Lumacaftor-Ivacaftor: A Detailed Overview

Overview:

Cystic fibrosis (CF) is an autosomal recessive condition brought on by mutations in the CF transmembrane conductance regulator (CFTR) protein-encoding gene on the long arm of chromosome 7. This protein functions as a passive chloride ion transporter across the surface membranes of epithelial cells in response to concentration gradients. It is controlled by cyclic adenosine monophosphate. The flow of bicarbonate and nearby sodium channels may also have significant interactions with it, although understanding these connections still needs improvement. Remarkably, the absence of this protein channel causes such a severe disease that shortens lifespan.

Patients with cystic fibrosis (CF) who are 12 years of age or older and have two copies of the F508del gene mutation can receive treatment with ORKAMBI. The primary cause of cystic fibrosis (CF) is having two copies of this mutation, one from each parent. A dangerous genetic condition called cystic fibrosis (CF) causes the body to produce excessive amounts of mucus, which accumulates in the lungs and other organs. This may result in serious respiratory issues.

For Patients:

Why Is Lumacaftor-Ivacaftor Recommended?

Lumacaftor and Ivacaftor are used to treat some forms of cystic fibrosis, an inborn disorder that impairs breathing, digestion, and reproduction in adults and children one year of age and older. Lumacaftor belongs to a class of medications called cystic fibrosis transmembrane conductance regulator (CFTR) correctors. Ivacaftor is a member of the class of medications known as cystic fibrosis transmembrane conductance regulators, or CFTR potentiators. By improving a protein's activity in the body, both of these medications lessen the accumulation of sticky mucus in the lungs and relieve other symptoms associated with cystic fibrosis.

How Is Lumacaftor-Ivacaftor To Be Taken?

Lumacaftor and Ivacaftor are sold separately as tablets and granules for oral use.

It is often taken twice daily, separated by 12 hours, along with fatty foods. Every day, take ivacaftor and Lumacaftor at around the same time. Ask the doctor or chemist to explain any instructions on the prescription label that one needs clarification on. Ivacaftor and Lumacaftor should be taken as prescribed. Never take it in larger or smaller amounts or more frequently than directed by the doctor.

A teaspoon (5 mL) of a soft food or beverage (cold or at room temperature), such as yogurt, applesauce, pudding, milk, or juice, should be mixed with the full packet of Lumacaftor and Ivacaftor granules to produce a dose. Consume the entire mixture within an hour after combining the granules with food or a beverage.

Eat fatty meals like eggs, avocados, almonds, butter, peanut butter, cheese, milk, and other milk products like cheese and yogurt while taking Lumacaftor and Ivacaftor. Discuss alternative fatty foods while taking Ivacaftor and Lumacaftor with the doctor. Cystic fibrosis is not cured but is controlled by Ivacaftor and Lumacaftor. Even if one feels better, keep taking Ivacaftor and Lumacaftor. Consult the doctor before discontinuing taking Ivacaftor and Lumacaftor. Wait to start retaking Lumacaftor or Ivacaftor until one has spoken to the doctor after a break of seven days or more. The dosage of this drug or other medications one is taking may need to be changed by the doctor.

Other Uses for Lumacaftor-Ivacaftor:

Ask the doctor or chemist for more details if one believes this drug should be used for something else.

What Specific Safety Measures Should One Take?

Before using Ivacaftor and Lumacaftor,

• If one has any allergies, including any of the chemicals in Lumacaftor and ivacaftor pills or granules, notify the doctor and chemist immediately. Request a list of the ingredients from the chemist.

• When using Lumacaftor and Ivacaftor, let the doctor and chemist know about any medications one is now taking or plans to take. The physician might need to adjust the dosage of the drugs or keep a close eye on one for side effects. Lansoprazole, Omeprazole, and Ranitidine, which are available over-the-counter or as herbal supplements, may interact with Lumacaftor and Ivacaftor tablets. Before using Lumacaftor and Ivacaftor pills, inform the doctor and chemist that one is taking these prescriptions. If one is currently using ivacaftor and Lumacaftor, one should talk to the doctor before starting either of these medications.

• Inform the doctor if one currently has previously had a liver or renal illness, breathing issues or disorders, or organ transplantation.

• It is important to be aware that hormonal contraceptives, such as birth control pills, patches, rings, injections, implants, or intrauterine devices, may become less effective when taken with Lumacaftor and Ivacaftor. During the Lumacaftor treatment, discuss with the doctor additional forms of birth control that will be effective for one.

• Inform the doctor if one is expecting, intends to get pregnant, or is nursing a baby. Call the doctor if one gets pregnant while taking ivacaftor and Lumacaftor.

What Specific Dietary Recommendations Should One Abide By?

During the first week of treatment with Lumacaftor and ivacaftor, avoid eating or drinking grapefruit. Keep eating normally unless the doctor instructs otherwise.

How Should One Proceed if One Forgets to Take a Dose?

Take the missed dose as soon as one remembers it if it has been more than six hours since the usual dose. However, omit the missed dosage and carry on with the regular dosing plan if more than six hours have passed since the time one typically takes Ivacaftor and Lumacaftor. Do not take a second one to make up for a missing dose.

What Negative Effects Might Lumacaftor-Ivacaftor Have?

Ivacaftor and Lumacaftor could have negative side effects. Notify the doctor straight away if any of the given below symptoms are severe or persist:

• Breathing difficulty.

• Diarrhea.

• Bloating.

• Extreme fatigue.

• Rash.

• Irregular, missing, painful, or heavy periods, especially among hormonal contraception users.

• Cough, sore throat, runny nose, sneezing, or other flu-like symptoms.

• Headache.

Some adverse effects can be very harmful. Call the doctor right away if any of these symptoms occur:

• Nausea.

• Vomiting.

• Reduced appetite.

• Stomach ache in the top right corner.

• Dark feces.

• Confusion.

• Eyes or skin that have a yellow tint.

Children and teenagers who use Ivacaftor and Lumacaftor may develop cataracts, a clouding of the eye's lens that can impair vision. Children should be treated with utmost respect. The hazards of administering the child Ivacaftor and Lumacaftor should be discussed with the child's doctor. Ivacaftor and Lumacaftor could bring on other adverse effects. If one experiences strange issues while taking this medicine, contact the doctor immediately.

What Should One Be Aware of About the Handling and Disposal of Lumacaftor-Ivacaftor?

This drug should be kept out of children's reach and securely closed in its original container. Store it at room temperature and keep it away from the bathroom and other areas that receive a lot of moisture or heat.

It's important to dispose of unused prescriptions properly to keep them out of the hands of children, pets, and other people. But this medicine shouldn't be flushed down the toilet. Rather, the best way to get rid of medications is through a program called medicine take-back. Speak with the city's recycling and rubbish department or chemist to learn about take-back programs in the region.

What Additional Details Should One Be Aware of?

• Keep all of the appointments with the physician and the lab. Before one starts therapy, the doctor will run a lab test to determine whether Lumacaftor and Ivacaftor are appropriate treatments for the illness.

• To monitor the body's reaction to Lumacaftor and Ivacaftor, the doctor will also prescribe several lab tests before and during the therapy.

• While one is taking this medicine, one should have the blood pressure monitored frequently.

• No one else should take the medication. Any queries one may have regarding prescription refills should be directed to the chemist.

• One should keep a written record of all the prescription and nonprescription (over-the-counter) medications one is taking, as well as any supplements one may be taking, such as vitamins, minerals, or herbal remedies.

For Doctors:

Medical Use:

Patients with cystic fibrosis who have two copies of the F508del mutation in the disease-causing protein cystic fibrosis transmembrane conductance regulator (CFTR) are treated with Lumacaftor and Ivacaftor. About half of Canadian cases of cystic fibrosis have this genetic defect. In the UK, as of 2018, its use is not advised for anyone with cystic fibrosis.

Although the medicine improved a person's ability to exhale air in one second, the improvement did not amount to a clinically significant amount. Additionally, it does not seem that the drug affects a person's quality of life or how frequently their lung function deteriorates each year.

Adverse Effects:

The combination medicine should be used with caution in patients with advanced liver disease, and liver function should be monitored for the first three months in all patients starting the combination drug because some people taking it had increased transaminases.

Some children who took the combo medicine acquired cataracts, and those starting the combination had respiratory discomfort. Hormonal contraceptives may be affected by Ivacaftor and Lumacaftor. If the patient takes a medication that inhibits CYP3A, the dosage of the combination drug should be decreased, and inducers of CYP3A should not be administered concurrently.

Mechanism Of Action:

Lumacaftor increases the quantity of CFTR proteins delivered to the cell surface and acts as a chaperone during protein folding. The F508del mutation causes the CFTR protein to misfold; once created, these proteins are rapidly destroyed by cells. One CFTR potentiator that is already on the cell surface is called ivacaftor. By doing this, there is a greater chance that the defective channel will be open, allowing chloride ions to enter the channel pore. The two drugs function well together.

Physical Characteristics:

A white to off-white powder, essentially insoluble in water, is what Lumacaftor and Ivacaftor both come in. One pill containing 200 mg (milligrams) of Lumacaftor and 125 mg of Ivacaftor makes up the combo medication.

Pharmacology:

Mechanism of Action

Lumacaftor:

CFTR Corrector: Corrects the F508del-CFTR protein's processing and trafficking deficiency to allow it to reach the cell surface, where the CFTR potentiator ivacaftor can further improve the CFTR protein's ion channel activity.

Ivacaftor:

CFTR Augmentation: Ivacaftor allows enhanced chloride transport by potentiating the channel-open probability (or gating) of mutant CFTR proteins, chloride channels found at the surface of epithelial cells in several organs.

Indicated for the CFTR gene mutations R117H, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R.

Absorption:

Foods High in Fat: When Lumacaftor or Ivacaftor was supplied with foods high in fat, exposure to Lumacaftor was around two times higher, and exposure to Ivacaftor was about three times higher than when taken while fasting.

Maximum Plasma Concentration: 25 mcg/mL of Lumacaftor.

Ivacaftor Dosage: 0.502/mcg.

AUC:

• 198 mcg/hr/mL for Lumacaftor.
• 3.66 mcg/hr/mL Ivacaftor.

Distribution: 86 L (Lumacaftor) of Vd.

Bound to Proteins: 99 percent of Lumacaftor is converted to albumin.

Ivacaftor: 99 percent; mostly to albumin and alpha 1-acid glycoprotein.

Metabolism:

Lumacaftor: Little to no metabolization.

Ivacaftor is extensively metabolized to the main metabolites M1 and M6, primarily by CYP3A.

Half-life: 25.2 hours for Lumacaftor.

Ivafax: 9.34 hours.

Clearance:

• 2.38 L/hr for Lumacaftor.
• 24.1/hour for Ivacaftor.

Excretion

Lumacaftor: 51 percent of feces (unchanged); 8.6 percent of urine.

Ivacaftor: 6.6 percent in urine and 87.8 percent (as metabolites) in feces.

Pharmacogenomics:

It is recommended only for people who are homozygous for the CFTR gene mutation F508del. An FDA-approved CF mutation test should be done to find the F508del mutation if the patient's genotype is unknown.

Administration:

Administration by mouth.

• Take along with fat foods, such as whole-milk dairy products (cheese, yogurt, eggs, avocados, almonds, butter, and peanut butter). Oral granules should be combined with one teaspoon (5 mL) of age-appropriate soft food or liquid; then, the entire mixture should be eaten. Soft foods include puréed fruits, flavored yogurt or custard, milk or juice.

• Food must be served at or below room temperature.

• Each packet is only intended for one use.

• After mixing, consume within an hour; the mixture will remain stable for an hour.

Untaken Dosages:

Take the medication within six hours with a meal high in fat.

If more than six hours have passed, leave out that dose and resume the regular schedule for the next dose.

Conclusion:

While Lumacaftor-Ivacaftor has been a groundbreaking treatment for CF, the next generation of CFTR modulators will take its place. Tezacaftor has already been used instead of Lumacaftor in the medication Symdeko/Symkevi, together with ivacaftor. Studies are ongoing in lower age groups, and this medication is now approved for use in CF patients 12 years of age and older. Despite having equal efficacy to Lumacaftor-Ivacaftor, this corrector-promoter medication combination seems to be more well-tolerated and has fewer adverse drug interactions. The medication combination of Lumacaftor-Ivacaftor is now used in innovative triple treatments coupled with additional prospective corrector compounds. Recently concluded Phase III trials and published Phase II results demonstrate significantly higher efficacy for this triple therapy.