Revolade® [Eltrombopag]

Pharmacological properties

thrombopoietin is the main cytokine that is involved in the regulation of megakaryopoiesis and platelet formation and is an endogenous ligand for thrombopoietin receptors. Eltrombopag interacts with the transmembrane domain of human thrombopoietin receptors and initiates a cascade of signals similar but not identical to those triggered by endogenous thrombopoietin, inducing the proliferation and differentiation of megakaryocytes from progenitor cells in the bone marrow.

Eltrombopag differs from thrombopoietin in its effect on platelet aggregation. Unlike thrombopoietin, eltrombopag does not enhance the aggregation of normal human platelets induced by ADP or induces P-selective expression. Eltrombopag is not an antagonist of platelet aggregation induced by ADP or collagen.

Pharmacokinetics The pharmacokinetic parameters of Eltrombopag when using this drug for the treatment of adult patients with idiopathic thrombocytopenic purpura are as follows: when using the drug in a dose of 50 mg once a day C_max will be 8.01 μg / ml (6.73; 9.53), and AUC - 108 μg / h / ml (88, 134). When using the drug in a dose of 75 mg 1 time per day C_max will be 12.7 μg / ml (11.0; 14.5), and AUC - 168 μg / h / ml (143, 198).

Absorption and bioavailability. WITH_max Eltrombopag is achieved 2-6 hours after oral administration. Combined use with antacids and other products that contain polyvalent cations, such as dairy products and mineral additives, significantly reduces the concentration of Eltrombopag. The absolute bioavailability of Eltrombopag when administered to humans has not been established. Based on urinary excretion and excretion of metabolites with feces, the oral absorption of substances associated with the drug after taking a single dose of 75 mg of Eltrombopag is about 52%.

Distribution. Eltrombopag mostly binds to human plasma proteins (99.9%), mainly with albumin. Eltrombopag is a substrate for breast cancer resistance protein, but it is not a substrate for P-glycoprotein and transport polypeptides of organic anions.

Metabolism. Eltrombopag is primarily metabolized by cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. During a radiological study, Eltrombopag was responsible for approximately 64% of the plasma radioactive carbon AUC. Minor metabolites resulting from glucuronidation and oxidation, each of which is responsible for less than 10% of plasma radioactivity, have also been identified. Based on the results of a study in a person with radiolabelled Eltrombopag, it can be expected that about 20% of the dose is metabolized by oxidation. According to an in vitro study, it was identified that the CYP 1A2 and CYP 2C8 isoenzymes are responsible for metabolism by oxidation, the uridine diphosphoglucuronyltransferase isoenzymes UGT1A1 and UGT1A3 are responsible for glucuronidation and bacteria from the lower gastrointestinal tract may be responsible for the cleavage process.

Elimination. Absorbed Eltrombopag is extensively metabolized. Eltrombopag is excreted mainly with feces (59%), 31% of the dose is in the urine in the form of metabolites. Unchanged Eltrombopag in the urine was not detected. Unchanged Eltrombopag, which is excreted with feces, is about 20% of the dose. T_½ plasma thrombopagus is about 21–32 hours

Pharmacokinetic interactions. Based on studies with radiolabelled Eltrombopag, it can be argued that glucuronidation plays an insignificant role in its metabolism. Clinically significant drug interactions involving glucuronidation cannot be expected due to the limited influence of individual UGT enzymes on the glucuronidation of Eltrombopag and potential concomitant drugs.

In vitro studies have shown that Eltrombopag is not a CYP inhibitor of 450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4 / 5 and 4A9 / 11, but is an inhibitor of CYP 2C8 and CYP 2C9.

Clinically significant interaction with the combined use of Eltrombopag and CYP 450 substrates, both inducers and inhibitors, is not expected.

In vitro studies have shown that Eltrombopag is an inhibitor of OATP1B1 (organic anion transporter polypeptide) and BCRP (breast cancer resistance protein) transporters. Administration of Eltrombopag at a dose of 75 mg once a day for 5 days in combination with a single dose of 10 mg of rosuvastatin, which is a substrate for OATP1B1 and BCRP, increases C_max rosuvastatin by 103% and AUC by 55%.

Taking a single dose of Eltrombopag 75 mg in combination with antacids that contain polyvalent cations (1524 aluminum hydroxide and 1425 magnesium carbonate) reduces the plasma AUC of Eltrombopag and C_max by 70%.

Taking a single dose of 50 mg Eltrombopag in combination with a standard high-fat, high-fat breakfast including dairy products reduces Eltrombopags plasma AUC by 59%, and C_max - by 65%. Foods low in calcium (50 mg) do not significantly affect the plasma concentration of Eltrombopag regardless of fat and calories.

Special Patient Groups

Renal failure. The pharmacokinetics of Eltrombopag was studied after use of the drug by adult patients with renal failure. After taking a single 50 mg dose, Eltrombopag AUC decreased by 32% in patients with mild renal failure, by 36% in patients with moderate renal failure, and 60% in patients with severe renal failure compared to healthy volunteers. Although, as a rule, in patients with renal failure, the plasma concentration of Eltrombopag decreases, there is significant variability in exposure indicators when comparing patients with renal failure and healthy volunteers. In patients with renal failure, it is necessary to use Eltrombopag with caution.

Liver failure. The pharmacokinetics of Eltrombopag was studied after the use of the drug in adult patients with liver failure. After taking a single 50 mg dose, the eltrombopag AUC increased by 41% in patients with mild liver failure, by 93% in patients with moderate liver failure, and by 80% in patients with severe liver failure compared to healthy volunteers. There is significant variability in exposure when comparing patients with liver failure and healthy volunteers. The effect of hepatic insufficiency on the pharmacokinetics of eltrombopag during repeated administration was studied by population pharmacokinetic analysis with 28 healthy volunteers and 79 patients with chronic liver diseases (37 with mild, 40 with moderate, 2 with severe liver failure). Given the assumption of a population pharmacokinetic analysis, patients with hepatic insufficiency had higher plasma AUC values ​​compared with healthy volunteers and these indicators increased with an increase in the Child-Pugh score. In patients with mild hepatic insufficiency, plasma levels of AUC of Eltrombopag were noted approximately 87–110% higher, and with moderate degrees of liver failure, plasma AUC of Eltrombopag in plasma was found to be 141–240% higher than in healthy volunteers. Therefore, Eltrombopag should not be used to treat patients with idiopathic thrombocytopenic purpura (ITP) and liver failure (Child-Pugh score ≥5), if the expected benefits of the drug will not exceed the risk of portal vein thrombosis (seeAPPLICATION AND SPECIAL INSTRUCTIONS).

Racial affiliation. According to the results of the pharmacokinetic analysis, in patients of East Asian origin with ITP, the AUC of Eltrombopag was approximately 87% higher than in patients of other races (mainly Eupropoid), with no dose adjustment relative to body weight.

Floor. According to the results of population pharmacokinetic analysis, in patients with female ITP, the plasma level of Eltrombopag is approximately 50% higher than that in male patients.

Indications

Treatment of adult patients with chronic ITP who underwent splenectomy and who cannot be treated with other drugs (e.g. corticosteroids, immunoglobulins). as a second-line drug for the treatment of adult patients who have not undergone splenectomy due to contraindications for surgery.

Application

Eltrombopag is for oral use. the drug should be taken at least 4 hours before or after taking antacids, dairy products or mineral supplements that contain polyvalent cations (for example, aluminum, calcium, iron, magnesium, selenium, zinc).

Eltrombopag treatment should be carried out under the supervision of a doctor who has experience in the treatment of hematological diseases.

The dosage regimen is individual and is based on the number of platelets in each patient. The goal of treatment with Eltrombopag is not to normalize the platelet count, but to maintain their number above the level representing a hemorrhagic risk (50,000 / μl).

In most patients, a moderate increase in platelet count is observed after 1-2 weeks.

Adults The recommended initial dose of the drug is 50 mg 1 time per day. Treatment of patients of the Mongoloid race should begin with a reduced dose of 25 mg once a day.

Monitoring and dose adjustment. After starting treatment with Eltrombopag, the dose should be corrected so as to reach a platelet count of ≥50,000 / μl and maintain it as necessary to reduce the risk of bleeding. Do not exceed a dose of 75 mg / day.

During treatment with Eltrombopag, it is necessary to regularly monitor liver function tests and hematological parameters and correct the dose of Eltrombopag based on platelet count, as indicated in the table. An extensive blood count, including platelet count and peripheral blood smear, should be performed weekly until a stable platelet count is established (50,000 / μl for at least 4 weeks). After this, a detailed blood test is performed monthly.

The smallest effective dose of the drug is used to maintain the required platelet level.

Eltrombopag Dose Correction Table

Eltrombopag can be used in addition to other drugs for the treatment of ITP. In accordance with the clinical condition, the dose of concomitant drugs for the treatment of ITP should be adjusted to avoid an excessive increase in platelet count during treatment with Eltrombopag.

Before each new dose adjustment, you must wait at least 2 weeks after the previous correction in order to determine the patients response to treatment.

The standard dose of Eltrombopag to increase or decrease the daily dose is 25 mg / day. However, some patients may need the combined use of different doses of the drug on different days.

Discontinuation of treatment. The use of Eltrombopag should be discontinued if the platelet count does not rise to a level sufficient to prevent clinically significant bleeding after 4 weeks of treatment with Eltrombopag at a dose of 75 mg / day.

Periodically, the doctor must conduct a clinical examination of the patient and decide on the extension of treatment on an individual basis. After discontinuation of treatment, a relapse of thrombocytopenia is possible.

Renal failure. A dose change is not required. Treatment of patients with renal failure should be carried out with caution and control the level of serum creatinine and / or urinalysis.

Liver failure. Eltrombopag is not used to treat patients with ITP with moderate or severe liver failure (≥5 on the Child-Pugh scale), unless the expected benefits of the application will prevail over the risk of portal venous thrombosis (see SPECIAL INSTRUCTIONS).

If the use of Eltrombopag is necessary for the treatment of patients with ITP with liver failure, the initial dose should be 25 mg / day. After starting treatment with Eltrombopag, patients with liver failure should wait 3 weeks until a further dose increase.

An increased risk of thromboembolic complications was found in patients with thrombocytopenia (platelet count 50,000 / μl) with chronic liver diseases and the absence of concomitant ITP disease in the treatment of Eltrombopag at a dose of 75 mg / day for 2 weeks in preparation for invasive intervention (see SPECIAL INSTRUCTIONS and SIDE EFFECTS).

Elderly patients. Data on the use of Eltrombopag for the treatment of patients over the age of 65 is limited. In general, according to clinical studies of Eltrombopag, a significant difference in the safety of the drug in patients older and younger than 65 years of age has not been established. According to other clinical observations, there were no differences in the therapeutic effect between the elderly and younger patients, but the possibility of the appearance of greater sensitivity in some elderly patients should not be ruled out.

Patients of the Mongoloid race. Patients from East Asian countries (China, Japan or Korea) should begin treatment with a reduced dose of 25 mg once a day. It is necessary to control the number of platelets and be guided by standard criteria for further dose modification.

Contraindications

Hypersensitivity to Eltrombopag or any other component of the drug.

Side effects

According to clinical studies of patients with itp, the overall incidence of side effects in patients who took Eltrombopag was 82% (the average duration of Eltrombopag was 304 days). the following side effects are systematized by organs and systems depending on the frequency of occurrence: very often (≥1 / 10), often (≥1 / 100 and 1/10), infrequently (≥1 / 1000 and 1/100), rarely (≥ 1/10 000 and 1/1000) and very rarely (1/10 000), it is unknown (according to the available data, the frequency cannot be determined).

Infections and infestations: infrequently - pharyngitis, urinary infections