Master in Biotechnology and Bioengineering
Introduction
The efficacy and safety of Brematozumab were evaluated in an ASCENT phase III study, randomized, multicentric and open with TNBC patients whose tumors on trop-2 and who generated relapse after one or more chemotherapy regimes. Brematozumab has also been used in combination with platinum, directed PLP and Abraxane inhibitors for the treatment of patients who have received chemotherapy for their metastatic disease.
The efficacy of Brematozumab has not been studied in combination with platinum, PLP inhibitors or Abraxane in patients who have not received previous chemotherapeutic treatment. The frequency of the progression towards the liver was significantly reduced in patients who were treated with the combination of Brematozumab and Abraxane compared to Abraxane only.
Brematozumab is a conjugate of a monoclonal antibody directed against Trop-2 attached to the SN-38 drug. Brematozumab Pharmacokinetics was evaluated by measuring the characteristics of the antibody, as well as the derivatives of RS7 and SN-38 total and not conjugated. After the Brematozumab union with its target, SN-38 is internalized and released by hydrolysis.
Developing
Triple negative metastatic breast cancer (TNBC)
Parixinti is indicated for the treatment of adult patients with metastatic breast-receptor (re) negative, progesterone receptor (RP) negative and receiver-2 of the human epidermal growth factor (her2) negative: in monotherapy, for treatment for the treatmentMetastatic disease of patients with two minimum chemotherapeutic regimes. Previous chemotherapy must have included at least one of the treatments with gemitinib or doetaxel.
In combination with cisplatin or directed PLP inhibitors (Lynparza), in patients who no longer present a response to common chemotherapy medications. In combination with Abraxane (Paclitaxel linked to albumin), in patients whose condition is advanced and produce PD-L1. The test for her2, RE and RP is mandatory before starting therapy. Parixinti treatment should be initiated only by a specialist with experience in cytotoxic chemotherapy administration and be administered only by health professionals.
Parixinti formulation must be administered only by intravenous perfusion. Vial labels must be checked to ensure that the medicine to be prepared and administered is Parixinti (Brematozumab), in order to avoid medication errors.
Guideline every 4 weeks
The recommended initial dose is 7 mg/kg of weight. The recommended maintenance dose is 5 mg/kg of weight every four weeks, starting starting four weeks after the initial dose.
Weekly guideline
The recommended initial dose of Parixint is 3 mg/kg of weight. The Weekly Dose of recommended maintenance of Parixint is 2 mg/kg of weight, starting a week after the initial dose.
Administration in combination with cisplatin or lynparsa
In pivotal studies (H0638 G, M77001), Platinum or the directed inhibitor of PLP were administered the next day after the starting dose of Brematozumab and immediately after the following doses of Brematozumab, if the preceding dose was well tolerated.
Administration in combination with Abraxane
In the pivotal study (B012132) Brematozumab was administered together with Abraxane from day 1. There were no restrictions on how to administer Brematozumab and Abraxane in time.
Dose reduction
During the clinical trials carried out, no Brematozumab dosage reduction was evidenced. Patients can continue with therapy during reversible periods of myosuppression induced by quimititeapicas, but only if they are monitored to detect possible complications due to neutropenia during these periods. With respect to Cisplatino, Lynparsa and Abraxane, consult their corresponding technical record for information on the reduction or delay of administrations of these medications.
Omitted doses
If the patient has not been administered from the dose of Parixinti and has elapsed a week or less, the usual maintenance dose should be administered as soon as possible (weekly regime: 2 mg/kg; regime every 4 weeks: 5 mg/kg). Do not wait for the next cycle. Subsequent maintenance doses must be administered 7 days or 21 days later, according to the weekly pattern or with the pattern every four weeks, respectively.
If any dose has not been administered to the patient for more than a week, the initial dose should be administered for approximately 120 minutes (weekly regime: 3 mg/kg; regime every 4 weeks: 7 mg/kg) as soon as possible.No specific pharmacokinetic studies have been carried out in elderly patients or in patients with renal or hepatic failure. There is no relevant use of Brematozumab in the pediatric population.
Form of administration
Parixinti is only for intravenous use. The initial dose should be administered by intravenous perfusion for 120 minutes. Administration as a pulse or intravenous bolus is prohibited. The intravenous perfusion of Parixinti must be carried out only by qualified health personnel in the handling of anaphylaxis.
Patients should be observed for at least 8 hours from the beginning of the first perfusion and for two hours from the following perfusions. Hypersensitivity to Brematozumab, to the murine proteins or an excipient such as: histidine, histidine monohydrochloride, trehalose dihydrate or polysorbate 20.
Security Profile Summary
Among the most serious and/or frequent adverse reactions communicated to date with the use of Brematozumab are: cardiac dysfunction, reactions related to perfusion, neutropenia and non -neutropenia conditions. Frequency categories: very frequent (> = 1/10), frequent (> = 1/100 a < 1/10), poco frecuentes (>= 1/1000 a < 1/100), raras (>= 1/10000 a < 1/1000) y muy raras (< 1/10000) y frecuencia no disponible, cuando la frecuencia no se puede estimar con los datos disponibles.
Table 1 presents the adverse reactions notified in relation to the use of intravenous, alone or in combination with chemotherapy, in pivotal clinical trials and in the post-commercialization phase. Give.
However, most of these allergic reactions are of mild to moderate intensity during the initial phase of the treatment;that is, between the first and third perfusion, reducing this reaction in subsequent perfusions. These allergic reactions include chills, dyspnea, itching, difficulty breathing and nausea.
Serious anaphylactic reactions that require additional immediate intervention could occur between the first or second perfusion, which was observed in some isolated cases. Pharmacotherapeutic group: antineoplastic, monoclonal antibody. Brematozumab is a conjugated RS7 Humanized IgG1K monoclonal antibody against antigen 2 of the human trophoblast cell surface (Trop-2), which has a SN-38 chemical bond. RS7 is the antigen binding protein associated with tumor called and SN-38 is an active metabolite of Iriotecan, a chemotherapy drug.
Trop2 participates in the regulation of several intracellular signaling paths related to the proliferation and migration of cancer cells. Trop-2 overexpression is observed in 80% of triple metastatic negative breast carcinomas (TNBC). Clinical trials in patients with TNBC indicate that tumors that overexpreate Trop-2 have a shorter survival in relation to patients with tumors with minor levels.
Brematozumab is a conjugated antibody that releases an antineoplastic drug and selectively produces the apoptotic cell death of tumor cells that express Trop-2. The preclinical data indicate that the biological activity of Brematozumab is through several stages: Trop-2 Union on the cell surface and formation of a Brematozumab-Top2 complex, which is transported to the Lysosomal Compartment. At the cellular level, SN-38 is released, by protein split. The SN-38 union generates the inhibition of topoisomerase 1, which produces breaks in the DNA chain, stops the cell cycle and induces the selective apopototic death of TNBC tumor cells that express Trop-2.
Distribution
In vitro, the union of Brematozumab to Trop-2 ranged from 68-82%. It is not likely that Brematozumab moves to the medications that bind stable with the target protein or that they are displaced by them. Once Brematozumab was released, the elimination of SN-38 released from Iinotecan was generated. SN-38 represents 0.8 to 0.43% of the drug recovered in the urine after 24 hours of the administration. Through preclinical tests it was determined that around 50% of the SN-38 load was released from the conjugated antibody after 24 hours.
Biotransformation
Brematozumab’s half-life was between 12-14 hours. The area under the curve for Brematozumab was approximately 5 mg-h/ml. The distribution volume was 34-36 ml/kg and the clearance rate was 2ml/h.
conclusion
Through an analysis with a population pharmacokinetic model, the Brematozumab Pharmacokinetics used a data set of 1500 subjects, which included patients with her2 positive -type breast cancer, her2 negative, triple negative, other types of tumor and healthy volunteers, in 12Phase I, II and II clinical trials, where they received intravenous Brematozum. The Brematozumab washing period was valued after the weekly intravenous administration using the population pharmacokinetic model. The results showed that at least 97% of patients reach concentrations.
Brematozumab’s profile of the concentration-time ratio was analyzed by a bicompartimental model with parallel and non-linear linear elimination. Total clearance increased with the decrease in concentration in the case of non -linear elimination, so a constant semi -tramitic value for Brematozumab was deduced. The clearance was linear of 0.163 l/day for her2 positive and 0.1561 l/day for her2 negative. Medias of 8.91 mg/day were obtained for the maximum elimination rate (VMAX) and 9.81 UG/ml for the consist of Michaelis-Muel (km) for all patients.
Bibliography
- 1. ]
- two. [Bookmark: _toc41321088] Qualitative and quantitative composition, Paraxinti 250 mg of concentrated dust for perfusion solution. Paraxinti’s reconstituted solution contains 35 mg/ml of Brematozumab. To consult the excipients present, see section 4.3.1. Contraindications.
- 3. [Bookmark: _toc41321089] Pharmaceutical form. Concentrated dust for perfusion solution. Lyophilized dust of white -white coloring.
- 4. [Bookmark: _toc41321090] Clinical data. [Bookmark: _toc41321091] 4.1. Therapeutic indications
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