Ecoral

Ecoral®

Ecoral® should only be used by a physician experienced in immunosuppressive therapy and able to organize appropriate monitoring of the patient, including a regular complete physical examination, blood pressure measurement and monitoring of serum creatinine concentrations. Monitoring of transplant patients receiving the drug should only be carried out in institutions that have trained medical personnel and adequate laboratory resources.

It should be borne in mind that when using cyclosporine, as well as other immunosuppressive drugs, the risk of developing lymphomas and other malignant neoplasms, especially of the skin, increases. The increased risk of developing these complications depends more on the degree and duration of immunosuppression than on the specific drug. Therefore, caution should be exercised when using combination immunosuppressive regimens, keeping in mind the potential for the development of lymphoproliferative diseases and solid malignancies, sometimes leading to death.

Given the potential risk of developing skin malignancies, patients receiving treatment with cyclosporine should avoid excessive exposure to direct sunlight, exposure to ultraviolet radiation (ultraviolet B (UVB)), and PUVA therapy (photochemotherapy).

The use of cyclosporine, like other immunosuppressive drugs, predisposes to the development of various bacterial, fungal, parasitic and viral infections, often involving opportunistic pathogens. Reactivation of polyomavirus from latency can lead to the development of PVAN or PMLEP. Such conditions are often associated with a high degree of immunosuppression and should be considered in the differential diagnosis of causes of renal and nervous system dysfunction in patients receiving immunosuppressive therapy. Given the potential danger of these infections for the patient's life, an effective system of preventive and therapeutic measures should be used, especially in cases of long-term use of combined immunosuppressive treatment.

During the first few weeks of therapy with Ecoral®, a common and potentially dangerous complication may occur - an increase in the concentration of creatinine and urea in the blood serum. These functional changes are reversible and dose-dependent, usually normalizing with dose reduction. With long-term treatment, some patients may develop structural changes in the kidneys (for example, interstitial fibrosis), which in patients with renal transplants should be differentiated from changes due to chronic rejection. The drug Ecoral® may also cause a dose-dependent, reversible increase in bilirubin concentration and, rarely, an increase in the activity of liver transaminases. During clinical practice, reports of cyclosporine hepatotoxicity were received, which was manifested by the development of cholestasis, hepatic jaundice and liver failure. In most cases, the patients' condition was aggravated by concomitant diseases and other aggravating factors (infectious complications and simultaneous use of drugs with hepatotoxic effects). In these cases, careful monitoring of renal and liver function parameters is required. If these indicators deviate from the norm, a reduction in the dose of cyclosporine may be necessary.

In elderly patients, renal function should be especially carefully monitored.

When using the drug Ecoral® in patients after transplantation, it is necessary to determine the concentration of cyclosporine in the blood plasma.

To monitor cyclosporine blood concentrations, it is preferable to use specific monoclonal antibodies (measurement of the amount of unchanged drug). High performance liquid chromatography can be used, which also measures the concentration of unchanged substance. If plasma or serum is used, standard separation procedures (time and temperature) should be followed. For initial determination of cyclosporine concentrations in patients with liver transplants, specific monoclonal antibodies should be used. It is also possible to conduct parallel determinations using specific and nonspecific monoclonal antibodies to achieve a dose that provides adequate immunosuppression.

It should be remembered that the concentration of cyclosporine in the blood, plasma or serum is only one of many factors characterizing the clinical condition of the patient. The results of determining the concentration of cyclosporine are only one of the factors determining the dosage regimen, and are considered in relation to various clinical and laboratory indicators.

During treatment with Ecoral®, blood pressure must be regularly monitored. If blood pressure increases, adequate antihypertensive therapy should be used. Preference should be given to antihypertensive drugs that do not affect the pharmacokinetics of cyclosporine.

Since in rare cases the drug Ecoral® causes minor reversible hyperlipidemia, it is recommended to determine the concentration of lipids in the blood plasma before treatment and one month after the start of therapy. If lipid concentrations increase, you should consider limiting dietary fat intake and, if necessary, reducing the dose of Ecoral®. The use of Ecoral® may increase the risk of hyperkalemia, especially in patients with impaired renal function. Caution should also be exercised when simultaneous use of cyclosporine with potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists and potassium-containing drugs, as well as in cases of using a diet enriched with potassium. In these cases, monitoring the concentration of potassium in the blood plasma is recommended.

Cyclosporine increases the excretion of magnesium from the body, which can lead to clinically significant hypomagnesemia, especially in the peritransplant period. In this regard, in the peritransplantation period it is recommended to monitor the concentration of magnesium in the blood plasma, especially when neurological symptoms appear. If necessary, use magnesium supplements. It is recommended to monitor serum uric acid concentrations, especially in patients with pre-existing hyperuricemia.

To prevent anaphylactoid reactions, you can administer antihistamines (H1-histamine receptor blocker) before using Ecoral®.

Additional precautions for non-transplant indications

Cyclosporine should not be used in patients with impaired renal function (except for patients with nephrotic syndrome and the acceptable degree of these disorders), uncontrolled arterial hypertension, infectious diseases that cannot be adequately treated, or malignant neoplasms.

Since Ecoral® may cause renal impairment, a reliable baseline serum creatinine concentration should be established in at least 2 measurements prior to treatment. Creatinine concentrations should be monitored at 2-week intervals during the first 3 months of therapy and monthly thereafter. After 6 months of therapy, creatinine concentrations should be determined every 4-8 weeks depending on the stability of the underlying disease, the type of concomitant therapy and concomitant diseases. More frequent monitoring is necessary when increasing the dose of Ecoral®, when adding concomitant NSAID therapy or increasing their dose. Additional precautions for endogenous uveitis

If the serum creatinine concentration remains elevated by more than 30% compared to the initial concentration (before treatment with Ecoral®) in more than one dimension, then a dose reduction of 25-50% is required. These recommendations should be followed even if the creatinine concentration remains within the laboratory normal range.

Experience with the use of Ecoral® in children with endogenous uveitis is limited.

Additional precautions for nephrotic syndrome

If the creatinine concentration remains elevated by more than 30% compared to the initial concentration (before treatment with Ecoral®) in more than one dimension, then a dose reduction of 25-50% is required. In patients with initially impaired renal function, the initial dose should be 2.5 mg/kg/day. It is necessary to ensure careful monitoring of the condition of these patients.

Because of the changes in kidney function caused by nephrotic syndrome, it may be difficult to detect renal dysfunction caused by immunosuppressive drugs in some patients. This explains the fact that in some cases, structural changes in the kidneys associated with taking an immunosuppressive drug were not accompanied by an increase in creatinine concentration. Kidney biopsy is indicated for patients with steroid-dependent minimal change nephropathy who have received maintenance therapy with Ecoral® for more than 1 year. In rare cases, malignancies, including Hodgkin's lymphoma, have been reported in patients with nephrotic syndrome treated with immunosuppressive drugs.

Additional precautions for rheumatoid arthritis

If the creatinine concentration remains elevated by more than 30% of the initial value and in more than one dimension, then the dose should be reduced. If the creatinine concentration increases by more than 50%, then the dose must be reduced by 50%. These recommendations should be followed even if the creatinine concentration remains within the laboratory normal range. If the dose reduction does not lead to a decrease in creatinine concentration within 1 month, then treatment with Ecoral® should be discontinued.

Discontinuation of treatment is also necessary if uncontrolled arterial hypertension occurs during treatment with Ecoral®.

As with other long-term immunosuppressive treatments, the increased risk of lymphoproliferative disorders should be kept in mind. Particular caution should be observed when using Ecoral® in combination with methotrexate.

Additional precautions for psoriasis

If the creatinine concentration increases and remains elevated by more than 30% of baseline values and in more than one dimension, then the dose should be reduced by 25-50%. These recommendations should be followed even if creatinine concentrations continue to remain within the laboratory normal range. If dose reduction does not lead to a decrease in creatinine concentration within 1 month, then treatment with Ecoral® should be discontinued.

Discontinuation of treatment is also necessary if uncontrolled arterial hypertension occurs during treatment with Ecoral®.

The use of Ecoral® in elderly patients is possible only in cases of disabling psoriasis, and careful monitoring of renal function is necessary.

Experience with the use of Ecoral® in children with psoriasis is limited.

It is known that patients with psoriasis treated with cyclosporine, as with other conventional immunosuppressive treatments, may develop malignant neoplasms, especially of the skin. If skin lesions are not typical for psoriasis, and if a malignant or precancerous disease is suspected, a biopsy should be performed before starting treatment with Ecoral®. Treatment of patients with malignant or precancerous lesions with Ecoral® is possible only after appropriate treatment of these diseases and in the absence of alternative effective therapy. Patients with psoriasis treated with cyclosporine may develop lymphoproliferative diseases. In these cases, the drug must be discontinued immediately. Patients being treated with Ecoral® should not simultaneously receive ultraviolet B radiation or PUVA therapy.

Additional precautions for atopic dermatitis

If the creatinine concentration increases and remains elevated by more than 30% of baseline values in more than one measurement, then the dose should be reduced by 25-50%. These recommendations should be followed even if the creatinine concentration remains within the laboratory normal range. If the dose reduction does not lead to a decrease in creatinine concentration within one month, then treatment with Ecoral® should be discontinued.

Discontinuation of treatment is also necessary if uncontrolled arterial hypertension occurs during treatment with Ecoral®.

Since experience with the use of Ecoral® in children with atopic dermatitis is currently still limited, the use of the drug in this category of patients is not recommended.

The use of Ecoral® in elderly patients is possible only in cases of a disabling course of the disease, and careful monitoring of renal function is necessary.

Benign lymphadenopathy is usually associated with sudden exacerbations of atopic dermatitis. It goes away either independently or against the background of a general improvement in the course of the disease. Lymphadenopathy occurring during treatment with cyclosporine should be monitored regularly.

Lymphadenopathy that persists despite decreased disease activity should be biopsied to rule out lymphoma.

Cases of herpes simplex in the acute period should be cured before starting treatment with Ecoral®, but the appearance of herpes simplex is not a reason to discontinue the drug if treatment has already been started, except in severe cases.

Skin infectious diseases caused by Staphylococcus aureus are not an absolute contraindication for therapy with Ecoral®, but must be controlled by the use of appropriate antibacterial drugs.

Due to the potential risk of skin malignancy, patients should be warned to avoid direct exposure to sunlight and ultraviolet B radiation or PUVA therapy when treated with Ecoral®.

Instructions for use EQUORAL

Medical observation

Equoral should only be used by physicians experienced in administering immunosuppressive therapy and able to provide adequate patient monitoring, including regular complete physical examination, measurement of blood pressure, and monitoring of serum creatinine concentrations. Monitoring of transplant patients receiving the drug should be carried out only in institutions that have trained medical personnel and adequate laboratory and other resources.

Lymphomas and other malignancies

It should be borne in mind that when using cyclosporine, as well as other immunosuppressants, the risk of developing lymphomas and other malignant neoplasms, most often of the skin, increases. The increased risk of developing this complication is related more to the degree and duration of immunosuppression than to the use of a specific drug. Therefore, caution should be exercised when using combination immunosuppressive regimens, keeping in mind the potential for the development of lymphoproliferative diseases and solid organ tumors, sometimes leading to death.

Given the potential risk of developing skin malignancies, patients receiving treatment with cyclosporine should avoid excessive exposure to direct sunlight, exposure to ultraviolet UV-B radiation, and PUVA therapy (photochemotherapy).

Infections

The use of cyclosporine, like other immunosuppressants, predisposes to the development of various bacterial, fungal, parasitic and viral infections, often involving opportunistic pathogens. Activation of latent polyomavirus infections, which can lead to polyomavirus nephropathy (PVAN), especially BK virus-associated nephropathy (BKVN) or JC virus-associated progressive multifocal leukoencephalopathy (PML), has been observed in patients receiving cyclosporine.

These conditions are often associated with a high overall immunosuppressive burden and should be considered in the differential diagnosis of immunocompromised patients with worsening renal function or neurological symptoms.

Serious and/or fatal effects have been reported.

An effective system of preventive and therapeutic measures should be used, especially in cases of long-term use of combined immunosuppressive treatment.

Renal toxicity

During the first few weeks of Equoral therapy, a common and potentially dangerous complication may occur - an increase in serum creatinine and urea levels. These functional changes are reversible and dose-dependent, normalizing with dose reduction. With long-term treatment, some patients may develop structural changes in the kidneys (for example, interstitial fibrosis), which in patients with renal transplants should be differentiated from changes due to chronic rejection.

Hepatotoxicity

Cyclosporine may also cause dose-dependent, reversible increases in serum bilirubin and liver enzymes. There have been spontaneous reports of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis and liver failure in patients receiving cyclosporine. Most reports included patients with significant comorbidities, underlying conditions, and other influencing factors, including infectious complications and concomitant use of drugs with hepatotoxic potential. In some cases, mainly in transplant patients, deaths have been reported. Careful monitoring of liver function indicators is necessary; if they deviate from the norm, it may be necessary to reduce the dose.

Elderly patients

In elderly patients, renal function should be especially carefully monitored.

Monitoring the concentration of cyclosporine in the blood

To monitor cyclosporine blood concentrations, it is preferable to use specific monoclonal antibodies (measurement of the amount of unchanged drug). An HPLC method can be used, which also measures the concentration of unchanged substance. If plasma or serum is used, standard separation procedures (time and temperature) should be followed. For the initial determination of cyclosporine concentrations in patients with liver transplants, specific monoclonal antibodies should be used. It is also possible to conduct parallel determinations using specific and nonspecific monoclonal antibodies to achieve a dose that provides adequate immunosuppression.

When using Equoral in patients for non-transplant indications, it is recommended to randomly monitor cyclosporine blood levels, for example, when Equoral is co-administered with substances that may affect the pharmacokinetics of cyclosporine, or in the case of an unusual clinical response (eg, lack of efficacy or increased drug intolerance such as renal dysfunction).

Hypertension

When treated with Equoral, regular blood pressure monitoring is required. If blood pressure increases, appropriate antihypertensive therapy should be prescribed. Preference should be given to an antihypertensive drug that does not affect the pharmacokinetics of cyclosporine.

Increased blood lipids

Since there are rare reports of a reversible slight increase in blood lipids during cyclosporine therapy, it is recommended to determine the concentration of lipids in the blood before starting treatment and 1 month after starting it. If elevated lipid concentrations are detected, a fat-restricted diet should be recommended and, if necessary, the dose of the drug should be reduced.

Hyperkalemia

Cyclosporine increases the risk of hyperkalemia, especially in patients with impaired renal function. Caution should also be exercised when cyclosporine is used concomitantly with potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists and potassium-containing drugs, as well as when using a potassium-enriched diet. In these cases, monitoring the concentration of potassium in the blood is recommended.

Hypomagnesemia

Cyclosporine increases the excretion of magnesium from the body, which can lead to clinically significant hypomagnesemia, especially in the peritransplant period. In this regard, it is recommended to monitor the concentration of magnesium in the blood during the peritransplantation period, especially when neurological symptoms appear. If necessary, magnesium supplements are prescribed.

It is recommended to monitor serum uric acid concentrations, especially in patients with pre-existing hyperuricemia.

Hyperuricemia

Caution is required when treating patients with hyperuricemia.

Use of live vaccines

Vaccinations may be less effective during treatment with cyclosporine; The use of live attenuated vaccines should be avoided.

Interaction with other drugs

Caution should be exercised when co-administering cyclosporine with drugs that may significantly increase or decrease the plasma concentration of cyclosporine by inhibiting or inducing CYP3A4 and/or the membrane transporter P-glycoprotein.

Renal toxicity should be monitored when cyclosporine is used concomitantly with substances that increase cyclosporine levels or with substances that exhibit nephrotoxic synergism.

Since cyclosporine is an inhibitor of cytochrome CYP3A4, a membrane transporter of P-glycoprotein molecules and organic anion transporters (OATP), when used simultaneously with Equoral, it is possible to increase the concentration of drugs that are substrates of cytochrome CYP3A4 and/or these transporters. Caution should be exercised when cyclosporine is used concomitantly with such drugs, or concomitant use should be discontinued. Cyclosporine enhances the effect of HMG-CoA reductase inhibitors (statins). When used simultaneously with cyclosporine, the dose of statins should be reduced. Co-administration of certain statins should be avoided according to their label recommendations. Statins should be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or in patients with risk factors predisposing to severe renal impairment, including renal failure secondary to rhabdomyolysis.

Following concomitant use of cyclosporine and lercanidipine, the AUC of lercanidipine increased threefold and the AUC of cyclosporine was increased by 21%. Therefore, concomitant use of cyclosporine and lercanidipine should be avoided. Taking cyclosporine 3 hours after taking lercanidipine did not lead to a change in the AUC of lercanidipine, while the AUC of cyclosporine increased by 27%. Concomitant use of these drugs should be done with caution and at least 3 hours apart.

Patients with fructose intolerance should inform their doctor about this, because the drug contains a sorbitol solution (up to 28.7 mg/capsule).

Additional guidance for non-transplant indications

Patients with impaired renal function (excluding nephrotic syndrome with acceptable degrees of renal insufficiency), uncontrolled hypertension, uncontrolled infectious diseases or any malignancy should not take cyclosporine.

Before initiating therapy, a reliable baseline assessment of renal function should be established with at least two measurements of GFR. Renal function should be assessed frequently while taking the drug in order to adjust the dose.

Additional instructions for use in endogenous uveitis

Equoral should be used with caution in patients with neurological Behçet's syndrome.

The neurological status of these patients should be carefully monitored.

Experience with the use of Equoral in children with endogenous uveitis is limited.

Additional instructions for use in nephrotic syndrome

Due to changes in renal function caused by nephrotic syndrome, it may be difficult to detect renal dysfunction caused by Equoral in some patients. This explains the fact that in some cases, structural changes in the kidneys associated with Equoral were observed without an increase in serum creatinine concentration. Kidney biopsy is indicated for patients with steroid-dependent minimal change nephropathy who have received maintenance therapy with cyclosporine for more than 1 year.

In rare cases, the appearance of malignant neoplasms (including Hodgkin's lymphoma) has been observed in patients with nephrotic syndrome treated with immunosuppressants (including cyclosporine).

Additional instructions for use in rheumatoid arthritis

After 6 months of therapy, serum creatinine concentrations should be determined every 4-8 weeks depending on the stability of the underlying disease, concurrent therapy and concomitant diseases. More frequent monitoring is necessary when increasing the dose of Equoral, when adding concomitant NSAID therapy or increasing their dose.

It may be necessary to discontinue Equoral if hypertension that develops during treatment cannot be controlled with appropriate treatment.

As with other long-term immunosuppressive treatments (including cyclosporine therapy), the increased risk of lymphoproliferative disorders should be kept in mind. Particular caution should be exercised when using Equoral in combination with methotrexate.

Additional instructions for use in psoriasis

Prescription to elderly patients is possible only in cases of disabling psoriasis, and careful monitoring of renal function is necessary.

Malignancies, especially of the skin, have been reported in patients with psoriasis treated with cyclosporine, as with other conventional immunosuppressive treatments. If there are skin lesions that are not typical for psoriasis, and if they are suspected of being malignant or a precancerous condition, a biopsy should be performed before starting treatment with Equoral. Treatment with Equoral of patients with malignant or precancerous skin lesions is possible only after appropriate treatment of these lesions and in the absence of alternative effective therapy.

Experience with Equoral in children with psoriasis is limited.

It is recommended to discontinue the drug if hypertension that develops during treatment cannot be controlled with appropriate treatment.

Patients taking cyclosporine should not receive concomitant UVB radiation or PUVA chemotherapy.

Additional instructions for use in atopic dermatitis

It is recommended to discontinue the drug if hypertension that develops during treatment cannot be controlled with appropriate treatment.

Prescribing Equoral to elderly patients is possible only in cases of a disabling course of the disease, and careful monitoring of renal function is necessary.

Cases of active herpes simplex should be cured before starting treatment with Equoral, but the appearance of herpes simplex is not a reason to discontinue the drug if treatment has already been started, except in severe cases.

Skin infectious diseases caused by Staphylococcus aureus are not an absolute contraindication to Equoral therapy, but must be controlled by the use of appropriate antibacterial drugs. Oral erythromycin should be avoided. If no alternative treatment is available, close monitoring of cyclosporine blood concentrations, renal function, and cyclosporine side effects is recommended. Experience with the use of cyclosporine in children with atonic dermatitis is limited.

Patients taking cyclosporine should not receive concomitant UVB radiation or PUVA chemotherapy.

Additional instructions for use in children for non-transplant indications

With the exception of nephrotic syndrome, there is no adequate experience with the use of Equoral. The use of cyclosporine in children under 16 years of age is not recommended for indications not related to transplantation, excluding nephrotic syndrome.

Impact on the ability to drive a car and operate machinery

There are no data on the effect of cyclosporine on the ability to drive a car and operate machinery.

On the issue of the safety of prescribing Ecoral in patients after cadaveric kidney allotransplantation

The article presents the results of a clinical study of the comparative bioequivalence of original (Neoral) and generic (Ekoral) drugs in patients with a transplanted kidney. It was found that the drug Ecoral can be considered bioequivalent to the original cyclosporine, since it meets the required safety parameters for generic drugs with a narrow therapeutic range.

Rice. 1. Average pharmacokinetic profiles of the drugs Neoral and Ecoral

Rice. 2. Diagram of average values and 90% confidence intervals of AUCtr for Neoral and Ecoral

Rice. 3. Diagram of mean Cmax values and 90% confidence intervals for Neoral and Ecoral

Rice. 4. Pharmacokinetic curves for patients in whom Cmax was reached 1.5 hours after taking the drugs

Table 1. Values of the main pharmacokinetic parameters of the drugs Neoral and Ecoral

Table 2. Dynamics of cyclosporine concentration in the study of Neoral and Ecoral, indicating the significance coefficient of the differences

Table 3. Average concentrations of cyclosporine in the group of patients in whom Cmax was reached one and a half hours after taking the drugs

Introduction

The biological effects of cyclosporine and its selective effect on T cells and its inhibitory effect on the production of interleukin-2 were discovered by JF Borel et al. in the 1970s [1]. In 1982, cyclosporine was introduced into the immunosuppression protocol for human organ transplantation. Since 1995, the original form of cyclosporine, oil-based Sandimmune, has been largely replaced by the microemulsion Neoral, due to its higher bioavailability compared to Sandimmune [2]. After the expiration of the patent term (20 years) of the original drug, any pharmaceutical company has the right to reproduce a generic cyclosporine. Thus, at the beginning of 2006, more than six analogues of cyclosporine from domestic and foreign manufacturers were registered in the Russian Federation. At that time, pharmacokinetic studies of two generic analogues of cyclosporine were carried out in our clinic [3].

The main requirement for a generic drug is confirmation of its bioequivalence (“pharmacokinetic equivalence”), that is, the drug must have comparable bioavailability when studied under similar experimental conditions [4, 5]. The importance of a serious and comprehensive approach to studying the equivalence of generic cyclosporine is evidenced by the fact that the generic cyclosporine Sang Cya (SangStat Medical Corporation of Fremont, USA) in the form of an oral solution, which passed all tests and was registered in the USA in 1997, was later withdrawn from the market due to lack of bioequivalence, as additional studies showed that its absorption was sharply reduced when taken concomitantly with apple juice [6].

The main feature of the clinical use of cyclosporine is that it belongs to the group of “critical dose drugs”, which implies a narrow therapeutic range of the drug, when the therapeutic concentration is close to toxic [5]. In other words, underdosing entails an insufficient immunosuppressive effect and, as a consequence, transplant rejection [3, 7], and conversely, even a small increase in drug concentration is dangerous due to the possibility of nephrotoxicity or other undesirable reactions [8, 9]. That is why, for generic drugs with a narrow therapeutic range, the limits of compliance with the original drug are narrowed from 80–125% to 90–111% [5]. Thus, the mean values and their 90% confidence interval (CI) for the generic drug under study must correspond precisely to these limits of the corresponding values for the original drug. Only in this case can the test cyclosporine preparation be considered bioequivalent to the original one.

There is another feature of cyclosporine - inter- and intra-individual variability of pharmacokinetic parameters, that is, differences in bioavailability are possible not only in different patients, but even in each individual patient [10, 11].

We conducted a study to assess the bioequivalence of the generic drug to the original drug in patients with a transplanted kidney, which would allow us to further judge the safety of transferring patients from Neoral (Novartis Pharma) to Ecoral (Ivex). To accomplish this task, we carried out monitoring based on determining the level of the drug in the blood for 12 hours after taking it. We compared the area under the concentration-time pharmacokinetic curve (AreaUnderCurve, AUC), which reflects the total amount of drug entering the body, in the same patients when taking Neoral and Ecoral. In addition, the highest cyclosporine concentrations (Cmax) at time Tmax were assessed.

Materials and methods

Pharmacokinetic studies were conducted in 42 patients (aged 23 to 67 years, mean age 51 ± 9 years) with allogeneic cadaveric kidney transplant (ALT). All patients are observed at the Moscow City Nephrology Center. The duration of transplantation at the time of examination ranged from 1 to 15 years (the average period after ATTP was 76 ± 50 months). The vast majority of patients had consistently satisfactory graft function. Only 4 (9.5%) recipients had graft dysfunction, but their creatinine levels were in the range of 150–190 μmol/L. All patients initially took Neoral. After a pharmacokinetic study, a conversion was made to Ecoral while maintaining the same dose of cyclosporine. After 14 days of taking Ecoral, a full pharmacokinetic study was repeated, with determination of concentration on an empty stomach, then after 1; 1.5; 2; 3; 4; 6; 8, 10 and 12 hours after taking cyclosporine per os. Along with this, azotemic blood parameters, levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol were re-determined and a general blood test was performed. Three patients stopped the study early due to the development of an adverse event, which was reported to the Federal State Institution “Scientific Center for Expertise of Medical Products” of Roszdravnadzor. There were no cases of exacerbation of gastrointestinal diseases or diarrhea that could alter the pharmacokinetics of cyclosporine.

The concentration of cyclosporine was determined by enzyme immunoassay (DimensionRXL, Siemens). For laboratory examination, an automatic biochemical analyzer Hitachi-902 (Roche) was also used, and the parameters of a general blood test were determined using an ABX Pentra XL 80 device (Horiba medical). The area under the pharmacokinetic curve (AUC) was calculated using the trapezoidal rule (AUCtr) and the Gaspari formula [12]:

AUC (Co + Q + С₃) = 5.189 × С₀ + + 1.267'Q + 4.15 × С₃ + 135.1.

Statistical processing of the material was performed using SPSS 11.5 for Windows. To test the hypothesis of normal distribution, the Kolmogorov–Smirnov test was used. Since this test established that the data obtained were subject to a normal distribution, we used a t-test for dependent samples to compare the corresponding indicators. The descriptive statistics method included the calculation of means with standard deviations. The results were considered statistically significant at p values

Research results

We initially compared the area under the pharmacokinetic curve for the two study drugs (Fig. 1). It was found that AUC values, both calculated using the trapezoidal rule and the Gaspari formula, do not have a statistically significant difference (Table 1). Thus, the area under the pharmacokinetic curve for Ecoral is 4204 ± 908 and is almost equal to the AUC of Neoral 4265 ± 902 at p = 0.6 (Fig. 1). The absorption profiles of Ecoral and Neoral (the area under the concentration-time curve during the first four hours) after taking the drugs also did not differ significantly and were equal to 2556 ± 596 when taking Neoral and 2457 ± 565 when taking Ecoral. This difference turned out to be insignificant, despite the fact that Neoral is a microemulsion and Ecoral is a microdispersion and they have different particle sizes of the drug substance.

To assess bioequivalence, in addition to analyzing graphs of pharmacokinetic curves of cyclosporine preparations, we needed to compare 90% confidence intervals of the found mean AUC values. For Neoral the 90% CI was in the range of 4021–4508, and for Ecoral the range was 3958–4450. The diagram (Fig. 2) shows that the 90% confidence interval for the average AUC value of the drug Ecoral is within the bioequivalence limits of Neoral (the appropriate level is from 3838 to 4734), that is, it corresponds to the permissible limit of 90–111% for drugs with a narrow therapeutic window.

The next step in assessing the bioequivalence of Ecoral to Neoral is the analysis of average Cmax values during the time period Tmax. In both cases, the concentration of cyclosporine was maximum one and a half hours after administration, while the concentration of cyclosporine after taking Neoral was slightly higher than the same indicator when taking Ecoral. However, these differences (concentration values of 1036 ± 309 ng/ml when taking Neoral and 931 ± 322 ng/ml when taking Ecoral) did not reach significant significance (p = 0.06). That is why it was very important to evaluate the peak concentrations (Cmax) of both drugs.

When assessing the mean Cmax values and their 90% confidence intervals, we obtained the following values: Cmax for Neoral was 1135 ± 254 ng/ml (90% CI 1066–1203), and for Ecoral – 1110 ± 278 ng/ml (90% CI 1035–1185).

Proof of bioequivalence is possible if the 90% confidence interval for Ecoral's Cmax is within the range of 1021–1260 ng/ml. Figure 3 shows that the 90% confidence interval for the mean Cmax of Ecoral is within the specified bioequivalence limits.

To compare drug absorption, we identified a group of patients (n = 18) from the total number of those examined with Cmax at point T1.5 when taking Neoral and compared their pharmacokinetic curves after taking Ecoral (Fig. 4). The choice of this particular point of the pharmacokinetic curve was not accidental: the maximum difference in cyclosporine concentrations was observed exactly one and a half hours after taking Neoral and Ecoral (Table 2). In almost half of the patients (44%), the time of maximum absorption of the drug shifted, which is explained by the intra-individual variability of cyclosporine.

By the fourth hour after taking Neoral, the concentration of cyclosporine in the blood of this group of patients decreased by 73% and amounted to 322 ± 107 ng/ml, and after taking Ecoral the concentration changed by 58% and amounted to 412 ± 234 ng/ml. No statistically significant differences were obtained using the t-test (p = 0.08). But statistically significant differences in the concentration values are shown at point C3, when the concentrations were 473 ± 152 ng/ml when taking Neoral and 568 ± 204 ng/ml when taking Ecoral (p = 0.014). By the 6th hour, the concentrations were equal and did not differ significantly until the 12th hour point (Fig. 3). AUC when taking Neoral was 4133 ± 776, and when taking Ecoral – 4289 ± 1019 (p = 0.46).

When evaluating generics, the absorption coefficient (ratio Cmax/AUCtr), which characterizes the rate of absorption of the drug, is also analyzed. When taking Neoral it was 0.27 ± 0.05, and when taking Ecoral it was 0.26 ± 0.04. The t-test carried out to compare these indicators did not establish a significant difference in the coefficients (p = 0.6).

In all patients, the indicators of general and biochemical blood tests at the end of the study, as well as at the beginning of the study, remained within normal limits. The average level of creatinine was 114 ± 26 µmol/l, urea – 10.8 ± 3.5 mmol/l, ALT – 24 ± 15 U, AST – 22 ± 9 U, total cholesterol – 5 ± 1.1 mmol/l, hemoglobin – 128 ± 16.7 g/l, leukocyte level – 7.5 ± 2.3 × 109/l.

Discussion of the results obtained

A fundamental issue when assessing the bioequivalence of drugs is to determine the area under the pharmacokinetic curve, which reflects the total amount of the substance entering the body and its maximum serum concentration Cmax. Our obtained average values and 90% confidence intervals of AUCtr and Cmax of the tested drug Ecoral confirm its bioequivalence to Neoral. At the same time, Ecoral meets the required safety parameters for generic drugs with a narrow therapeutic range. The Tmax indicator in both cases was at the one and a half hour point.

At the same time, we received data that indicate some difference in the absorption of the drug, although their absorption coefficients did not differ. The results of the analysis in the group of patients with a peak concentration at the one and a half hour point still indicate a different absorption profile.

After the Sandimmune Neoral microemulsion was created, the particle size of the active substance in the drug began to be considered as the most important factor affecting the bioavailability of cyclosporine [11]. To assess the effect of particle size on bioavailability, a comparison was made of the average area under the concentration-time curve for drugs that differ only in particle size [13]. It turned out that the bioavailability of dosage forms with maximum and minimum particle sizes did not have statistically significant differences. According to researchers, the reason for the high bioavailability of some dosage forms that form large particles in solution is the adhesive properties of such particles, which are capable of providing a large effective contact surface on the epithelial layer. It is likely that dispersed Ecoral particles are able to remain in contact with the wall of the gastrointestinal tract longer due to their bioadhesiveness.

Conclusion

According to our results, the drug Ecoral can be considered bioequivalent to Neoral, since it provides similar bioavailability to cyclosporine. Conversion to Ecoral in the kidney transplanted patients we examined was carried out with great caution. The importance of monitoring cyclosporine concentrations after transferring a patient to a generic drug should be emphasized. The transplantologist should inform the patient about the need to monitor the concentration of cyclosporine, blood creatinine and blood pressure levels after such a transition. The patient must be aware that it is prohibited to mix different dosage forms.

To date, there are insufficient studies examining the results of treatment with generic drugs in certain groups of patients. Thus, when switching from Neoral to generic Gengraf, a clinically significant change in the pharmacokinetics of sirolimus was identified in patients taking a combination of Gengraf and sirolimus. When taking this generic cyclosporine, the area under the pharmacokinetic curve of sirolimus was significantly lower than when taking Neoral [14]. This example demonstrates the importance of the moment of switching from the original drug to generic analogues and the need for close monitoring of the patient in each individual case.

The increase in the number of patients after allogeneic kidney transplantation, associated with improved graft survival rates, leads to increased healthcare costs, so the emergence of an increasing number of generic immunosuppressive drugs is quite predictable. Undoubtedly, the most important issue in their selection and evaluation should remain safety criteria for patients.

IV drip: for adults with a bone marrow transplant on the day before the transplant - 2-6 mg/kg/day. This dose is continued during the immediate post-transplant period for 2 weeks, then switched to oral maintenance therapy. In cases where absorption is impaired, intravenous administration may be required. For solid organ transplantation, 4-12 hours before surgery - once, 3-5 mg/kg. For 1-2 weeks after surgery - daily at the same dose, after which the dose is gradually reduced, under the control of the drug concentration in the blood, until a maintenance dose of 0.7-2 mg/kg/day is reached.

When prescribed in combination with GCS or other immunosuppressants, smaller doses are used (for example, 1 mg/kg/day IV, in the initial phase of treatment).

Children over 1 year of age are prescribed in the same doses as adults (per 1 kg).

Rules for the preparation and administration of the infusion solution: the concentrate should be diluted with a 0.9% NaCl solution or a 5% dextrose solution in a ratio of 1/20-100 and administered over approximately 2-6 hours. The unused ready-made solution should be discarded after 48 hours.

Orally: for adults undergoing solid organ transplantation, treatment should begin 12 hours before surgery at a dose of 10-15 mg/kg, divided into 2 doses. For 1-2 weeks after surgery - daily, at the same dose, after which the dose is gradually reduced (5%/week) until the maintenance level is reached - 2-6 mg/kg/day.

When prescribed in combination with GCS or other immunosuppressants, smaller doses are used (3-6 mg/kg/day in the initial phase of treatment).

In case of bone marrow transplantation - on the day preceding the transplantation, and during the transplantation period, for 2 weeks, at a daily dose of 12.5-15 mg/kg, then switch to maintenance therapy at a dose of about 12.5 mg/kg/day (if absorption is impaired, they may require higher oral doses or switch to IV administration). Maintenance treatment is continued for at least 3-6 months (preferably 6 months), after which the dose is gradually reduced so that treatment is stopped 1 year after transplantation.

Some patients develop a rejection reaction after stopping treatment, in which case treatment should be resumed.

For endogenous uveitis, to induce remission - in an initial daily dose of 5 mg/kg, in 1 or several doses, until inflammation subsides and visual acuity improves. In severe cases, the dose can be increased to 7 mg/kg/day for a limited period. During maintenance therapy, the dose should be slowly reduced until the lowest effective dose is reached, which during the period of remission of the disease should not exceed 5 mg/kg/day.

For nephrotic syndrome, to induce remission - in a daily dose of 5 mg/kg for adults and 6 mg/kg for children (in 2 doses), provided that there is no decrease in renal function (except in cases of proteinuria). For patients with impaired renal function, the initial daily dose should not exceed 2.5 mg/kg.

If monotherapy with the drug fails to achieve the desired effect, it can be combined with small doses of corticosteroids, taken orally. If after 3 months of treatment no positive effect is observed, therapy should be discontinued. For maintenance treatment, the dose should be slowly reduced to the minimum effective dose.

For rheumatoid arthritis, during the first 6 weeks of treatment, the daily dose is 3 mg/kg in 2 doses. In case of insufficient effect, the daily dose can be gradually increased subject to satisfactory tolerability (not higher than 5 mg/kg/day). The course of treatment is up to 12 weeks. For maintenance therapy, the dose should be selected individually depending on tolerability (can be prescribed in combination with small doses of GCS and/or NSAIDs).

For psoriasis, to induce remission, the daily dose is 2.5 mg/kg in 2 divided doses. In severe cases of the disease, when rapid achievement of an effect is required, the initial daily dose may be 5 mg/kg. If it is not possible to achieve an adequate effect when used at a daily dose of 5 mg/kg for 6 weeks, the drug should be discontinued. The dose for maintenance treatment of psoriasis should be minimally effective (should not exceed 5 mg/kg/day).

For atopic dermatitis - the initial dose is 2.5 mg/kg/day. In severe cases, the dose may be increased to 5 mg/kg/day. If a positive result is achieved, the dose should be gradually reduced until completely discontinued.