Carfilzomib Advantages

This drug is better preferred than bortezomib due to many of its advantages, such as its more specific and with a small activity outside of the proteasome. Carfilzomib doesn’t become resistance to the tumor cell compared to bortezomib due to this reason this drug was synthesized for better treatment for cancer. The process of this drug is similar to bortezomib in some way, it is capable to delay proliferation and induce apoptosis to malignant plasma cells due to the selectivity and irreversible of the inhibition of proteasomes [27]. The administration for carfilzomib is through intravenous due to the same problem of BTZ, having a low bioavailability. In clinical trials, the dose of 20 mg/m2 is given to all the patients which immediately, scientist

brought into conclusion that when the drug is administered is reaches its maximum plasma concentrations within minutes and the systematic exposure in less than one hour [7]. This can be taken into consideration that the amount of dose is dependent on the plasma concentration, so the greater the dose the longer the effects will last.

The metabolism of carfilzomib consists of two pathways peptidase cleavage and epoxide hydrolysis, that were found in peptide pieces with the diol metabolite in carfilzomib. The drug has a half-life of less than one hour and is excreted by biliary and renal excretion, less than one percent of the drug remains complete [7]. All drugs eventually have severe side effects depending on the type of drug used. This drug, carfilzomib has mostly common side effects such as a cough, diarrhea, hypertension, thrombocytopenia, muscle spasms, upper respiratory tract infection, and hypokalemia, these side effects are not life-threatening, but during clinical trials a 3.8% of the patients were reported with cardiac failure [7]. In further studies, researchers were able to understand that the higher the drug dose caused severe side effects, patients experience cardiovascular adverse events (CVAE) mainly heart failure, heart attacks, and arrhythmia [4]. This side effects can be taken into account that they may depend on the age and obesity of the

patients. The addition of lenalidomide and a low-dose of dexamethasone are combined chemicals with carfilzomib to enhance the quality and effects into patients with relapsed/refractory MM [18].

This can be taken into consideration that patients taking the drug bortezomib for the treatment of multiple myeloma is not effective so the second-generation drug carfilzomib with lenalidomide and desxamethasone can be taken into account that the drug may overcome the bortezomib resistance and treat MM. Lenalidomide is an immunomodulatory drug that is an analogue of thalidomide that possess pleiotropic anti-myeloma properties that include such as anti-angiogenic, anti-inflammatory, and anti-tumor necrosis factor activity [10]. This drug is derived by adding an amigo group to the fourth carbon of the phthaloyl ring of thalidomide [10]. Dexamethasone is a corticosteroid that is an anti-inflammatory medication that also has the ability to treat some types of cancers when its combined with a proteasome inhibitor drug

[9].
A recent second-generation drug is known as ixazomib (brand name NINLARO) has been approved by the FDA in 2016 also known as MLN9708, which is a strong drug that is reversible boronate that contains proteasome inhibitors, illustrated in Figure 3 [19]. During the studies of this drug, researchers concluded that the drug showed a shorter dissociation of half-life and also had superior tissue penetration compared to BTZ [19]. When the drug is administered and reaches to the plasma or any other aqueous solution it hydrolyzed from a stable citrate ester to an active form known as MLN2238 [19]. MLN2238 consists of a dipeptidyl leucine boronic acid with the same binding as BTZ [19]. Studies suggest that ixzomib shouldn’t be taken with previous patients that undergone chemotherapies with the drugs: bortezomib, lenalidomide, and dexamethasone taking these drugs will cause cytotoxicity against the myeloma cells [31]. Ixzaomib is the first orally bioavailability that was able to undergo through clinical trials that inhibits the chymotrypsin from the 20S proteasome and immunoproteasome [21]. Although it can also be administered through IV that provides a greater plasma exposure compared to bortezomib and it also has five times higher distribution from the blood into the tissue [5]. This drug has the ability to induce apoptosis of multiple myeloma that is resistant to in the previous drug as mention earlier. The biological mechanism for ixazomib follows through the apoptotic activity that was mediated by the activation of caspase-8, caspase-9, and caspase-3 with pathways such as p53-p2, p53-NOXA-PUMA [5]. It also induces from binding the immunoglobulin protein and CCAAT- enhancer protein, which both are connected to endoplasmic reticulum stress response [5]. A clinical trial known as TOURMALINE-MM is a multinational, randomized, double-blind study, compared ixazomib plus dexamethasone and dexamethasone versus placebo plus lenalidomide and dexamethasone in patients from previous chemotherapy that didn’t affect the patient with the increased growth of multiple myeloma [31]. Studies showed that ixazomib with the addition of the two drugs versus the placebo with the two drugs, ixzomib has a stronger effect against the multiple myeloma it also has a less median time to response the placebo has 1.9 months and ixazomib 1.1 months [31]. The side effects of the drug ixzaomib include gastrointestinal toxicity, skin rash, and common effects as fatigue, vomiting, nausea, etc [11].
Another second-generation drug known as marizomib (NPI-0052) is an irreversible proteasome inhibitor that is derived from a marine actinomycete that inhibits the three major catalytic activities of the 26S proteasomes that is able to be administered through oral and intravenous, shown in Figure 4 [22].