Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antianemic preparations other antianemic preparations, ATC code: B03XA01

Binocrit is a biosimilar medicinal product, that has been demonstrated to be similar in quality, safety and efficacy to the reference medicinal product Eprex®. More detailed information is available on the website of the Ministry of Health http://www.health.gov.il/hozer/dr_127.pdf Mechanism of action
Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response to hypoxia and is the key regulator of RBC production. EPO is involved in all phases of erythroid development, and has its principal effect at the level of erythroid precursors. After EPO binds to its cell surface receptor, it activates signal transduction pathways that interfere with apoptosis and stimulates erythroid cell proliferation.

Recombinant human EPO (epoetin alfa), expressed in Chinese hamster ovary cells, has a 165 amino acid sequence identical to that of human urinary EPO; the 2 are indistinguishable on the basis of functional assays.
The apparent molecular weight of erythropoietin is 32,000 to 40,000 dalton.
Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.


Pharmacodynamic effects
Healthy volunteers

After single doses (20,000 to 160,000 IU subcutaneously) of epoetin alfa, a dose-dependent response was observed for the pharmacodynamic markers investigated including reticulocytes, RBCs, and haemoglobin. A defined concentration-time profile with peak and return to baseline was observed for changes in percent reticulocytes. A less defined profile was observed for RBCs and haemoglobin. In general, all pharmacodynamics markers increased in a linear manner with dose reaching a maximum response at the highest dose levels.

Further pharmacodynamic studies explored 40,000 IU once weekly versus 150 IU/kg 3 times per week. Despite differences in concentration-time profiles, the pharmacodynamic response (as measured by changes in percent reticulocytes, haemoglobin, and total RBCs) was similar between these regimens. Additional studies compared the 40,000 IU once-weekly regimen of epoetin alfa with biweekly doses ranging from 80,000 to 120,000 IU subcutaneously. Overall, based on the results of these pharmacodynamic studies in healthy subjects, the 40,000 IU once-weekly dosing regimen seems to be more efficient in producing RBCs than the biweekly regimens despite an observed similarity in reticulocyte production in the once-weekly and biweekly regimens.

Chronic renal failure

Epoetin alfa has been shown to stimulate erythropoiesis in anemic patients with CRF, including dialysis and pre-dialysis patients. The first evidence of a response to epoetin alfa is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, haemoglobin and haematocrit, usually within 2 to 6 weeks. The haemoglobin response varies between patients and may be impacted by iron stores and the presence of concurrent medical problems.


Chemotherapy-induced anemia
Epoetin alfa administered 3 times per week or once weekly has been shown to increase haemoglobin and decrease transfusion requirements after the first month of therapy in anemic cancer patients receiving chemotherapy.

In a study comparing the 150 IU/kg, 3 times per week and 40,000 IU, once-weekly dosing regimens in healthy subjects and in anemic cancer subjects the time profiles of changes in percent reticulocytes, haemoglobin, and total red blood cells were similar between the two dosing regimens in both healthy and anemic cancer subjects. The AUCs of the respective pharmacodynamic parameters were similar between the 150 IU/kg, 3 times per week and 40,000 IU, once-weekly dosing regimens in healthy subjects and in anemic cancer subjects.
Adult surgery patients in an autologous predonation programme

Epoetin alfa has been shown to stimulate red blood cell production in order to augment autologous blood collection, and to limit the decline in haemoglobin in adult patients scheduled for major elective surgery who are not expected to predeposit their complete perioperative blood needs. The greatest effects are observed in patients with low haemoglobin (≤13 g/dl).

Treatment of adult patients scheduled for major elective orthopaedic surgery 
In patients scheduled for major elective orthopaedic surgery with a pre-treatment haemoglobin of >10 to ≤13 g/dl, epoetin alfa has been shown to decrease the risk of receiving allogeneic transfusions and hasten erythroid recovery (increased haemoglobin levels, haematocrit levels, and reticulocyte counts).


Clinical efficacy and safety
Chronic renal failure

Epoetin alfa has been studied in clinical dudies in adult anemic CRF patients, including haemodialysis and pre-dialysis patients, to treat anemia and maintain haematocrit within a target concentration range of 30 to 36%.

In clinical studies at starting doses of 50 to 150 IU/kg, three times per week, approximately 95% of all patients responded with a clinically significant increase in haematocrit. After approximately two months of therapy, virtually all patients were transfusion-independent.
Once the target haematocrit was achieved, the maintenance dose was individualised for each patient.

In the three largest clinical studies conducted in adult patients on dialysis, the median maintenance dose necessary to maintain the haematocrit between 30 to 36% was approximately 75 IU/kg given 3 times per week.

In a double-blind, placebo-controlled, multicenter, quality of life study in CRF patients on haemodialysis, clinically and statistically significant improvement was shown in the patients treated with epoetin alfa compared to the placebo group when measuring fatigue, physical symptoms, relationships and depression (Kidney Disease Questionnaire) after six months of therapy. Patients from the group treated with epoetin alfa were also enrolled in an open-label extension study which demonstrated improvements in their quality of life that were maintained for an additional 12 months.

Adult patients with renal insufficiency not yet undergoing dialysis

In clinical studies conducted in patients with CRF not on dialysis treated with epoetin alfa, the average duration of therapy was nearly five months. These patients responded to epoetin alfa therapy in a manner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and sustained increase in haematocrit when epoetin alfa was administered by either an intravenous or subcutaneous route. Similar rates of rise of epoetin alfa doses of 75 to 150 IU/kg per week have been shown to maintain haematocrits of 36 to 38% for up to six months.

In 2 studies with extended interval dosing of epoetin alfa (3 times per week, once weekly, once every 2 weeks, and once every 4 weeks) some patients with longer dosing intervals did not maintain adequate haemoglobin levels and reached protocol-defined haemoglobin withdrawal criteria (0% in once weekly, 3.7% in once-every-2-weeks, and 3.3% in the once- every-4-weeks groups).
A randomised prospective study evaluated 1,432 anemic chronic renal failure patients who were not undergoing dialysis. Patients were assigned to epoetin alfa treatment targeting a maintenance haemoglobin level of 13.5 g/dl (higher than the recommended haemoglobin concentration level) or 11.3 g/dl. A major cardiovascular event (death, myocardial infarction, stroke or hospitalisation for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher haemoglobin group compared to 97 (14%) among the 717 patients in the lower haemoglobin group (hazard ratio [HR] 1.3, 95% CI: 1.0, 1.7, p = 0.03).

Pooled post-hoc analyses of clinical studies of ESAs have been performed in chronic renal failure patients (on dialysis, not on dialysis, in diabetic and non-diabetic patients). A tendency towards increased risk estimates for all-cause mortality, cardiovascular and cerebrovascular events associated with higher cumulative ESA doses independent of the diabetes or dialysis status was observed (see section 4.2 and section 4.4).

Treatment of patients with chemotherapy-induced anemia

Epoetin alfa has been studied in clinical studies in adult anemic cancer patients with lymphoid and solid tumors, and patients on various chemotherapy regimens, including platinum and non-platinum-containing regimens. In these studies , epoetin alfa administered 3 times per week and once weekly has been shown to increase haemoglobin and decrease transfusion requirements after the first month of therapy in anemic cancer patients. In some studies, the double-blind phase was followed by an open-label phase during which all patients received epoetin alfa and a maintenance of effect was observed.

Available evidence suggests patients with haematological malignancies and solid tumours respond equivalently to epoetin alfa therapy, and that patients with or without tumour infiltration of the bone marrow respond equivalently to epoetin alfa therapy. Comparable intensity of chemotherapy in the epoetin alfa and placebo groups in the chemotherapy studies was demonstrated by a similar area under the neutrophil time curve in patients treated with epoetin alfa and placebo-treated patients, as well as by a similar proportion of patients in groups treated with epoetin alfa and placebo-treated groups whose absolute neutrophil counts fell below 1,000 and 500 cells/μl.

In a prospective, randomised, double-blind, placebo-controlled study conducted in 375 anemic patients with various non-myeloid malignancies receiving non-platinum chemotherapy, there was a significant reduction of anemia -related sequelae (e.g. fatigue, decreased energy, and activity reduction), as measured by the following instruments and scales: Functional Assessment of Cancer Therapy-Anemia (FACT-An) general scale, FACT- An fatigue scale, and Cancer Linear Analogue Scale (CLAS). Two other smaller, randomised, placebo-controlled studies failed to show a significant improvement in quality of life parameters on the EORTC-QLQ-C30 scale or CLAS, respectively.

Survival and tumour progression have been examined in five large controlled studies involving a total of 2,833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. The studies either recruited patients who were being treated with chemotherapy (two studies) or used patient populations in which ESAs are not indicated: anemia in patients with cancer not receiving chemotherapy, and head and neck cancer patients receiving radiotherapy. The desired haemoglobin concentration level in two studies was >13 g/dl (8.1 mmol/l); in the remaining three studies it was 12 to 14 g/dl (7.5 to 8.7 mmol/l). In the open-label study there was no difference in overall survival between patients treated with recombinant human erythropoietin and controls. In the four placebo- controlled studies the hazard ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have shown a consistent unexplained statistically significant excess mortality in patients who have anemia associated with various common cancers who received recombinant human erythropoietin compared to controls. Overall survival outcome in the studies could not be satisfactorily explained by differences in the incidence of thrombosis and related complications between those given recombinant human erythropoietin and those in the control group.
A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-, radio-, chemoradio-, or no therapy) participating in 53 controlled clinical studies involving several epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in favour of controls (95% CI: 1.00, 1.12; 53 studies and 13,933 patients) and for the cancer patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 studies and 10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section 4.4: ”Special warnings and precautions for use”).

A randomised, open-label, multicentre study was conducted in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non inferiority study designed to rule out a 15% risk increase in tumour progression or death of epoetin alfa plus standard of care as compared with standard of care alone. At the time of clinical data cutoff, the median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. Significantly fewer patients received RBC transfusions in the epoetin alfa plus standard of care arm (5.8% versus 11.4%); however, significantly more patients had thrombotic vascular events in the epoetin alfa plus standard of care arm (2.8% versus 1.4%) At the final analysis, 1653 deaths were reported. Median overall survival in the epoetin alfa plus standard of care group was 17.8 months compared with 18.0 months in the standard of care alone group (HR 1.07, 95% CI: 0.97, 1.18). The median time to progression (TTP) based on investigator-determined progressive disease (PD) was 7.5 months in the epoetin alfa plus standard of care group and 7.5 months in the standard of care group (HR 1.099, 95% CI: 0.998, 1.210). The median TTP based on IRC-determined PD was 8.0 months in the epoetin alfa plus standard of care group and 8.3 months in the standard of care group (HR 1.033, 95% CI: 0.924, 1.156).


Autologous predonation programme

The effect of epoetin alfa in facilitating Autologous blood donation in patients with low haematocrits (≤39% and no underlying anemia due to iron deficiency) scheduled for major orthopaedic surgery was evaluated in a double-blind, placebo-controlled study conducted in 204 patients, and a single-blind placebo-controlled study in 55 patients.

In the double-blind study, patients were treated with epoetin alfa 600 IU/kg or placebo intravenously once daily every 3 to 4 days over 3 weeks (total 6 doses). On average, patients treated with epoetin alfa were able to predeposit significantly more units of blood (4.5 units) than placebo-treated patients (3.0 units).

In the single-blind study, patients were treated with epoetin alfa 300 IU/kg or 600 IU/kg or placebo intravenously once daily every 3 to 4 days over 3 weeks (total 6 doses). Patients treated with epoetin alfa were also able to predeposit significantly more units of blood (epoetin alfa 300 IU/kg = 4.4 units; epoetin alfa 600 IU/kg = 4.7 units) than placebo-treated patients (2.9 units).

Epoetin alfa therapy reduced the risk of exposure to allogeneic blood by 50% compared to patients not receiving epoetin alfa.

Major elective orthopaedic surgery

The effect of epoetin alfa (300 IU/kg or 100 IU/kg) on the exposure to allogeneic blood transfusion has been evaluated in a placebo-controlled, double-blind clinical study in non-iron deficient adult patients scheduled for major elective orthopaedic hip or knee surgery. Epoetin alfa was administered subcutaneously for 10 days prior to surgery, on the day of surgery, and for four days after surgery. Patients were stratified according to their baseline haemoglobin (≤10 g/dl, >10 to ≤13 g/dl and >13 g/dl).
Epoetin alfa 300 IU/kg significantly reduced the risk of allogeneic transfusion in patients with a pretreatment haemoglobin of >10 to ≤13 g/dl. 16% of epoetin alfa 300 IU/kg, 23% of epoetin alfa 100 IU/kg and 45% of placebo-treated patients required transfusion.

An open-label, parallel-group study in non-iron deficient adult subjects with a pre-treatment haemoglobin of ≥10 to ≤13 g/dl who were scheduled for major orthopaedic hip or knee surgery compared epoetin alfa 300 IU/kg subcutaneously daily for 10 days prior to surgery, on the day of surgery and for four days after surgery to epoetin alfa 600 IU/kg subcutaneously once weekly for 3 weeks prior to surgery and on the day of surgery.

From pre-treatment to pre-surgery, the mean increase in haemoglobin in the 600 IU/kg weekly group (1.44 g/dl) was twice than that observed in the 300 IU/kg daily group (0.73 g/dl).
Mean haemoglobin levels were similar for the two treatment groups throughout the postsurgical period.

The erythropoietic response observed in both treatment groups resulted in similar transfusion rates (16% in the 600 IU/kg weekly group and 20% in the 300 IU/kg daily group).

Paediatric population

Chronic renal failure
Epoetin alfa was evaluated in an open-label, non-randomised, open dose-range, 52-week clinical study in paediatric CRF patients undergoing haemodialysis. The median age of patients enrolled in the study was 11.6 years (range 0.5 to 20.1 years).
Epoetin alfa was administered at 75 IU/kg/week intravenously in 2 or 3 divided doses post- dialysis, titrated by 75 IU/kg/week at intervals of 4 weeks (up to a maximum of 300 IU/kg/week), to achieve a 1 g/dl/month increase in haemoglobin. The desired haemoglobin concentration range was 9.6 to 11.2 g/dl. 81% of patients achieved the haemoglobin concentration level. The median time to target was 11 weeks and the median dose at target was 150 IU/kg/week. Of the patients who achieved the target, 90% did so on a 3 times-per-week dosing regimen.

After 52 weeks, 57% of patients remained in the study, receiving a median dose of 200 IU/kg/week.

Clinical data with subcutaneous administration in children are limited. In 5 small, open label, uncontrolled studies (number of patients ranged from 9-22, total N = 72), Epoetin alfa has been administered subcutaneously in children at starting doses of 100 IU/kg/week to 150 IU/kg/week with the possibility to increase up to 300 IU/kg/week. In these studies, most were predialysis patients (N = 44), 27 patients were on peritoneal dialysis and 2 were on haemodialysis with age ranging from 4 months to 17 years. Overall, these studies have methodological limitations but treatment was 21 associated with positive trends towards higher haemoglobin levels. No unexpected adverse reactions were reported (see section 4.2).

Chemotherapy-induced anemia
Epoetin alfa 600 IU/kg (administered intravenously or subcutaneously once weekly) has been evaluated in a randomised, double-blind, placebo-controlled, 16-week study and in a randomised, controlled, open-label, 20-week study in anemic paediatric patients receiving myelosuppressive chemotherapy for the treatment of various childhood non-myeloid malignancies.
In the 16-week study (n = 222), in the epoetin alfa-treated patients there was no statistically significant effect on patient-reported or parent-reported Paediatric Quality of Life Inventory or Cancer Module scores compared with placebo (primary efficacy endpoint). In addition, there was no statistical difference between the proportion of patients requiring pRBC transfusions between the Epoetin alfa group and placebo.
In the 20-week study (n = 225), no significant difference was observed in the primary efficacy endpoint, i.e. the proportion of patients who required a RBC transfusion after Day 28 (62% of epoetin alfa patients versus 69% of standard therapy patients).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Following subcutaneous injection, serum levels of epoetin alfa reach a peak between 12 and 18 hours post-dose. There was no accumulation after multiple dose administration of 600 IU/kg administered subcutaneously weekly. The absolute bioavailability of subcutaneous injectable epoetin alfa is approximately 20% in healthy subjects


Distribution
The mean volume of distribution was 49.3 ml/kg after intravenous doses of 50 and 100 IU/kg in healthy subjects. Following intravenous administration of epoetin alfa in subjects with chronic renal failure, the volume of distribution ranged from 57-107 ml/kg after single dosing (12 IU/kg) to 42–64 ml/kg after multiple dosing (48–192 IU/kg), respectively. Thus, the volume of distribution is slightly greater than the plasma space.

Elimination
The half-life of epoetin alfa following multiple dose intravenous administration is approximately 4 hours in healthy subjects. The half-life for the subcutaneous route is estimated to be approximately 24 hours in healthy subjects.

The mean CL/F for the 150 IU/kg 3 times-per-week and 40,000 IU once-weekly regimens in healthy subjects were 31.2 and 12.6 ml/h/kg, respectively. The mean CL/F for the 150 IU/kg, 3 times-per week and 40,000 IU, once-weekly regimens in the anemic cancer subjects were 45.8 and 11.3 ml/h/kg, respectively. In most anemic subjects with cancer receiving cyclic chemotherapy, CL/F was lower after subcutaneous doses of 40,000 IU once weekly and 150 IU/kg, 3 times per week compared with the values for healthy subjects.

Linearity/Non-linearity
In healthy subjects, a dose-proportional increase in serum epoetin alfa concentrations was observed after intravenous administration of 150 and 300 IU/kg, 3 times per week.
Administration of single doses of 300 to 2,400 IU/kg subcutaneous epoetin alfa resulted in a linear relationship between mean Cmax and dose and between mean AUC and dose. An inverse relationship between apparent clearance and dose was noted in healthy subjects.

In studies to explore extending the dosing interval (40,000 IU once weekly and 80,000, 100,000, and 120,000 IU bi-weekly), a linear but non-dose-proportional relationship was observed between mean Cmax and dose, and between mean AUC and dose at steady state.


Pharmacokinetic/pharmacodynamic relationships
Epoetin alfa exhibits a dose-related effect on haematological parameters, which is independent of route of administration.


Paediatric population
A half-life of approximately 6.2 to 8.7 hours has been reported in paediatric subjects with chronic renal failure following multiple dose intravenous administration of epoetin alfa. The pharmacokinetic profile of epoetin alfa in children and adolescents appears to be similar to that of adults.

Pharmacokinetic data in neonates is limited.

A study of 7 preterm very low birth weight neonates and 10 healthy adults given i.v.
erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in healthy adults.

Renal impairment
In chronic renal failure patients, the half-life of intravenously administered epoetin alfa is slightly prolonged, approximately 5 hours, compared to healthy subjects.