lumacaftor/ivacaftor

Action and Spectrum

Actions and Spectrum 

Action: 

lumacaftor: lumacaftor is a corrector agent that helps improve the function of the CFTR protein. It acts by assisting in the processing and trafficking of the defective CFTR protein to the cell surface, allowing it to reach the correct location where it can perform its function of regulating ion transport. 

ivacaftor: ivacaftor is a potentiator agent that enhances the function of the CFTR protein once it reaches the cell surface. It works by improving the chloride channel activity of the CFTR protein, thereby increasing the transport of chloride ions across the cell membrane. 

Spectrum:  

lumacaftor/ivacaftor is specifically indicated for the treatment of cystic fibrosis in patients who have two copies of the F508del mutation in the CFTR gene. This mutation is the most common cause of cystic fibrosis, accounting for a significant portion of CF cases.

Drug Interaction

Adverse Reaction

Frequency defined  

>10% 

Nasopharyngitis (13%) 

Diarrhea (12%) 

Dyspnea (13%) 

Nausea (13%) 

1-10% 

Rhinorrhea (6%) 

Fatigue (9%) 

Abnormal respiration (9%) 

Rash (7%) 

Increased blood CPK (7%) 

Menstrual abnormalities (10%) 

Upper respiratory tract infection (10%) 

Flatulence (7%) 

<1% 

Increased ALT or AST 

Hepatic encephalopathy 

Increased bilirubin 

Black Box Warning

Black Box Warning:  

None  

Contraindication / Caution

Contraindication/Caution:  

Hypersensitivity: The drug should not be used in individuals who have a known hypersensitivity or allergic reaction to any of its components. allergic reactions may manifest as rash, itching, swelling, dizziness, or difficulty breathing. 

Severe liver disease: Patients with severe liver disease or those with elevated liver enzymes should avoid using this drug. This medication can cause an elevation in liver enzymes, and severe liver disease may increase the risk of adverse effects.  

Use with certain medications: The drug can interact with other medications, leading to potentially harmful effects. It is important to consult with a healthcare professional about any other medications being taken, including prescription drugs, over-the-counter medications, and herbal supplements, to evaluate potential interactions. 

Pregnancy and breastfeeding: The safety of this drug in pregnancy and breastfeeding has not been well established. It is generally recommended to avoid its use during pregnancy and breastfeeding, unless the potential benefits outweigh the risks.

Pregnancy / Lactation

Pregnancy warnings:     

Pregnancy category: N/A 

Lactation: Excreted into human milk is unknown 

Pregnancy Categories:         

Category A: Studies that were well-controlled and met expectations revealed no risk to the fetus in either the first or second trimester. 

Category B: There were a lack of studies on pregnant women and no evidence of risk to the fetus in animal experiments.   

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 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:  

lumacaftor/ivacaftor is a combination medication used for the treatment of cystic fibrosis (CF) in patients who have specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It consists of two active ingredients: lumacaftor and ivacaftor. 

Pharmacodynamics:  

lumacaftor/ivacaftor is a combination therapy that consists of two drugs: lumacaftor and ivacaftor. lumacaftor acts as a corrector and is designed to improve the processing and trafficking of CFTR to the cell surface. It helps to overcome the defective protein folding and increases the amount of CFTR available for function. 

ivacaftor, on the other hand, is a potentiator that enhances the activity of CFTR at the cell surface. It improves the function of CFTR channels by keeping them open longer, allowing chloride ions to pass through and restore the transport of chloride and other ions across the cell membrane. 

The combination of lumacaftor and ivacaftor in lumacaftor/ivacaftor works synergistically to address the underlying defects in CFTR protein processing, trafficking, and function. lumacaftor helps correct the protein misfolding issues, leading to increased levels of CFTR at the cell surface, while ivacaftor enhances the activity of CFTR channels, allowing for improved chloride ion transport.   

Pharmacokinetics: 

Absorption 

The drugs are taken orally in the form of tablets. After oral administration, both drugs are rapidly absorbed from the gastrointestinal tract. Consuming food can enhance the absorption of lumacaftor, making it advisable to take the medication alongside a meal that contains fats. On the other hand, ivacaftor can be consumed with or without food. 

Distribution 

The drugs are extensively distributed throughout the body. They are highly protein-bound, with lumacaftor being approximately 99% protein-bound and ivacaftor being around 99.9% protein-bound. Both drugs have a relatively large volume of distribution, indicating their distribution into tissues beyond the bloodstream.  

Metabolism 

lumacaftor is primarily metabolized by the liver via the cytochrome P450 (CYP) enzyme system, primarily CYP3A. It undergoes extensive metabolism, resulting in multiple metabolites, some of which are pharmacologically active. ivacaftor is also metabolized by CYP3A enzymes, as well as other enzymes such as CYP2C9 and CYP1A2. The main metabolites of ivacaftor are inactive.  

Excretion and elimination 

The elimination of lumacaftor and ivacaftor and their metabolites primarily occurs via feces (approximately 87% for lumacaftor and 70% for ivacaftor) and to a lesser extent through urine (approximately 3% for lumacaftor and 1% for ivacaftor). The elimination half-life of lumacaftor is approximately 8 to 10 hours, while for ivacaftor, it is approximately 12 hours. 

Adminstartion

Administration:  

The administration of the drug typically involves taking tablets orally. The recommended dosage and treatment duration can vary depending on the individual’s age, weight, and specific CFTR gene mutations. It is essential to follow the prescribing doctor’s instructions and the medication’s package insert for the correct dosage and administration guidelines. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: lumacaftor/ivacaftor 

Why do we use lumacaftor/ivacaftor?   

Improved lung function: lumacaftor/ivacaftor can improve lung function in patients with CF by reducing mucus buildup and promoting better clearance of the airways. This may result in a reduction of respiratory symptoms, including coughing, wheezing, and difficulty breathing. 

Reduced exacerbations: CF patients often experience recurrent respiratory exacerbations, which are episodes of increased respiratory symptoms and worsening lung function. Studies have demonstrated the drug’s effectiveness in decreasing the occurrence of exacerbations and enhancing respiratory well-being. 

Enhanced weight gain: CF can impair the absorption of nutrients from the digestive system, leading to poor weight gain and malnutrition. The drug can improve the absorption of nutrients, resulting in better weight gain and overall nutritional status. 

Improved quality of life: By addressing the underlying cause of CF and improving lung function, The drug can have a significant positive response. It can reduce symptoms, decrease the need for hospitalizations, and allow for a more active and fulfilling lifestyle.