For the doctors

Drug action mechanism

THE RUSSIAN FEDERATION

/Coat of arms of the Russian Federation/

PATENT
FOR AN INVENTION

No 2599462

METHOD FOR POLYSIGNAL ACTIVATION OF MALIGNANT SOLID TUMOR CELLS APOPTOSIS

Patent holder(s): _______ (____) Limited Liability Company (RU)
Author(s): see overleaf

/Seal: (FEDERAL SERVICE FOR INTELLECTUAL PROPERTY (ROSPATENT) * PSRN 1047730015200 * TIN 7730176058 * CRR 773001001
-illegible-

Application No 2015140255
Priority date September 22, 2015
Recorded in the Russian Federation State Invention Register on September 15, 2016
Patent expiration date September 22, 2035

Head of the Federal Service for Intellectual Property
/signature/   G.P. Ivliev
The blood vessels of the tumor are structurally deficient. They often do not have the pericytes, and their basement membrane is weak and defective. The irregular structure predisposes tumors to metastasis. The irregular structure of the tumor vasculature causes a high interstitial fluid pressure, which reduces the penetration of drug into the tumor tissue. Insufficient penetration of drug reduces the potential of anti-tumor activity and ends up¬¬ with acquired resistance to the drug.

Neyrofilin-1 and neyrofilin-2 are the key molecules that regulate vascular permeability¬. The peptides that penetrate through the tissues get connected with NRPs through amino acid sequence RXXR/K, increasing the transport of molecules into the tumor tissue¬ iRGD ligand serves for that, it is aimed at ανβ3 integrin specifically expressed in tumor vasculature¬. The greatest number of ανβ3 was found in melanomas, glioblastomas and sarcomas, a lower level of expression is found in breast cancer and renal cell cancer cases. Integrin ανβ3 levels are correlated with the disease progression in some malignant tumours, including: melanoma, glioblastoma, ovarian cancer and breast cancer. Through binding to integrin ανβ3, iRGD ligand brings the medications into the vasculature of the tumor - the inhibitors of tumor growth and the spread of metastases. Antimetastatic effects of iRGD prevent metastasis and overcome prometastatic side effects of anti-angiogenic therapies¬. Thus, iRGD provides an easy way to enhance the therapeutic index of various drugs against cancer.

Pharmacokinetics

The pharmacokinetic properties of XXX were evaluated among adult healthy volunteers and adult patients;

after repeated administration of the drug its accumulation within the tumor nodes and metastases was observed.

Absorption

XXX has good bioavailability at oral administration. Maximal concentrations in plasma are usually reached within 5-10 minutes after ingestion.

According to the results of in vitro experiments with human Caco-2 cells, XXX is not a substrate of P-glycoprotein (pumps of drug resistance pumping out different inhibitors from the cells).

Distribution

XXX largely binds to integrin ανβ3 receptor (>99,9%).

Metabolism

After a single oral administration of the XXX dose in healthy volunteers, most of the active ingredient presented an unmodified drug.

Excretion

Excretion of XXX occurs via kidneys. Kidneys play a significant role in the excretion of the drug. After a single oral administration of the XXX dose in healthy volunteers, an average of 90% was excreted with the urine. Unchanged XXX in feces was on average 10% of the dose.

XXX half-life period when receiving a dose in healthy volunteers was 5-7 days and in patients with tumors - 10 days.

Indications for use

Treatment of solid tumors in combination with surgery and other therapies is permitted. The drug may be used as monotherapy.

Contraindications

- pediatric use (up to 18 years old)

- pregnancy

- lactation period

- decompensated liver cirrhosis, impaired renal function.

Carefully

Sovriad® should be used carefully:

- in patients with severe impaired renal function, (creatinine clearance less than 30 ml/min)

Dosage and administration

The recommended dose is 5 ml - the content is to be administered orally, once in every three - five days, depending on tolerability and the body's response to the drug. The type of food does not influence the pharmacokinetic parameters of XXX.

Side effects

The adverse reaction observed in the drug therapy is tumor lysis syndrome (TLS), the fight against which is described in the relevant instructions.

Overdose

TLS

TLS preventive measures:

•   Allopurinol prescription.
•   At leukocytosis more than 100 thousand in 1 μl, the leukapheresis is the method of choice before the special treatment, if available in the clinic.
•   All the patients with risk of urate nephropathy should receive hydration to correct the existing fluid deficit and provide forced diuresis in the future. Hydration starts with the patient's admission to hospital before the special treatment. Increasing urine volume, achieved by hydration, reduces the concentration of urates in urine. There must be strict control of administered and discharged liquid.
•   Due to the threat of hyperkalemia or because of already existing hyperkalemia, potassium is not included in the infusion at early hydration. Further, the potassium infusion should be strictly corrected by its concentration in the blood. Moderate hypopotassemia is tolerable.
•   Urine alkalizing with sodium bicarbonate until a urine pH 7.0, but not more than 7.5. It is necessary to control the level of ionized calcium. Correction of bicarbonate dose depends on the pH of urine.
•   Furosemide prescription.
•   Acetazolamide (carbonic anhydrase inhibitor) may be used to enhance the alkalizing effect.
•   At the risk of oliguria in terms of preventative measures it is necessary to administrate micro-doses of dopamine.
•   Limitation of enteral nutrition, aluminum hydroxide through mouth for phosphate binding.
•   Control (every 12 hours) of potassium level, ionized calcium, phosphorus, uric acid, creatinine, blood urea. Careful hourly diuresis, perspiration. Determination of urinary pH.
•   Body weight monitoring twice a day.
•   Daily monitoring of levels of magnesium, sodium, albumin, ECG, ABB (acid-base balance), CRP (C-reactive protein), coagulation.

TLS treatment.

The basics of treatment are the same activities that are carried out to prevent TLS development.
Hyperuricemia is an increase in volume of IV fluid to 5 l/m² per day. At normal level of phosphorus the additional alkalization of urine pH can be adjusted to 7.5.
Hyperpotassemia (potassium concentration more than 6 mmol/L) - begin the preparations for hemodialysis: glucose with insulin, calcium gluconate, sodium bicarbonate. At potassium concentration mare than7 mmol/l - immediate hemodialysis.
Hyperphosphatemia is an increase in the fluid volume to 5 l/m2, urine pH nit more than 7.0. Stop enteral nutrition, aluminum hydroxide through the mouth. At phosphorus concentration of more than 5 mmol/l - hemodialysis.
Hypopotassemia is a calcium dotation only at normal or low phosphorus concentration. Control of magnesium level is required. At hypomagnesemia - the administration of magnesium
Oligo- and anuria (v less than 50 ml/m per hour), despite the administration of furosemide and fluid. Therapy: hemodialysis at the potassium level higher than 6 mmol/L. It is necessary to exclude ureteral obstruction, infiltration of both kidneys.
Indications for hemodialysis:

•   Potassium level above 6 mmol/l, despite liquid and diuretic therapy.
•   Potassium level above 7 mmol/l - immediate hemodialysis.
•   Phosphorus level above 5 mmol/l.
•   Diuresis less than 50 ml/m2 per hour with liquid loading of 130-200 ml/m per hour.
•   Obstruction of both ureters.

Coagulopathy. Treatment of DIC syndrome (disseminated intravascular coagulation) includes replenishment of coagulation factors deficit - the transfusion of fresh frozen plasma. At the constant hypofibrinogenaemia - transfusion of factor VIII cryoprecipitate. Often the proteolysis syndrome develops more rapidly than the growth of procoagulant activity and the development of DIC syndrome, especially in patients with a large number of blast cells in the periphery. The issue of use of heparin or antifibrinolytic therapy depends on the prevalence of the DIC or proteolytic syndrome. At pulmonary vessels thrombembolia the urokinase is assigned. At pneumopathy and 3rd grade acute respiratory failure the artificial pulmonary ventilation is assigned.

Treatment:

A specific antidote is Prussian blue (antidote V03AB31). In case of overdose it is recommended to conduct a maintenance therapy (for example, washing the gastrointestinal tract) and monitoring the patient's condition.

XXX is characterized by a high degree of plasma proteins binding, therefore the hemodialysis will highly likely not result in a significant removal of XXX.

Shelf life:

2 years

Do not use after the expiration date.

Storage conditions

Store at a temperature not exceeding 25°C in a dark place.

Keep out of reach of children.

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