What Is Sirolimus?

Sirolimus yellow solid, molecular formula is C51H79NO13, molecular weight is 914.17200, density is 1.182 g / cm3, melting point is 183-185 ° C, boiling point is 973.017ºC at 760 mmHg, flash point is 542.261ºC, refractive index is 1.55.

Chinese name: Sirolimus
Foreign name: sirolimus

CAS number: 53123-88-9
Molecular formula: C51H79NO13
Molecular weight: 914.17200

Introduction to sirolimus compounds

Overview of sirolimus

Sirolimus is a new macrolide immunosuppressant. It is a white solid crystal with a melting point of 183-185 ° C. It is lipophilic and is soluble in organic solvents such as methanol, ethanol, acetone, and chloroform. It is slightly soluble in water. Almost insoluble in ether. It was developed as early as the 1970s, and was initially used as a low-toxicity antifungal drug.It was found to have immunosuppressive effects in 1977.In 1989, RAPA was tried as a new drug for the rejection of organ transplantation. Looking at the effect of clinical application, it is a new immunosuppressant with good curative effect, low toxicity and no renal toxicity. It is often used as a drug to maintain the immunity of transplanted organs (especially kidney transplants) to slow down the immune rejection after transplantation. However, scientists have recently found another use: it can be used to treat Alzheimer's disease (senile dementia). ). What interest them is that the main component of rapamycin is also present in the bacterial product in the isolated soil of the resurrection island. The latest experiments show that the substance can restore the ability of recognizing defects in experimental rats. ^[1]

Sirolimus Basic Information

Chinese name: Sirolimus

Chinese alias: rapamycin

English name: sirolimus

English alias: RPM; RAPA; Rapamycin (Sirolimus); RAPAMUNE; Rapamycin / Sirolimus;

CAS number: 53123-88-9

MDL number: MFCD00867594

RTECS number: VE6250000

PubChem number: 24899339

Molecular formula: C ₅₁ H ₇₉ NO ₁₃

Molecular weight: 914.17200

Exact mass: 913.55500

PSA: 195.43000

LogP: 6.11850

Sirolimus physical and chemical properties

Appearance and properties: yellow solid

Density: 1.182 g / cm ³

Melting point: 183-185 ° C

Boiling point: 973.017ºC at 760 mmHg

Flash point: 542.261ºC

Refractive index: 1.55

Stability: Stable if stored as directed.

Storage conditions: -20ºC ^[2]

Sirolimus computational chemistry data

1. Reference value for calculation of hydrophobic parameters (XlogP): 6

2. Number of hydrogen-bonded donors: 3

3. Number of hydrogen bond acceptors: 13

4. Number of rotatable chemical bonds: 6

5. Number of tautomers: 15

6. Topological molecular polar surface area (TPSA): 195

7. Number of heavy atoms: 65

8. Surface charge: 0

9. Complexity: 1760

10. Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 15

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 4

14. Number of stereochemical center of chemical bond: 0

15. Number of covalent bond units: 1 ^[3]

Sirolimus uses

A new and highly effective immunosuppressant, used clinically for anti-rejection and autoimmune diseases in organ transplantation. ^[2]

Sirolimus related drug label information

History of sirolimus

Sirolimus (also known as "rapamycin") is a secondary metabolite secreted by soil streptomyces from the soil of Easter Island, Chile, which was first discovered by scientists in 1975. Its chemical structure belongs to "triene" "Macrolide" compounds. Due to factors such as low rapamycin fermentation yield and complicated extraction process, this product was developed and marketed by the American Household Chemicals Company until 1999, and subsequently marketed in more than a dozen countries in Europe and the United States.

At that time, the US Food and Drug Administration (FDA) approved the indication for rapamycin not as an antibiotic but as an "immunosuppressive agent." This is because rapamycin has shown a strong immunosuppressive effect in clinical trials, and it can replace cyclosporine with a clinical history of more than 30 years. And compared with cyclosporine, rapamycin oral solution has a smaller dose (only 2 to 3 mg each time), stronger anti-rejection effect, and fewer side effects. Therefore, since rapamycin has been marketed, It quickly became a common oral immunosuppressant for organ transplanters around the world.

Sirolimus classification name

Chemicals & Biological Products >> Drugs Affecting Immune Function >> Immunosuppressants >> Other Immunosuppressants

English name of sirolimus

Sirolimus

Sirolimus drug alias

Rapamycin, Rapamycin, RAPAMUNE, RAPMIC

Sirolimus dosage form

Properties: white crystalline solid, hardly soluble in water, soluble in organic solvents such as methanol, ether, acetone and chloroform.
Preparation: Oral liquid: 1mg / ml. Tablets: 1mg per tablet. ^[4]

Sirolimus pharmacology and toxicology:

Mechanism of sirolimus

Sirolimus inhibits the activation and proliferation of T lymphocytes stimulated by antigens and cytokines (interleukin [IL] -2, IL-4, and IL-15). This mechanism of action is distinct from other immunosuppressive agents. Sirolimus also inhibits the production of antibodies. In cells, sirolimus binds to immunophilin, FK-binding protein-12 (FKBP-12), to form an immunosuppressive complex. This sirolimus FKBP-12 complex has no effect on calcineurin activity. This complex binds to mammalian sirolimus target molecules (mTOR, a key regulatory kinase) and inhibits its activity. This inhibition inhibits the proliferation of cytokine-driven T cells, that is, the development of the G1 phase to the S phase in the cell cycle.

Experimental model studies have shown that sirolimus can extend Survival period. Sirolimus can reverse the acute rejection of heart and kidney allografts in rats and prolong the survival time of transplanted organs in presensitized rats. In some studies, the immunosuppressive effects of sirolimus can persist up to 6 months after discontinuation of treatment. This immune tolerance effect is alloantigen-specific.

In rodent autoimmune disease models, sirolimus inhibits immune-mediated responses related to the following diseases: systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, Experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune retinal retinitis. ^[5]

Sirolimus pharmacodynamics

In patients with low to moderate immune risk 6 months after kidney transplantation, oral rapamycin® (dose 2 mg / day and 5 mg / day) significantly reduces organ rejection compared to azathioprine or placebo Risk (see [clinical trial]). A starting dose of 15 mg and a maintenance dose of 5 mg per day have no demonstrable therapeutic advantage compared to a starting dose of 6 mg and a maintenance dose of 2 mg per day. The blood concentration should be monitored to keep the sirolimus concentration within a target concentration range (see [Dosage and Administration]).

Sirolimus toxicology study

Carcinogenic, mutagenic and impaired fertility

Carcinogenicity tests were performed in mice and rats. In the 86-week female mouse test, sirolimus was administered 30-120 times the clinically used dose (2mg / day) (corrected for body surface area). Compared with the control group, malignant lymphoma was at various dose levels. There was a statistically significant increase. In another mouse test, sirolimus was administered at 3-16 times the clinically used dose (2mg / day) (corrected for body surface area). Compared to the control group, hepatocellular carcinoma was induced in all doses of male mice. And hepatocellular adenomas are thought to be related to sirolimus. In the 104-week rat test, the dose was equal to or lower than the clinically used dose of 2 mg / day (corrected for body surface area). No significant findings were found.

In vitro microbial reverse mutation test, Chinese hamster ovary cell chromosome aberration test, mouse lymphoma cell forward mutation test and in vivo mouse micronucleus test, sirolimus was not genotoxic.

In male and female rats, sirolimus was administered at 10 or 2 times the clinically used dose of 2 mg / day (corrected for body surface area), and fertility was slightly reduced. In male rats, testicular, epididymal, prostate, and seminiferous tubule atrophy and reduced sperm counts were observed. In female rats, ovarian and uterine reductions were observed, and in one experiment, the reduction in sperm count was reversible when the administration was stopped. In a 4-week monkey test, sirolimus was administered intravenously at a clinically equivalent dose (corrected for body surface area), and a tubular regression of the testes was found. ^[5]

Sirolimus pharmacokinetics:

Pharmacokinetics of sirolimus after oral administration was performed on healthy volunteers, children, patients with liver impairment and kidney transplantation.

In adult renal transplant patients with low to moderate immune risk, 2 mg of rapaming® is given daily in multiple doses in combination with cyclosporine and corticosteroids. The pharmacokinetic parameters are summarized in the table below:

Steady-state pharmacokinetic parameters (mean ± SD) of 2 mg sirolimus per day in renal transplant patients with low to moderate immune risk a, b

a: Take cyclosporine 4 hours before taking rapaming®.
b: Based on data from 1 and 3 months after transplantation.
c: Mean Cmax after 6 months.

LC / MS / MS method was used to determine the blood concentration of sirolimus in renal transplant patients, and it was found that the whole blood valley concentration of sirolimus had a significant correlation with AUC, ss. In repeated, twice-daily dosing and multi-dose trials with no initial loading, the mean sirolimus whole blood trough concentration increased approximately 2-3 times within 6 days of initial treatment (a steady state) . Most patients (when the load is 3 times the maintenance dose) reach almost steady-state drug concentration within one day of administration (see [Dosage and Administration] and [Cautions]).

Sirolimus absorption

After taking sirolimus oral solution, in healthy volunteers, sirolimus was quickly absorbed, and the average peak time after a single dose was about 1 hour; in kidney transplant recipients, the average time after multiple doses was The peak time is about 2 hours. The systemic availability of sirolimus was low after taking the sirolimus oral solution, approximately 14%. Compared to oral solutions, the average bioavailability of sirolimus can be increased by about 27% after taking tablets. Sirolimus tablets are not biologically equivalent to oral solutions; however, they have proven clinically equivalent at the 2 mg level (see [Clinical Trials] and [Dosage and Administration]). In stable renal transplant patients, after taking sirolimus oral solution at 3-12 mg / m, the concentration of sirolimus is proportional to the dose.

Food effects : To minimize differences in sirolimus plasma concentrations, rapaming® should be taken with or without food at all times (see [Dosage and Administration]). In healthy volunteers taking sirolimus, compared to fasting, high-fat meals (861.8 kcal, 54.9% of calories from fat) increased total sirolimus exposure (AUC) from 23% Increased to 35%. The effect of food on sirolimus Cmax varies depending on the sirolimus dosage form being evaluated.

Grapefruit juice slows the metabolism of rapamycin® mediated by CYP3A4 and potentially enhances the reverse transport of rapamycin® from small intestinal epithelium to the intestinal cavity by P-gp. Division.

Sirolimus distribution

In stable renal transplant recipients, the mean (± SD) of the sirolimus blood / plasma ratio after taking rapamine® oral solution was 36 ± 18, indicating that sirolimus is widely distributed into the tangible blood Ingredients. The mean value of the distributed volume (Vss / F) of sirolimus was 12 ± 8 L / kg. Sirolimus binds extensively to human plasma proteins (about 92%). In men, the binding of sirolimus is mainly related to serum albumin (97%), 1-acid glycoprotein, and lipoprotein.

Sirolimus metabolism

Sirolimus is a substrate for CYP3A4 and P-gp. Sirolimus can be extensively metabolized by CYP3A4 isoenzymes in the intestinal wall and liver, and can be reversely transported from small intestinal epithelial cells to the intestinal lumen by the P-gp drug outflow pump. Inhibitors of CYP3A4 and P-gp can increase the concentration of sirolimus. CYP3A4 and P-gp inducers reduce the concentration of sirolimus (see [Precautions] Warnings and [Drug Interactions]). Sirolimus is extensively metabolized by O-demethylation and / or hydroxylation. Seven major metabolites can be detected in whole blood, including hydroxylated, demethylated, and hydroxydemethylated metabolites. Some of them can also be detected in plasma, stool, and urine. In human whole blood, sirolimus is the main component, and its immunosuppressive activity reaches more than 90% of the total activity.

Sirolimus excretion

After taking a single dose of [14C] -labeled sirolimus oral solution in healthy volunteers, most of the radioactivity (91%) appeared in the feces, and only a small amount (2.2%) was excreted in the urine. In stable renal transplant patients, the mean ± standard deviation of the terminal elimination half-life (t1 / 2) after multiple dose administration is estimated to be 62 ± 16 hours.

The following table shows the sirolimus plasma concentrations (values measured by chromatography) observed in Phase III clinical trials ([Clinical Trials])

Pharmacokinetics of sirolimus in special populations

Hepatic impairment : A single dose of sirolimus was given to volunteers with normal liver function and patients with liver impairment of type A (mild), type B (moderate), and type C (severe) according to Child-Pugh classification. Compared with the data of the normal liver function group, the AUC values of sirolimus in the mild, moderate, and severe hepatic impairment group were 43%, 94%, and 189% higher, respectively, and the mean Cmax values were not statistically significant. As the severity of liver damage increased, the average half-life of sirolimus also increased steadily, while the average unit weight clearance of sirolimus decreased.

The maintenance dose of rapamide® in patients with mild to moderate liver damage should be reduced by about 1/3, and in patients with severe liver damage should be reduced by about 1/2 (see [Dosage and Administration]). In patients with mild, moderate, and severe hepatic impairment, there is no need to adjust the loading dose of rapaming®. All patients with liver dysfunction need to monitor blood concentration (see [Dosage and Administration]).

Renal impairment : The effect of renal impairment on the pharmacokinetics of sirolimus is unknown. However, in subjects with normal renal function, this product or its metabolites are excreted from the kidneys very rarely (2.2%). Patients with impaired renal function also do not need to adjust the load and maintenance of rapaming® (see [Dosage and Administration]).

Pediatric : The pharmacokinetic data of sirolimus is derived from concentration-dose trials in children with kidney transplants who received both cyclosporine and corticosteroids. Among them, 21 patients took tablets and 1 patient took oral solution. The target ranges of whole blood trough concentration were 10-20 ng / mL and 5-15 ng / mL. The mean ± standard deviation of the dose for children aged 6-11 (8 persons) was 1.75 ± 0.71 mg / day (0.064 ± 0.018 mg / kg, 1.65 ± 0.43 mg / m2), and for children aged 12-18 ( 14 people) The mean ± SD of the dose was 2.79 ± 1.25 mg / day (0.053 ± 0.015 mg / kg, 1.86 ± 0.61 mg / m2). When taking a blood sample for sirolimus pharmacokinetic evaluation, most (80%) children were taking sirolimus 16 hours after taking cyclosporine once a day.

Pharmacokinetic parameters (mean ± SD) of sirolimus (multidose, concentration monitoring) in children with renal transplantation a, b

a: Sirolimus is taken in combination with a cyclosporine oral solution (improved) (such as Xinshan Diming Oral Solution) and / or capsules (improved) (such as Xinshan Diming Soft Capsule).
b: Detection by liquid chromatography / tandem mass spectrometry (LC / MS / MS).
c: Oral dose clearance is corrected by body weight (kg) or body surface area (m2).

Pharmacokinetic parameters (mean ± SD) of sirolimus (single dose 1, 3, 9, 15 mg / m2) in children with stable chronic renal failure maintained by hemodialysis or peritoneal dialysis *

* All subjects took an oral solution of sirolimus

Elderly patients : In clinical trials of sirolimus, there is insufficient data to demonstrate whether patients older than 65 years respond differently than younger patients. After taking rapamine® oral solution or tablets, the sirolimus valley concentration values for kidney transplant patients over 65 years of age are similar to those for adults aged 18-65 years.

Gender : Male sirolimus clearance is 12% lower than that of females; males have significantly longer half-lives than females, 72.3 hours and 61.3 hours, respectively. No dose adjustment is required by sex.

Race : When using sirolimus oral solution or tablets and cyclosporine oral solution (improved) (such as Johor Bahrain Diming oral solution) and / or cyclosporine capsule (improved) (such as Xin Shan Di Ming soft capsule) (See [Clinical Trials]) In phase III clinical trials, there was no significant difference in mean sirolimus valley concentrations between black patients (n = 190) and non-black patients (n = 852) within 6 months after transplantation. .

The whole blood trough concentration of sirolimus was evaluated in an open, non-randomized, multicenter, continuous clinical study conducted in adult Chinese patients who received an allogeneic kidney transplant for the first time. Patients received 3 After a month of sirolimus combined with CsA induction therapy, CsA reduction (stage I) or CsA withdrawal (stage II) was performed. The total course of treatment is up to 12 months. According to the protocol, the dose of sirolimus was adjusted in this study to keep the whole blood valley level at 6-12 ng / mL in the first 3 months, and the dose of CsA was adjusted to make the whole blood valley Levels were maintained at 125-250 ng / mL during the first 3 months. The dose of sirolimus was adjusted so that the whole blood trough concentration level was maintained at 6-12 ng / mL during Phase I of this study and thereafter, and maintained at 12 during the fourth to sixth months of Phase II of this study. -20 ng / mL, maintained at 10-20 ng / mL from 7 to 12 months. The dose of CsA was adjusted to maintain the whole blood trough level at 50-100 ng / mL at the end of the fourth month of Phase I of the study; during the second phase of the study, the CsA dose was reduced by about 25% per week, so that It was discontinued at the end of the 4th month. In Study Phase I, the average whole blood trough concentration of sirolimus observed when administered at an average daily dose of 2.1 mg reached a maximum (9.31 ng / mL) at 1 month, after which the average of sirolimus The blood valley level was maintained between 8.30 and 8.69 ng / mL. In Study Phase II, the mean sirolimus average trough concentration observed when administered at an average dose of 2.8 mg reached a maximum (10.72ng / mL) at 3 months, after which the mean sirolimus trough The level was maintained between 8.53-10.33ng / mL. Population pharmacokinetic analysis was performed on 804 sirolimus blood valley concentration data of 112 patients in this study. The mean values of apparent oral clearance and apparent volume of distribution (% CV) were estimated to be 10.1 L / h ( 23.8%) and 3670L (56.7%). The median values (range) of sirolimus daily dose, sirolimus blood valley concentration, and CsA blood valley concentration were 2.0 (0.5 to 6.0) mg, 8.25 (1.5 to 30.6) ng / mL, and 104 (0 to 508) ng / mL. In this study, the average daily doses of sirolimus, sirolimus blood trough concentration, and CsA blood trough concentration (± SD) were 2.64 ± 1.07 mg, 8.83 ± 3.69 ng / mL, and 126 ± 110 ng / mL.

After sirolimus 1mg tablets were administered to Chinese stable allogeneic kidney transplantation adult patients (n = 24) once a day with individualized therapeutic doses (1-4 mg / day), the results showed that they were used with food or combined medication When not used together, the steady-state pharmacokinetic characteristics of sirolimus are comparable. Steady-state CsA trough concentration levels observed in patients using CsA as a co-administered drug ranged from about 30 to 110 ng / mL. In this study, no significant differences in sirolimus PK were found in patients treated with and without CsA. The observed steady-state pharmacokinetic results of sirolimus in all study subjects are summarized in the table below.

Pharmacokinetic results of steady-state sirolimus after sirolimus administration in individualized daily oral doses in patients with stable allogeneic kidney transplantation ^[5]

Sirolimus indication

Sirolimus is suitable for patients 13 years of age or older who have received a kidney transplant to prevent organ rejection. Sirolimus is recommended in combination with cyclosporine and corticosteroids. Monitoring of blood concentrations of therapeutic drugs is recommended for all patients receiving sirolimus. ^[5]

Sirolimus dosage

Sirolimus is intended for use only by physicians experienced in immunosuppressive therapies and in treating patients with kidney transplants. Patients receiving this drug should be treated in institutions with appropriate laboratories and supporting medical facilities and personnel. The physician responsible for maintenance treatment should have complete information necessary for patient follow-up.

Frequent adjustment of sirolimus doses based on unstable sirolimus blood concentrations may lead to overdose or underdose because of the longer half-life of sirolimus. Once the maintenance dose of sirolimus has been adjusted, patients should continue to take it for at least 7 to 14 days under the new maintenance dose, and then further dose adjustment under blood concentration monitoring. In most patients, the dose adjustment can be calculated based on a simple ratio: new sirolimus dose = current dose × (target blood concentration / current blood concentration). When it is necessary to substantially increase the trough concentration of sirolimus, a loading dose can be considered based on the new maintenance dose: sirolimus loading dose = 3 × (new maintenance dose-current maintenance dose). The maximum dose of sirolimus should not exceed 40 mg / day. If the estimated daily dose of sirolimus exceeds 40 mg due to an additional loading dose, the loading dose may be given over two days. After taking a loading dose, the trough concentration of sirolimus should be monitored at least 3 to 4 days later.

2 mg sirolimus oral solution has been proven to be clinically equivalent to 2 mg sirolimus tablets, and therefore, they can be interchanged in equal amounts. However, the clinical equivalence of larger doses of sirolimus oral solution with larger doses of tablets is unknown (see [Pharmacokinetics]).

To minimize differences in sirolimus absorption, this medicine should be taken with or without food. Grapefruit juice can slow the metabolism of sirolimus mediated by CYP3A4 and potentially enhance the reverse transport of sirolimus from small intestinal epithelium to the intestinal lumen mediated by P-glycoprotein (P-gp), so it is not available In serving sirolimus.

Patients with sirolimus at low to moderate immune risk

Combination of sirolimus and cyclosporine: For new kidney transplant recipients, sirolimus is recommended in combination with cyclosporine and corticosteroids. The first time you should take the load of sirolimus, which is 3 times the maintenance amount. The recommended loading for kidney transplant patients is 6 mg, and the maintenance amount is 2 mg / day. In order to maintain the sirolimus blood concentration within the target range, the sirolimus blood concentration should be monitored. Although a 15 mg loading and a 5 mg maintenance daily dose are safe and effective in clinical trials, the benefit of a dose greater than 2 mg in renal transplant patients is unknown. The overall safety of patients taking sirolimus oral solution 2 mg daily was better than that of patients taking sirolimus oral solution 5 mg daily.

Blood concentration monitoring

When changing the dose of sirolimus, and during coadministration of strong CYP3A4 inducers or inhibitors, it is recommended for all patients, especially those who may experience changes in drug metabolism, who are 13 years or older but weigh less than 40 kg, and liver damage Monitoring of sirolimus valley concentration. (See [Drug Interactions])

Blood concentration monitoring should not be used as the sole basis for adjusting the sirolimus dose. Clinical signs / symptoms, tissue biopsy and laboratory parameters should be carefully observed

For patients who stop taking the oral solution and change to tablets on the principle of 1mg instead of 1mg, it is recommended to monitor the whole blood valley concentration for 1 or 2 weeks to ensure that the blood valley concentration is within the recommended target range.

When combined with cyclosporine, the sirolimus blood valley concentration should be maintained within a target concentration range (see [Clinical Trials] and [Pharmacokinetics]).

In a controlled clinical trial (Trials 1 and 2) in which cyclosporine was co-administered, the average whole blood trough concentration of sirolimus (expressed as a chromatographic value) during the 12 months after transplantation was approximately 2 mg / day in the treatment group. It was 7.2 ng / mL (3.6 to 11.2 ng / mL [10% -90% interval]), and the 5 mg / day treatment group was about 13.6 ng / mL (8.0 to 22.4 ng / mL [10% to 90% interval]). (All reported sirolimus concentrations are measured by chromatography or have been converted to chromatography.)

In a clinical pharmacological study in 24 adult patients with stable renal function after kidney transplantation in China, the stability of sirolimus was administered once daily with a sirolimus 1 mg tablet after a personalized treatment dose was administered. Pharmacokinetic characteristics were evaluated. As determined by chromatography, the average steady state blood trough concentration of sirolimus at a standard dose (2 mg / day) was approximately 7.1 ng / mL (range 4.2 to 9.6 ng / mL [10% to 90%]).

Sirolimus dose adjustment

Low weight patients

The starting dose for patients aged 13 years and over but not more than 40 kg should be adjusted to 1 mg / m 2 / day based on body surface area. The loading dose should be adjusted to 3 mg / m 2.

Patients with impaired liver function

It is recommended that the maintenance dose of sirolimus be reduced by approximately 1/3 to 1/2 in patients with liver impairment. The loading dose of sirolimus does not need to be adjusted. For patients with impaired liver function, it is recommended to monitor sirolimus for trough levels.
Patients with impaired renal function < br No need to adjust the loading dose of sirolimus. No dose adjustment is needed due to impaired renal function.

Sirolimus for children

The safety and efficacy of sirolimus in children under 13 years of age have not been determined.

Studies on the safety and effectiveness of sirolimus have been performed in children 13 years of age and older with low to moderate immune risk. The use of sirolimus in this population of children 13 years and older has been supported by adequate, well-controlled clinical trials of sirolimus oral solutions in adults. In these trials, the pharmacokinetic data of children with kidney transplants were specifically analyzed (see [Pharmacokinetics]

Sirolimus medication for elderly patients

No dose adjustment is required. ^[5]

Sirolimus adverse reactions:

The most common adverse reactions (present in> 10% of patients) are thrombocytopenia, anemia, fever, hypertension, hypokalemia, hypophosphatemia, urinary tract infections, hypercholesterolemia, hyperglycemia, hyperglycerin Triesteremia, abdominal pain, lymph cysts, peripheral edema, joint pain, acne, diarrhea, pain, constipation, nausea, headache, elevated blood creatinine levels, and elevated blood lactate dehydrogenase levels (LDH).

The frequency of adverse reactions listed below includes those reported by patients based on sirolimus. Overall, adverse events related to taking sirolimus were dose / concentration dependent. The incidence of adverse reactions may increase with the concentration of sirolimus in the blood.

The following adverse reactions are based on clinical studies and post-marketing experience.

In the classification of each system organ, the adverse reactions are listed according to the incidence rate (number of patients who may have the adverse reaction). The classification criteria are as follows: very common ( 1/10); common ( 1/100 to <1 / 10); uncommon ( 1/1000 to <1/100); rare ( 1 / 10,000 to <1/1000); unknown (unable to evaluate based on available data).

In each frequency group, adverse reactions are ranked in order of decreasing severity.

Most patients use an immunosuppressive regimen that includes sirolimus in combination with other immunosuppressants.

Description of some sirolimus adverse reactions

The safety and efficacy of converting a calcineurin inhibitor to sirolimus in a maintenance treatment regimen for a kidney transplant population has not yet been established. An experimental study assessing the safety and efficacy of the conversion of calcineurin inhibitors to sirolimus (target blood concentration of 12-20 ng / mL) in maintenance treatment regimens for kidney transplantation. Patients with a baseline glomerular filtration rate of less than 40 mL / min were discontinued (n = 90). Among these patients, the incidence of serious adverse events (including pneumonia, acute rejection, graft failure, and death) was west. Romus treatment group (n = 60, median time after kidney transplantation was 36 months) was higher.

Combination of sirolimus and calcineurin inhibitor may increase calcineurin inhibitor-induced hemolytic uremic syndrome / thrombotic thrombocytopenic purpura / thrombotic microangiopathy (HUS / TTP / TMA) risks of. (See [Precautions]-Immunosuppressive regimen without calcineurin inhibitor (CNI) in new kidney transplant patients)

In patients with delayed renal transplant function recovery, sirolimus may delay renal function recovery. (See [Notes]-Renal function)

Focal segmental glomerulosclerosis has been reported.

Interstitial lung disease

Some patients who are receiving immunosuppressive therapy (including sirolimus) have an infectious interstitial lung disease, and some may be fatal. Such diseases include non-infectious pneumonia, occlusive bronchiolitis with organizing pneumonia (BOOP) (less frequent), and pulmonary fibrosis. In some cases, discontinuing sirolimus or reducing doses can eliminate this interstitial lung disease. As the concentration of sirolimus in the blood increases, so does the risk of the disease (see [Precautions]-Interstitial Lung Disease).
Potential viral infection

Nephropathy and progressive multifocal leukoencephalopathy (PML) associated with BK virus have been observed in patients treated with immunosuppressants, including sirolimus. This infection may be associated with serious or fatal consequences, including failure of the kidney graft (see [Caution]-Potential Viral Infection).
Liver toxicity

Hepatotoxicity has been reported, including fatal liver necrosis caused by elevated sirolimus valley concentrations (ie, above therapeutic concentration levels).

Poor healing

Poor healing after transplantation has been reported, including cracking of fascia, incisional hernia, and rupture of anastomotic sites (such as wounds, blood vessels, airways, ureters, biliary tract, etc.)

child

Controlled clinical trials of sirolimus in children with high-risk immune kidney transplant recipients (under 18 years of age) evaluated the safety of sirolimus as a risk of one or more acute transplant rejections Medical history, and / or the presence of chronic graft nephropathy confirmed by renal biopsy (see [Clinical Trials]). Compared with calcineurin inhibitor-based therapy, sirolimus is used in combination with calcineurin inhibitors and corticosteroids with renal failure (elevated creatinine), dyslipidemia (including but not limited to serum Triglycerides and elevated cholesterol) are associated with high rates of urinary tract infections. Treatment options from previous clinical studies (continuation of sirolimus and calcineurin inhibitors) are not appropriate for adult or pediatric patients.

In another study of kidney transplant patients 20 years of age and younger, immunosuppressive regimens starting after transplantation (including the use of sirolimus and calcineurin inhibitors and baliximab inducers Full-dose immunosuppressive regimen) Safety of phasing out corticosteroids starting six months after transplantation. Of the 274 enrolled patients, 19 (6.9%) reported lymphoproliferative abnormalities (PTLD) after transplantation. Of the 89 patients who were known to be seropositive to EBV before transplantation, 13 (15.6%) had PTLD. All patients with PTLD were under 18 years of age.

Insufficient experience can recommend the use of sirolimus in children and adolescents.

Suspected adverse reaction report

It is important to report suspected adverse reactions after the drug has been approved for marketing. This will continue to monitor the benefit / risk balance of the drug. Medical staff should report any suspected adverse reactions.

Other clinical experience with sirolimus

Spermia deficiency has also been reported in patients receiving sirolimus, and most patients have improved after stopping sirolimus.

Ovarian cysts and menstrual disorders are reported (including amenorrhea and excessive menstruation. Patients with symptomatic ovarian cysts should be further evaluated. The incidence of ovarian cysts in premenopausal women may be higher than in postmenopausal women. In some patients, Western medicine Romus can solve ovarian cysts and menstrual disorders.

Clostridium difficile enterocolitis has been reported in patients receiving sirolimus. ^[5]

Sirolimus contraindications:

This product is contraindicated in patients who are allergic to sirolimus, derivatives of sirolimus, or any ingredient in this product. ^[5]

Sirolimus notes

Hypersensitivity

Hypersensitivity reactions associated with taking sirolimus include allergic / allergic reactions, angioedema, exfoliative dermatitis, and allergic vasculitis (see [Adverse Reactions]).

Liver transplantation-increased mortality, graft failure, and hepatic arterial thrombosis ( HAT )

A trial of patients with new liver transplantation found that the combined use of sirolimus and tacrolimus was associated with increased mortality and graft failure (22 %% combined group vs. 9% tacrolimus alone group). Many of these patients show signs of infection at or near death. In this trial and another trial in patients with new liver transplantation, the combined use of sirolimus with cyclosporine or tacrolimus was associated with an increased incidence of HAT (7 %% combined group vs. 2% alone Tacrolimus group), most of the HAT occurred within 30 days after transplantation, and most of them caused graft failure or death.

A clinical trial was performed in liver transplant patients. Patients 6 to 144 months after transplantation were randomly grouped into a switch from a calcineurin inhibitor to a sirolimus treatment group and continued use of a calcineurin inhibitor ( CNI) treatment group. The comparison found that at 12 months, the conversion group did not show a significant improvement in GFR (glomerular filtration rate) from baseline levels (-4.45 mL / min and -3.07 mL / min, respectively). The sirolimus conversion group also showed no non-inferiority to graft failure or mortality (lack of survival data) compared to the CNI continuation group. The trial demonstrated that, although the difference was not statistically significant compared with the continued use of the calcineurin inhibitor group, mortality was increased in patients who switched to the sirolimus treatment group. At 12 months, the rates of premature study termination, overall adverse events (especially infections), and biopsy-proven acute liver transplant rejection were significantly higher in the sirolimus conversion group than in the CNI continuation group.

The safety and effectiveness of sirolimus as an immunosuppressant in patients with liver or lung transplantation is unknown, and therefore it is not recommended for use in such patients.

Lung Transplantation-Dehiscence at Tracheal Anastomosis

New lung transplant recipients received immunosuppressive treatment including sirolimus, and cases of tracheal anastomosis were reported, most of which were fatal.

Interaction with potent inhibitors and inducers of CYP3A4 and / or P-gp

Strong inhibitors of sirolimus and CYP3A4 and / or P-gp (eg ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin) or CYP3A4 and / or A potent inducer of P-gp (eg rifampicin and rifabutin) is used in combination (see [Pharmacokinetics]-Metabolism and [Drug Interactions]). Sirolimus is extensively metabolized by the CYP3A4 isoenzyme in the intestinal wall and liver. Inhibitors of CYP3A4 can slow the metabolism of sirolimus and increase the blood concentration of sirolimus. The inducer of CYP3A4 accelerates the metabolism of sirolimus and reduces the blood concentration of sirolimus (see [Drug Interactions]).

General considerations

Sirolimus is for oral administration only.

There have not been sufficient clinical studies to confirm the use of sirolimus in patients with a high immune risk, and therefore it is not recommended for use in this patient group.

Angioedema

Taking sirolimus is associated with the development of angioedema. Sirolimus in combination with other drugs known to cause angioedema, such as angiotensin-converting enzyme inhibitors, may increase the risk of angioedema formation.

Wound healing and effusion

Poor or delayed wound healing has been reported in patients receiving sirolimus, including lymphocysts and wound dehiscence. In vitro studies have shown that mammalian rapamycin target molecule (mTOR) inhibitors, such as sirolimus, can inhibit the production of certain growth factors, thereby affecting angiogenesis, fibroblast proliferation, and vascular permeability. Lymphatic cysts, a known complication of kidney transplant surgery, are more common in patients receiving sirolimus and are dose-related. Care should be taken to minimize this complication. Medical research data show that patients with a body mass index (BMI) greater than 30 Kg / m 2 are at an increased risk of poor wound healing.

There are also reports of effusion in patients receiving sirolimus, including peripheral edema, lymphedema, pleural effusion, and pericardial effusion (including those that have a significant effect on hemodynamics in children and adults). liquid).

Skin malignancy

Immunosuppression has the potential to increase susceptibility to infections and may increase the chance of developing lymphomas and other malignancies, especially skin cancer. Therefore, patients taking sirolimus should limit their exposure to sunlight and ultraviolet rays by wearing protective clothing and using high protection sunscreens.

Hyperlipidemia

The use of sirolimus in kidney transplant patients may cause increased serum cholesterol and triglycerides in need of treatment. Therefore, patients must be monitored for the occurrence of hyperlipidemia.

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In a single-dose drug-drug interaction trial, 24 healthy volunteers took sirolimus (rapam Naruto® tablets) 10 mg. The average Cmax and AUC of sirolimus increased by 512% and 148% when taken in combination with Xinshan Diming Soft Capsule, respectively, compared with sirolimus. However, after taking Xinshan Diming Soft Capsule (Cyclosporine Capsule [Modified]) for 4 hours, the Cmax and AUC of sirolimus increased by 33% compared with sirolimus alone.

In a multi-dose trial (150 patients with psoriasis), sirolimus was administered at 0.5, 1.5, and 3.0 mg / m2 / day, while taking Shandiming oral solution (cyclosporine oral solution) 1.25 mg / kg / day Compared with taking sirolimus alone, the average trough concentration of sirolimus increased by 67-86%. The inter-individual difference (CV%) of sirolimus valley concentration was 39.7-68.7%. Multi-dose sirolimus had no significant effect on the concentration of cyclosporine valley after taking Shandiming oral solution (cyclosporine oral solution), but the CV% (85.9-165%) was higher than that measured in previous experiments.

Inhibitors and inducers of cytochrome CYP3A4 and P- glycoprotein ( P-gp )

Strong inhibitors of sirolimus and CYP3A4 and / or P-gp (eg ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin) or CYP3A4 and / or A potent inducer of P-gp (eg, rifampicin and rifampin) is used in combination (see [Caution]-Warning). Sirolimus is extensively metabolized by CYP3A4 isoenzymes in the intestinal wall and liver, and can be reversely transported from small intestinal epithelial cells to the intestinal lumen by the P-gp drug outflow pump. The potential circulation of sirolimus between small intestinal cells and the intestinal lumen allows it to be continuously metabolized by CYP3A4. Therefore, sirolimus systemic absorption and elimination after absorption can be affected by drugs acting on the two proteins mentioned above. CYP3A4 and P-gp inhibitors can slow the metabolism of sirolimus and increase the blood concentration of sirolimus; while CYP3A4 and P-gp inducers can accelerate the metabolism of sirolimus and make sirolimus The blood concentration decreased. For patients who need a strong inhibitor or inducer of CYP3A4, it is recommended to consider switching to a drug that has weaker CYP3A4 inhibition or induction.

Use caution when using sirolimus in combination with CYP3A4 substrates or inhibitors and / or inducers. Substances that can inhibit CYP3A4 and increase sirolimus plasma concentrations also include (but are not limited to):
Calcium channel blockers: diltiazem, nicardipine, verapamil.
Antifungal drugs: clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole.
· Antibiotics: clarithromycin, erythromycin, telithromycin, aceandromycin.
Gastrointestinal motility regulators: cisapride, metoclopramide.
· Other drugs: bromocriptine, cimetidine, cyclosporine, danazol (ethynol), HIV-protease inhibitors (such as ritonavir, indinavir).
· Grapefruit juice can induce CYP3A4 and reduce the blood concentration of sirolimus. It also includes (but is not limited to):
Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
Antibiotics: rifabutin, rifampin, rifapentin.
Herbal preparation: St. John's Wort (St. John's Wort).

The pharmacokinetic interactions of sirolimus with the following drugs at the same time are discussed below. Interactions with the following drugs have been studied:

Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; if used in combination with diltiazem, the concentration of sirolimus should be monitored and the dose adjusted if necessary. Eighteen healthy volunteers took 10 mg of sirolimus oral solution and 120 mg of diltiazem at the same time. The bioavailability of sirolimus was significantly affected. Cmax, tmax, and AUC of sirolimus increased by 1.4, 1.3, and 1.6 times, respectively. Sirolimus does not affect the pharmacokinetics of diltiazem or its derivatives (deacetyldiltiazem and demethyldiltiazem).

Erythromycin: Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp. Monitor the concentration of sirolimus and consider appropriate dose reductions for these two drugs; sirolimus tablets and erythromycin are not recommended Vaccines are taken at the same time (see [Precautions]-Warning). 24 healthy volunteers took sirolimus oral solution 2 mg orally once daily and erythromycin tablets (at steady state concentration) 800 mg once every 8 hours. Bioavailability is significantly affected. The sirolimus increased Cmax and AUC by a factor of 4.4 and 4.2, respectively, while tmax increased by 0.4 hours. Cmax and AUC of erythromycin increased by 1.6 and 1.7 times, respectively, and tmax increased by 0.3 hours.

Ketoconazole: Ketoconazole is a potent inhibitor of CYP3A4 and P-gp; rapaming® is not recommended to be taken with ketoconazole (see [Caution]-Warning). After taking rapamide® oral solution, taking ketoconazole in multiple doses significantly affected the absorption rate and extent of sirolimus, which was reflected by a 4.3-fold, 38%, and 10.9-fold increase in sirolimus, respectively. . However, the terminal half-life of sirolimus remained unchanged. A single dose of sirolimus did not affect the 12-hour steady-state plasma concentration of ketoconazole.

Rifampicin: Rifampicin is a potent inducer of CYP3A4 and P-gp; rapaming® is not recommended to be taken with rifampicin (see [Cautions]-Warning). Fourteen healthy volunteers were given multiple doses of rifampicin 600 mg / day for 14 consecutive days, followed by a single dose of 20 mg of sirolimus oral solution. The oral dose clearance of sirolimus increased significantly by a factor of 5.5 (range: 2.8-10), indicating that AUC and Cmax decreased by about 82% and 71%, on average. For patients who need to take rifampicin, consideration should be given to using therapeutic drugs with less enzyme induction.

Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; the concentration of sirolimus should be monitored and appropriate dose reductions should be considered for these two drugs. Twenty-six healthy volunteers were taking sirolimus oral solution 2 mg once daily and verapamil 180 mg once every 12 hours (to a steady state concentration). Bioavailability is significantly affected. Cmax and AUC of sirolimus increased by 2.3 and 2.2 times, respectively, while tmax did not change significantly. Both the Cmax and AUC of the pharmacologically active S-enantiomer of verapamil increased by a factor of 1.5, while tmax decreased by 1.2 hours.

Drugs that can be taken simultaneously without dose adjustment The following drugs have not been found to have clinically significant pharmacokinetic interactions in the study. Sirolimus can be taken at the same time as these medications and does not require dose adjustment.
· Acyclovir · Atorvastatin · Digoxin · Glibenclamide · Nifedipine · Nethrogesterone / Estradiol (Lo / Ovral)
· Prednisolone · Sulfamethoxazole / Trimethoprim (Compound Neoprene) ^[5]

- Sirolimus other drug-food interactions

After taking sirolimus tablets, the bioavailability of sirolimus can be affected by eating. To minimize differences in blood concentrations, sirolimus should be taken with or without food.

Grapefruit juice can slow the metabolism of sirolimus mediated by CYP3A4 and potentially enhance the reverse transport of sirolimus from small intestinal epithelium to the intestinal lumen mediated by P-gp. This juice cannot be used to deliver sirolimus tablets.

- Sirolimus drug-herb interaction

St. John's Wort can induce CYP3A4 and P-gp. Since sirolimus is a common substrate for cytochromes CYP3A4 and P-gp, the use of St. John's Wort in patients receiving sirolimus can lead to a decrease in sirolimus plasma concentrations.

When taking HMG-CoA reductase inhibitors and fibrates in combination with sirolimus and HMG-CoA reductase inhibitors and / or fibrates, the occurrence of rhabdomyolysis should be monitored.

Calcineurin inhibitor In patients taking sirolimus and calcineurin inhibitors, there is hemolytic uremic syndrome / thrombotic thrombocytopenic purpura / thrombotic Case report of microangiopathy (HUS / TTP / TMA).

Vaccine immunosuppressants may affect vaccination responses. The effect of the vaccine may therefore be reduced during rapaming® treatment. Live vaccines should be avoided; live vaccines include, but are not limited to, measles, mumps, rubella, oral polio, BCG, yellow fever, chicken pox, and TY21a typhoid. ^[5]

Sirolimus expert review

This medicine is used for the treatment of rejection and autoimmune diseases in organ transplantation. The drug is metabolized by liver P450 3A. Elimination half-life is about 60 hours. The time limit for organ transplantation to resist rejection and autoimmune diseases is long. Pay attention to peptic ulcer, interstitial pneumonia, and vasculitis. Anemia, thrombocytopenia, hyperlipidemia, and hypertension. ^[4]