tucatinib

Action and Spectrum

Actions and Spectrum 

Tucatinib is a small molecule kinase inhibitor that selectively targets human epidermal growth factor receptor 2 (HER2) and her family members. It blocks the activity of HER2 and HER3 by inhibiting the phosphorylation of tyrosine residues on these receptors, which leads to the inhibition of downstream signaling pathways that drive cancer cell proliferation and survival.  

Tucatinib is approved for the treatment of advanced or metastatic breast cancer in patients with HER2-positive tumors who have received prior treatment with trastuzumab and taxane chemotherapy. It is typically used in combination with capecitabine and trastuzumab. Tucatinib has demonstrated activity in preclinical models of other HER2-positive cancers, including gastric, pancreatic, and ovarian cancer, but it is not approved for the treatment of these indications. 

Drug Interaction

Adverse Reaction

Frequency Defined  

>10%   

Decreased hemoglobin (59%)  

Increased bilirubin (47%)  

Nausea (58%)  

Decreased phosphate (57%)  

Increased ALT (46%)  

Hepatotoxicity (42%)  

Increased AST (43%)  

Decreased magnesium (40%)  

Decreased potassium (36%)  

Diarrhea (81%)  

Vomiting (36%)  

Increased creatinine (33%)  

Decreased sodium (28%)  

Stomatitis (32%)  

Increased alkaline phosphatase (26%)  

Anemia (21%)  

Decreased appetite (25%)  

Rash (20%)  

Increased creatinine (14%)  

Arthralgia (15%)  

Black Box Warning

Contraindication / Caution

Contraindications/ Cautions  

• Contraindications are none  
• Tucatinib is a medication that is used to treat breast cancer.    
• In patients with severe liver problems, as it has been known to cause severe hepatotoxicity.   
• It may also cause fetal harm and diarrhea, and therefore antidiarrheal treatment and diagnostic tests may be necessary in some cases.   
• It is a substrate for several enzymes and transporters in the body, including CYP3A4, CYP2C8, P-gp, and BCRP. It is also a reversible inhibitor of CYP3A4 and CYP2C8 and a time-dependent inhibitor of CYP3A4 and P-gp inhibitor.   
• Therefore, it can interact with other medications that are metabolized by these enzymes or transported by these transporters. For example, coadministration with strong CYP3A or moderate CYP2C8 inducers may decrease tucatinib plasma concentrations, which may reduce its efficacy.   
• Similarly, concomitant use of tucatinib with strong CYP2C8 inhibitors may increase tucatinib plasma concentrations, which may increase the risk of tucatinib toxicity.   
• Coadministration with sensitive CYP3A substrates or P-gp substrates may also lead to serious or life-threatening toxicities and may require dose adjustment.   
• It is important for patients taking tucatinib to inform their healthcare provider about all the medications they are taking to avoid potential drug interactions.

Pregnancy / Lactation

Pregnancy warnings:     

US FDA pregnancy category: N/A 

Lactation:   

Excreted into human milk is unknown  

Pregnancy Categories:         

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester.    

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women.   

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.     

Category D: adequate data available with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.     

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.     

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology:  

tucatinib is an oral, small molecule inhibitor of the tyrosine kinase HER2 (human epidermal growth factor receptor. It is used in the treatment of advanced or metastatic HER2-positive breast cancer in combination with trastuzumab and capecitabine.  

The mechanism of action of tucatinib is to block the activity of HER2, a protein that is overexpressed in certain types of cancer cells, including breast cancer cells. By inhibiting HER2, tucatinib may help to slow the growth and spread of cancer cells.  

Pharmacodynamics:  

The pharmacodynamics of tucatinib involve targeting HER2 signaling and inhibiting cancer cell proliferation and survival, as well as having anti-inflammatory effects.  

When tucatinib binds to HER2, it prevents the protein from activating and signaling for cell growth and division. This can halt the proliferation of cancer cells and potentially lead to cell death.  

Tucatinib has been shown to have activity against tumor cells that have developed resistance to other HER2-targeted therapies, such as trastuzumab and lapatinib.  

In addition to its anti-tumor effects, tucatinib has also been shown to have anti-inflammatory properties, which may contribute to its effectiveness in cancer treatment.   

Pharmacokinetics:  

Absorption  

tucatinib is a small molecule tyrosine kinase inhibitor that is specifically designed to inhibit the HER2 receptor. It is administered orally and is readily absorbed from the gastrointestinal tract. The maximum plasma concentration of tucatinib is achieved within 2-4 hours after oral administration.  

Distribution  

tucatinib has a moderate to low binding affinity to plasma proteins, with approximately 65% of the drug bound to plasma proteins. It is distributed widely throughout the body, including to the liver, spleen, and bone marrow.  

Metabolism   

tucatinib is metabolized in the liver by the cytochrome P450 enzyme system, with CYP3A4 being the major enzyme involved. The metabolism of tucatinib results in the formation of several active and inactive metabolites, including a metabolite known as M9, which is pharmacologically active.  

Elimination and excretion  

Elimination of tucatinib occurs mainly through the feces, with approximately 75% of the drug being excreted in this manner. The elimination half-life of tucatinib is approximately 6-9 hours. tucatinib, approximately 75% of the drug is excreted in the feces, with only 4.1% being excreted in the urine.  

Adminstartion

Administration:  

Capecitabine should be taken orally (by mouth) twice a day, within 30 minutes after a meal.  

Capecitabine and tucatinib can be taken simultaneously when used in combination.  

The tablets should not be chewed, crushed, or divided; they should only be swallowed whole.  

If a tablet is cracked, damaged, or otherwise not entire, do not take it.  

The tablets should be taken about 12 hours apart, at the same time each day. If you miss a dose or vomit after taking a dose, you should take the next dose at your usual scheduled time.  

Storage:  

Capecitabine and tucatinib should be stored at room temperature (20-25°C or 68-77°F), with excursions permitted to 15-30°C (59-86°F).   

They should be kept in the original container to protect them from moisture, and the cap should be replaced securely each time after opening. Do not discard the desiccant.  

Once opened, the tablets should be used within 3 months. Any unused tablets should be discarded 3 months after opening.  

Patient Information Leaflet

Patient information leaflet 

Generic Name: tucatinib  

Why do we use tucatinib? 

tucatinib is a type of medication that is used to treat certain types of cancer. It is a small molecule inhibitor of the protein tyrosine kinase HER2, which is overexpressed in many types of cancer, including breast cancer and colorectal cancer.  

By inhibiting the activity of HER2, tucatinib may help to slow the growth and spread of cancer cells. It is typically used in combination with other cancer treatments, such as chemotherapy or radiation therapy.