Carfilzomib is a proteasome inhibitor. It is suitable for the treatment of patients with multiple myeloma.

Multiple myeloma (MM) is a malignant tumor originating from the B-cell line. It is characterized by the clonal proliferation of malignant plasma cells in the bone marrow microenvironment, causing fractures and bone marrow failure. It is the second most common blood system tumors and cannot be cured by traditional chemotherapy.

Bortezomib is the first proteasome inhibitor and is the first-line drug for multiple myeloma. It has made a breakthrough in the treatment of multiple myeloma. Due to its strong drug resistance and people’s resistance, carfilzomib was approved by the FDA as the second proteasome inhibitor, before receiving at least 2 drugs (including bortezomib and immunomodulators) for multiple myeloma treatment. Carfilzomib is a specific and irreversible targeted inhibitor. It was originally developed by Proteolix and produced by Onyx Pharmaceuticals. It was approved by the FDA on July 20, 2012.

Related researches on Carfilzomi

The purpose of study is to determine the proportion of patients with complete or partial tumor disappearance after treatment (total response rate). The overall response rate is 23%. The median response time was 7.8 months.

The most common side effects observed in more than 30% of the participants were fatigue, low blood count and platelet levels, shortness of breath, diarrhea, and fever. The severe side effects observed with Kyprolis include heart failure and shortness of breath. If these serious side effects occur, the patient should be closely monitored and treated.

Kyprolis was approved through the FDA's accelerated approval process. The accelerated approval process allows the FDA to approve drugs for the treatment of serious diseases based on alternative endpoints shown by clinical trial data that can reasonably predict clinical benefits. The accelerated approval process aims to provide patients with promising new drugs earlier. After the drug is approved for marketing, the company must submit more clinical data confirming the clinical benefits of the drug.

Pharmacology of Carfilzomib

26S proteosomal enzyme is a protein complex widely distributed in the cytoplasm and nucleus of eukaryotic cells. It is mainly composed of the 20S core complex and the 19S regulatory complex. It is responsible for the degradation of most proteins in the cell. It has a key regulatory role in life activities. The 20S core part includes three catalytic sites: chymotrypsin, trypsin and hemiacyl aspartase-like sites, and the chymotrypsin region is the main functional area that prevents cell growth.

Carfilzomib is an analogue of epoxy ketone tetrapeptide proteasome inhibitor, which mainly inhibits 20S proteasome chymotrypsin. Its structure and mechanism of action are different from the dipeptide boronic acid analogue bortezomib. Bortezomib binds to the proteasome catalytic β5 subgroup reversibly, while carfilzomib irreversibly covalently binds to the proteasome catalytic β5 subgroup and immunity The proteasome β5i (LMP7) subgroup has better efficacy and resistance than bortezomib.

Pharmacodynamics and Pharmacokinetics of Carfilzomib

One hour after the first intravenous injection of carfilzomib, the inhibitory effect of chymotrypsin-like activity can be monitored, and the sustained inhibitory effect of the proteasome can reach 48 hours. After the first treatment in the first course of treatment, the dose is 15mg/m, the inhibition of proteasome chymotrypsin-like activity of whole blood reaches 80%, and the inhibition of proteasome chymotrypsin-like activity of peripheral blood mononuclear cells (PBMCs) reaches 70%; the administration dose is 27mg/m, and the degree of inhibition of PBMCs proteasome chymotrypsin-like activity reaches 90%. Repeated administration can observe continuous chymotrypsin-like activity inhibition, and can inhibit the LMP2 and MecL1 subunits of immune proteasomes. The degree reached 30% and 40% respectively.

In clinical trials, a single dose of 27 mg/m of carfilzomib was administered intravenously, and the peak concentration Cmax and the area under the concentration-time curve AUC were 4232 and 379 ng/h·mL, respectively. Repeated administration of carfilzomib 15 and 27 mg/m, the AUC and half-life of the drug on the 1, 15, and 16 days of the first course of treatment are similar, suggesting that carfilzomib has no accumulation effect. AUC and Cmax increased disproportionately with the increase of carfilzomib dosage.

The steady-state volume of distribution of carfilzomib is large and varies greatly under different doses, suggesting that it is widely distributed in the tissues. Given this product 20mg/m, the average steady-state volume of distribution is 28L. Carfilzomib is rapidly metabolized in the body and can produce 21 kinds of metabolites. Among them, peptide fragments and the glycol of carfilzomib are the main metabolites, indicating that peptidase decomposition and epoxide hydrolysis are the main metabolic pathways. Cytochrome P450 metabolic pathway plays a small role in the entire metabolic process of carfilzomib. The plasma clearance rate is greater than the hepatic blood flow rate, suggesting the existence of extrahepatic metabolic pathways. The product has a half-life of 0.29~0.48h, no accumulation in the body, and rapid elimination ensures the safety of medication.

Interactions between Carfilzomib

Because the P450 metabolic pathway plays a small role in the metabolism of carfilzomib, taking P450 inhibitors or inducers at the same time does not change its metabolic properties. In vitro studies have shown that carfilzomib inhibits human liver CYP3A and can reduce the gene expression of CYP3A and 1A2, but it does not affect the drug interaction clinically. Midazolam is a substrate of CYP3A, but carfilzomib does not affect the metabolism of midazolam. Carfilzomib is a substrate of P-glycoprotein (P-gp), but it does not interact with P-gp inhibitors or inducers.

In clinical trials conducted so far, there are no restrictions on the use of combined drugs, including inducers or inhibitors of cytochrome P450. Based on the metabolic pathways of carfilzomib and the results of clinical trials, it is predicted that there will be no significant drug interactions. Continued clinical experience will help confirm this prediction.