Fluoxymesterone halotestin – a recombinant fusion protein consisting of binding VEGF (vascular endothelial growth factor) portions of the extracellular domains VEGF receptor 1 and VEGF receptor 2, connected to the Fc domain (fragment capable of crystallization) Gl immunoglobulin (IgGl) human.Aflibercept produced by recombinant DNA techniques fluoxymesterone halotestin using an expression system ovary cells Chinese hamster ovary (CHO) K-1.Aflibercept is a chimeric glycoprotein having a molecular weight of 97 kDa.
Aflibercept soluble acts as “decoy receptors,” which binds to VEGF-A with a greater affinity than native receptors VEGF-A, except that it also binds to the cognate ligands VEGF-B and P1GF. Aflibercept binds human VEGF-A, VEGF-B and P1GF inert to form stable complexes which do not have biological activity. Acting as a “trap” for the ligands aflibercept prevents binding of endogenous ligands to their respective receptors, and thereby block the signaling through these receptors.
Aflibercept blocks VEGF receptor activation and proliferation of endothelial cells, thereby inhibiting the formation of new blood vessels that supply the tumor with oxygen and nutrients.
Application aflibercept mice xenografted tumors allotransplantirovannymi or inhibit the growth of various types of adenocarcinomas.
In patients with metastatic colorectal cancer who oxaliplatin-containing chemotherapy (with the previous fluoxymesterone halotestin administration of bevacizumab with or without prior administration of bevacizumab), chemotherapeutic regimens Zaltrap previously conducted ® / FOLFIRI [fluorouracil, irinotecan, calcium folinate] showcased the statistically significant increase in life expectancy compared to chemotherapy FOLFIRI scheme.
In preclinical studies performed on the tumors models aflibercept bioactive dose correlated with the doses needed to create a circulating concentration in the systemic circulation free aflibercept excess circulating concentrations in the systemic circulation aflibercept associated with VEGF. Circulating concentration in the systemic circulation aflibercept VEGF associated with increasing the dose to increase until most of VEGF is not related. Further increasing the dose aflibercept leads to dose-dependent increase in the concentration of circulating in the systemic circulation free aflibercept and only a small further increase in concentration associated with VEGF aflibercept.
Patients drug Zaltrap ® is administered at a dose of 4 mg / kg body weight intravenously every 2 weeks, during which a place the excess concentration of circulating free aflibercept of concentration aflibercept associated with VEGF.
at the recommended dose of 4 mg / kg body weight once every two weeks, the concentration of free aflibercept, is close to the equilibrium concentrations were achieved during the second cycle of treatment with little or no accumulation (accumulation factor 1.2 in the equilibrium state, compared to the concentration of free aflibercept the first introduction).
The volume of distribution of free aflibercept in equilibrium is 8 liters.
Since aflibercept is a protein, its metabolism studies have been conducted.
It is expected that aflibercept will split into small peptides and individual amino acids.
circulating in the systemic circulation free aflibercept mainly binds to VEGF-family to form stable inactive complexes.
It is expected that, as with other major proteins associated with VEGF and free aflibercept will be gradually removed from the systemic circulation due to other biological mechanisms, such as proteolytic catabolism.
At doses higher than 2 mg / kg of free aflibercept clearance was 1.0 l / day with a terminal half-life – 6 days.
High-molecular proteins are not excreted by the kidneys, therefore it is expected that renal excretion aflibercept will be minimal.
Linearity / non-linearity of elimination
in relation to the target binding aflibercept with its “target” (endogenous of VEGF), free aflibercept at doses below 2 mg / kg showed a rapid (non-linear) decrease in its concentration in the systemic circulation, apparently associated with its high affinity binding endogenous VEGF. In the dose range from 2 to 9 mg / kg of free aflibercept clearance becomes linear, apparently by saturating the biological elimination mechanisms such as protein catabolism.
Special patient groups
The pharmacokinetic profile aflibercept not established in children.
Age has no effect on the pharmacokinetics of aflibercept.
Despite the differences in the clearance of free aflibercept and volume of distribution in men and women, there was no gender-related differences in its systemic exposure when used in a dose of 4 mg / kg body weight.
Body Mass Index
Body mass effect on the clearance of free aflibercept and volume of distribution, as in patients with a body weight> 100 kg was observed increase in systemic exposure aflibercept 29%.
Race and ethnicity had no effect on the pharmacokinetics of aflibercept.
Patients with hepatic insufficiency
formal studies on the use of Zaltrap drug in patients with hepatic impairment have been conducted. In patients with mild (concentration of total bilirubin <1.5 ULN [upper limit of normal] for any values of aspartate aminotransferase activity [the ACT] and medium (concentration of total bilirubin> 1.5-3 ULN at any values of ACT) hepatic activity failure showed no change in the clearance aflibercept. There are no data on the pharmacokinetics of aflibercept in patients with severe degrees of hepatic impairment (total bilirubin concentration in the blood of> 3 × ULN at any values of ACT activity).
Patients with renal insufficiency
No official studies on the use of the drug Zaltrap ® in patients with renal impairment have been conducted. There were no differences in the systemic exposure (area under the concentration-time curve “concentration-time» [AUC]) aflibercept free patients with renal failure at various degrees of application of the drug Zaltrap 4 mg / kg body weight.
Metastatic colorectal cancer (MKRR) (in adults), resistant to oxaliplatin-containing chemotherapy or progressive after its use (drug Zaltrap in combination with the regime, including irinotecan, fluorouracil, calcium folinate (FOLFIRI)).
- Hypersensitivity to aflibercept or any of the excipients Zaltrap drug.
- Heavy bleeding.
- Hypertension is not amenable to medical correction.
- Chronic heart failure class III-IV (according to NYHA classification).
- Severe hepatic insufficiency (lack of data on the application).
- Ophthalmic application or intravitreal (in connection with hyperosmotic properties Zaltrap drug ® ).
- The period of breastfeeding.
- Children and teens under 18 years (due to lack of sufficient experience in the application).
Contraindications to the use of irinotecan, fluorouracil and calcium foliinata cm. In the instructions for use.
- Severe renal failure.
- Arterial hypertension.
- Clinically significant cardiovascular disease (ischemic heart disease, chronic heart failure, I-II NYHA class classification).
- Elderly age.
- The general condition of> 2 points on the rating scale to assess the general condition of the patient’s ECOG (Eastern Cooperative Oncology Group).
Pregnancy and breast-feeding
Data on the use of aflibercept in pregnant women are missing. Studies in animals have revealed aflibercept embryotoxic and teratogenic effects. Since angiogenesis is important for fetal development, inhibition of angiogenesis when administered drug Zaltrap ® can lead to adverse effects for the development of pregnancy.
The use of the drug Zaltrap ® during pregnancy and in women who may become pregnant is not recommended.
Women of childbearing age should be advised to avoid becoming pregnant during treatment with Zaltrap, and they should be informed of the potential for adverse effects of the drug Zaltrap ® on the fetus.
Women of childbearing potential and fertile males must use effective methods of contraception during treatment and for at least for up to 6 months after the last dose of treatment.
There is a possibility of impaired fertility in men and women during treatment aflibercept (based on data from studies conducted on monkeys, males and females which aflibercept caused impaired fertility, completely reversible after 8-18 weeks).
Clinical studies to evaluate the effects of the drug Zaltrap on production of breast milk, the allocation of aflibercept in breast milk and its effects on infants have been conducted.
It is not known whether aflibercept excels in human breast milk. However, due to the fact that we can not yet rule out the possibility of penetration aflibercept into breast milk and because of the possibility of serious adverse reactions caused by aflibercept in infants, it is necessary or not to breastfeed, or do not use the drug Zaltrap (depending on the importance of the drug to the mother).
Dosing and Administration
Zaltrap drug is administered as a 1 hour intravenous infusion followed by chemotherapeutic regimen FOLFIRI.
The recommended dose Zaltrap drug used in combination with a chemotherapeutic regime FOLFIRI, is 4 mg / kg body weight.
Chemotherapeutic diagram FOLFIRI:
the first day of the cycle – simultaneous intravenous infusion via the Y-shaped catheter is irinotecan at a dose of 180 mg / m for 90 minutes and calcium folinate (left and dextrorotatory racemates) at a dose of 400 mg / m 2 for 2 hours, followed by intravenous (bolus) administration of fluorouracil at 400 mg / m 2 , followed by a continuous intravenous infusion of fluorouracil at a dose of 2400 mg / m 2 for 46 hours. The
chemotherapy cycles repeated every 2 weeks.
Treatment with the drug Zaltrap should continue until disease progression development or unacceptable toxicity.
Recommendations for a sharp correction and dosing / deferral treatment
Treatment with Zaltrap ® should be discontinued:
– the development of heavy bleeding;
– the development of perforating the wall of the gastrointestinal tract (GIT);
– the formation of a fistula;
– the development of hypertensive crisis or hypertensive encephalopathy;
– the development of arterial thromboembolic complications;
– in the development of nephrotic syndrome or thrombotic microangiopathy;
– the development of severe hypersensitivity reactions (including bronchospasm, dyspnea, angioedema, anaphylaxis);
– in violation of the healing of wounds requiring medical intervention;
– the development of the syndrome of reversible posterior encephalopathy (SOZE), also known as reversible posterior leukoencephalopathy (SLDF).
at least 4 weeks prior to elective surgery should suspend treatment with Zaltrap.