;
rarely - meningitis (including bacterial), Epstein-Barr viral infection, genital herpes, tonsillitis, mastoiditis, chronic fatigue syndrome.
Benign, malignant and unspecified neoplasms (including cysts and polyps):
rarely - malignant neoplasms, plasmacytic leukemia, kidney carcinoma, neoplasms, mycosis fungoides, benign neoplasms.
Blood and lymphatic system disorders:
very often - thrombocytopenia, neutropenia, anemia;
often - leukopenia, lymphopenia;
uncommon - pancytopenia, febrile neutropenia, coagulopathy, leukocytosis, lymphadenopathy, hemolytic anemia;
rarely - disseminated intravascular coagulation syndrome (DIC), thrombocytosis, thrombocytopenic purpura, hyperviscosity syndrome, platelet disorders, blood disorders, hemorrhagic diathesis, lymphocytic infiltration.
Immune system disorders:
uncommon - Quincke's edema, hypersensitivity;
rarely - anaphylactic shock, amyloidosis, reactions with the formation of immune complexes (type III).
Endocrine system disorders:
infrequently - Itsenko-Cushing syndrome, hyperthyroidism, impaired secretion of antidiuretic hormone;
rarely - hypothyroidism.
Metabolic and nutritional disorders:
very often - loss of appetite;
often - dehydration, hypokalemia, hyponatremia, changes in blood glucose concentrations, hypocalcemia, changes in enzyme activity;
uncommon - tumor lysis syndrome, lack of weight gain, hypomagnesemia, hypophosphatemia, hyperkalemia, hypercalcemia. hypernatremia, changes in uric acid concentration, diabetes mellitus, fluid retention;
rarely - hypermagnesemia, acidosis, water-electrolyte imbalance, excess fluid accumulation, hypochloremia, hypovolemia, hyperchloremia, hyperphosphatemia, metabolic disorders, B vitamin deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance.
Mental disorders:
often - mood disorders and disturbances, anxiety, disorders and sleep disorders;
Uncommon: mental status changes, hallucinations, psychotic disorder, confusion, agitation;
rarely - suicidal thoughts, adjustment disorder, delirium, decreased libido.
Nervous system disorders:
very often - neuropathy, peripheral sensory neuropathy, dysesthesia, neuralgia;
often - motor neuropathy, loss of consciousness (including fainting), dizziness, taste disturbance, lethargy, headache;
uncommon - tremor, peripheral sensorimotor neuropathy, dyskinesia, balance disorder, memory loss (except dementia), encephalopathy, posterior reversible encephalopathy syndrome, neurotoxicity, convulsions, postherpetic neuralgia, speech disorder, restless legs syndrome, migraine, sciatica, impaired concentration attention, pathological reflexes, parosmia;
rarely - intracerebral hemorrhage, intracranial hemorrhage (including subarachnoid), cerebral edema, transient ischemic attack, coma, imbalance of the autonomic nervous system, autonomic neuropathy, cranial nerve palsy, paralysis, paresis, presyncope, brain stem lesion syndrome, disorder cerebral circulation, radicular syndrome, psychomotor hyperactivity, spinal cord compression, cognitive disorders, movement disorders, nervous system disorders, sciatica, salivation, muscle hypotonia.
Visual disorders:
often - swelling of the eyes, blurred vision, conjunctivitis;
Uncommon: eye hemorrhage, eyelid infections, eye inflammation, diplopia, dry eyes, eye irritation, eye pain, increased lacrimation, eye discharge;
rarely - corneal damage, exophthalmos, retinitis, scotoma, eye damage (including eyelids), dacryoadenitis, photophobia, photopsia, optical neuropathy, varying degrees of visual impairment (up to blindness).
Hearing and balance disorders:
often - vertigo;
infrequently - ringing in the ears, hearing loss (up to deafness), discomfort in the ear area;
rarely - bleeding, vestibular neuronitis, ear damage.
Cardiac disorders:
uncommon - cardiac tamponade, cardiopulmonary shock, cardiac fibrillation (including atrial fibrillation), heart failure (including left and right ventricles), arrhythmia, tachycardia, palpitations, angina pectoris, pericarditis (including exudative pericarditis), cardiomyopathy, ventricular dysfunction, bradycardia;
rarely - atrial flutter, myocardial infarction, atrioventricular block, cardiovascular disorders (including cardiogenic shock), ventricular tachysystolic arrhythmia of the “pirouette” type, unstable angina, heart valve disease, coronary insufficiency, sinus node arrest.
Vascular system disorders:
often - decreased blood pressure, orthostatic hypotension, increased blood pressure;
uncommon - stroke, deep vein thrombosis, bleeding, thrombophlebitis (including superficial), circulatory collapse (including hypovolemic shock), phlebitis, hot flashes, hematoma (including perirenal), decreased peripheral circulation, vasculitis, hyperemia (including ocular);
rarely - peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vasodilation, discoloration of veins, venous insufficiency.
Respiratory, thoracic and mediastinal disorders:
often - shortness of breath, nosebleeds, upper and lower respiratory tract infections, cough;
uncommon - pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage, bronchospasm, chronic obstructive pulmonary disease, hypoxemia, airway congestion, hypoxia, pleurisy, hiccups, rhinorrhea, dysphonia, wheezing;
rarely - respiratory failure, acute respiratory distress syndrome, apnea, pneumothorax, atelectasis, pulmonary hypertension, hemoptysis, hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial disorders, hypocapnia, interstitial lung disease, pulmonary infiltration, feeling of tightness in the throat, dry throat, increased secretion in the upper respiratory tract, throat irritation, upper respiratory tract cough syndrome.
Gastrointestinal disorders:
very often - nausea, vomiting, diarrhea, constipation;
often - bleeding from the gastrointestinal tract (including bleeding of the mucous membrane), dyspepsia, stomatitis, disturbance of gastrointestinal tone, pain in the throat and pharynx, pain in the abdomen (including gastrointestinal pain and pain in the spleen) , disorders of the oral cavity, flatulence;
uncommon - pancreatitis (including chronic), vomiting blood, swelling of the lips, gastrointestinal obstruction (including intestinal obstruction), abdominal discomfort, ulceration of the oral mucosa, enteritis, gastritis, bleeding from the gums, gastroesophageal reflux disease, colitis (including pseudomembranous colitis), ischemic colitis, inflammation of the gastrointestinal mucosa, dysphagia, irritable bowel syndrome, gastrointestinal disorders, coating on the tongue, gastrointestinal motility disorders, salivary gland disorders;
rarely - acute pancreatitis, peritonitis, swelling of the tongue, ascites, esophagitis, cheilitis, fecal incontinence, atony of the anal sphincter, fecaloma, ulceration and perforation of the gastrointestinal tract, gum hypertrophy, megacolon, discharge from the rectum, blisters in the throat, pain in lips, periodontitis, anal fissure, change in defecation rhythm, proctalgia, stool disorders.
Disorders of the hepatobiliary system:
often - changes in the activity of liver enzymes;
uncommon - hepatotoxicity (including liver disorders), hepatitis, cholestasis;
rarely - liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, hepatic bleeding, cholelithiasis.
Skin and subcutaneous tissue disorders:
often - rash, itching, erythema, dry skin;
uncommon - erythema multiforme, urticaria, acute febrile neutrophilic dermatosis, toxic skin rash, toxic epidermal necrolysis, Stevens-Johnson syndrome, dermatitis, changes in hair structure, petechiae, ecchymosis, skin lesions, purpura, skin neoplasms, psoriasis, hyperhidrosis, night sweats, bedsores, acne, blisters, skin pigmentation disorders;
rarely - skin reactions, Jessner's lymphocytic infiltration, palmoplantar erythrodysesthesia, subcutaneous bleeding, livedo reticularis, skin induration, papule, photosensitivity reactions, seborrhea, cold sweat, unspecified skin lesions, erythrosis, skin ulcers, nail lesions.
Musculoskeletal and connective tissue disorders:
very often - musculoskeletal pain;
often - muscle spasms, pain in the limbs, muscle weakness;
uncommon - muscle twitching, joint swelling, arthritis, joint stiffness, myopathy, feeling of heaviness;
rarely - rhabdomyolysis, temporomandibular joint syndrome, fistula, joint effusion, jaw pain, bone disorders, infections and inflammation of musculoskeletal and connective tissue, synovial cysts.
Renal and urinary tract disorders:
often - renal dysfunction;
uncommon - acute renal failure, chronic renal failure, urinary tract infections, urinary tract complaints, hematuria, urinary retention, urinary dysfunction, proteinuria, azotemia, oliguria, pollakiuria;
rarely - bladder irritation.
Disorders of the genital organs and breast:
uncommon - vaginal bleeding, pain in the genitals, erectile dysfunction;
rarely - dysfunction of the testicles, prostatitis, dysfunction of the mammary gland, tenderness of the epididymis, epididymitis, pain in the pelvic area, ulceration of the vulva.
Congenital, hereditary and genetic disorders:
rarely - aplasia, gastrointestinal malformation, ichthyosis.
General disorders and disorders caused by the method of application:
very often - pyrexia, increased fatigue, asthenia;
often - swelling (including peripheral), chills, pain, discomfort;
Uncommon: deterioration in general physical health, facial swelling, injection site reactions, mucous membrane disorders, chest pain, gait disturbance, feeling cold, extravasation, catheter complications, change in thirst, chest discomfort, feeling of change body temperature, pain at the injection site;
rarely - death (including sudden), multiple organ failure, bleeding at the injection site, hernia, impaired healing processes, inflammation, phlebitis at the injection site, pain, ulceration, irritability, non-cardiac chest pain, pain at the catheter insertion site, foreign body sensation.
Changes in laboratory parameters:
often - weight loss;
infrequently - hyperbilirubinemia, changes in protein parameters, increase in body weight, changes in blood parameters, increased concentration of C-reactive protein;
rarely - changes in the content of gases in the blood, changes in the cardiogram (including an increase in the QT wave), changes in prothrombin time, a decrease in the pH of gastric juice, an increase in platelet aggregation, an increase in the concentration of troponin I, detection of viruses and changes in serology, changes in urine analysis.
Injuries, intoxications and complications of manipulations:
infrequently - falls, concussions;
rarely - transfusion reactions, fractures, rigidity, facial injuries, joint injuries, burns, ruptures, pain during the procedure, radiation injury.
Surgical and therapeutic procedures:
rarely - activation of macrophages.
Patients with mantle cell lymphoma
The safety profile of bortezomib in these patients was similar to that observed in patients with multiple myeloma. Significant differences between the two groups of patients were that thrombocytopenia, neutropenia, anemia, nausea, vomiting, and fever were more common in patients with multiple myeloma compared with patients with mantle cell lymphoma; and peripheral neuropathy, rash and pruritus in patients with mantle cell lymphoma.
Special instructions for the use of Bortezomib
Bortezomib should only be prescribed by a doctor experienced in anticancer chemotherapy. Peripheral neuropathy. If neuropathy occurs during treatment with bortezomib (see SIDE EFFECTS), predominantly sensory (although other cases have been reported, including mixed sensory-motor neuropathy), maintenance therapy is carried out. In patients with previous symptoms (numbness, pain or burning in the arms or legs) and/or signs of peripheral neuropathy, an exacerbation of the disease may occur. Patients should be monitored for early detection of symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort or neuropathic pain. If new or worsening symptoms of neuropathy appear, a dose reduction and a change in dosage regimen may be required. Hypotension. Since bortezomib therapy is accompanied by the development of orthostatic hypotension, caution should be exercised when treating patients with a history of episodes of loss of consciousness, receiving antihypertensive drugs, as well as in patients with dehydration due to diarrhea or vomiting. With the use of bortezomib, the development or worsening of existing congestive heart failure, to which fluid retention may predispose, has been described. Before and during each cycle of therapy, it is necessary to conduct a blood test to determine the leukocyte formula and platelet count. Thrombocytopenia is usually maximal on the 11th day of the cycle, with platelet levels returning to baseline by the next cycle. If the platelet count decreases to less than 25 thousand/μl, therapy should be suspended; if it recovers, continue in reduced doses with careful comparison of the possible benefits and risks of treatment. There are reports of gastrointestinal and intracerebral hemorrhages associated with bortezomib-induced thrombocytopenia. Colony-stimulating factors, platelet and red blood cell transfusions can be used to treat hematological toxicity. To prevent nausea and vomiting, antiemetic drugs are used; if diarrhea occurs, antidiarrheal drugs are used; to prevent or treat dehydration, rehydration therapy and maintaining water and electrolyte balance are used. Due to the possible development of intestinal obstruction, patients with constipation should be closely monitored. Due to the possible development of hyperuricemia associated with tumor lysis syndrome, it is recommended to determine the concentration of uric acid and creatinine in the blood serum during therapy. To prevent hyperuricemia, drink plenty of fluids and, if necessary, prescribe allopurinol and alkalinize the urine. When treating patients with amyloidosis, caution should be exercised, since the effect of inhibition of proteasome activity in diseases accompanied by an increase in protein content is unknown. When working with the drug, generally accepted rules for handling cytotoxic drugs should be followed. Children's age: safety and effectiveness in children have not been established. Toxicity study. Bortezomib exhibited clastogenic activity (structural chromosomal aberrations) in an in vitro on Chinese hamster ovary cells. It did not show genotoxic properties in tests in vitro (Ames test) and in vivo (micronucleus test in mice). The effect of bortezomib on the condition of reproductive tissues was assessed in general toxicity studies. A 6-month toxicology study in rats assessed ovarian degeneration at doses ≥0.3 mg/m2 (1/4 of the recommended clinical dose) and testicular degeneration at 1.2 mg/m2. Thus, bortezomib may have an effect on fertility in both sexes. Use during pregnancy and lactation. Bortezomib can be prescribed during pregnancy only if the benefits of therapy outweigh the potential risk to the fetus (there are no adequate and strictly controlled studies in pregnant women). It is unknown whether bortezomib crosses the placenta. If it is used during pregnancy or when planning pregnancy, the patient must be warned about the potential risk to the fetus. Women of reproductive potential must use effective contraception during therapy. It is not known whether bortezomib passes into women's breast milk. Because many drugs are excreted into breast milk and may have serious adverse effects on breast-fed infants, breast-feeding should be discontinued during bortezomib therapy. Some side effects (fatigue, dizziness, orthostatic hypotension, blurred vision) may affect the ability to drive a car and perform activities that require increased concentration and speed of psychomotor reactions, so special care should be taken.
Description of the drug BORTEZOMIB
Use with caution in severely impaired liver and kidney function, with a history of fainting, diabetic neuropathy, in patients receiving antihypertensive drugs, as well as in cases of dehydration due to diarrhea or vomiting.
If orthostatic hypotension develops, hydration, administration of corticosteroids and/or sympathomimetics are recommended; if necessary, reduce the dose of antihypertensive drugs.
Particular caution is required when prescribing the drug to patients with risk factors for seizures.
Before starting and during each cycle of therapy, it is necessary to conduct a complete blood count with calculation of the leukocyte formula and platelet content.
If the platelet count decreases to <25,000/μL, therapy should be suspended. When the platelet count is restored, treatment should be continued in reduced doses with careful comparison of the possible benefits and risks of treatment. Colony-stimulating factors, platelet and red blood cell transfusions can be used to treat hematological toxicity.
To prevent nausea and vomiting, the use of antiemetic drugs is recommended. If diarrhea occurs, antidiarrheal drugs are prescribed. To prevent or treat dehydration, patients need to undergo rehydration therapy and maintain fluid and electrolyte balance.
Due to the possible development of intestinal obstruction, patients with constipation should be closely monitored.
If neuropathy occurs, maintenance therapy is carried out. Typically, the incidence of peripheral neuropathy reaches a maximum on the 5th cycle of treatment. If new or worsening symptoms of peripheral neuropathy appear, a dose reduction and modification of the bortezomib administration regimen may be required.
Fluid retention may predispose to the development of symptoms of heart failure.
Due to the possible development of hyperuricemia associated with tumor lysis syndrome, patients are advised to determine serum uric acid and creatinine levels during therapy. To prevent hyperuricemia, it is recommended to drink plenty of fluids, if necessary, use allopurinol and alkalinize the urine.
When treating patients with amyloidosis with bortezomib, caution should be exercised because The effect of inhibition of proteasome activity in diseases accompanied by an increase in protein content is unknown.
When used in patients receiving oral hypoglycemic drugs, blood glucose levels should be carefully monitored and, if necessary, the dose of hypoglycemic drugs should be adjusted.
When working with bortezomib, generally accepted rules for handling cytotoxic drugs should be followed.
Drug interactions Bortezomib
In vitro studies on human liver microsomes showed that bortezomib is a substrate for cytochrome P450 isoenzymes CYP 3A4, CYP 2D6, CYP 2C19, CYP 2C9, CYP 1A2. Patients receiving bortezomib concomitantly and drugs that are inhibitors or inducers of CYP 3A4 should be carefully monitored due to the possibility of developing toxic effects or reducing the effectiveness of therapy. During clinical trials, hypoglycemia and hyperglycemia were reported in patients with diabetes mellitus receiving oral hypoglycemic agents. Patients receiving bortezomib and oral hypoglycemic agents concomitantly may require monitoring of blood glucose levels and dosage adjustment of the antidiabetic agent.
