Ibrutinib

Ibrutinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

The FDA approved Ibrutinib for treating chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia (WM), and chronic graft-versus-host disease (cGVHD).

Ibrutinib rapidly absorbs in the gastrointestinal tract, exhibiting 2.9% bioavailability with a peak time of 1-2 hours. It extensively distributes (volume: ~10,000 L, protein binding: 97%) and undergoes hepatic metabolism via CYP3A4, generating weakly active metabolites. The drug is primarily excreted in faeces (80%) and minimally in urine (10%), with a half-life ranging from 4 to 13 hours.

The most common side effects of Ibrutinib include bruising, muscle pain, diarrhea, and fatigue.

Ibrutinib is available as an oral tablet and capsule.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Ibrutinib is an antineoplastic agent belonging to the pharmacological class of tyrosine kinase inhibitors.

The inhibitor of Bruton's tyrosine kinase (BTK) is ibrutinib. The inhibition of BTK occurs when it forms a covalent bond with the cysteine residue (Cys481) in the active site. Ibrutinib inhibits the phosphorylation of downstream substrates like PLC-γ because it plays a part in the B-cell receptor signalling process.

Ibrutinib exhibits an AUC (area under the curve) value of 953 ng•hr/mL.

Ibrutinib reaches peak plasma concentration within 1-2 hours after administration.

Ibrutinib is available as an oral tablets and capsules.

Tablets/Capsules: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, with or without food.

Orally: Administer Ibrutinib orally once daily at approximately the same time. Swallow tablets or capsules whole with a glass of water; do not open, break, or chew them. When given with rituximab or obinutuzumab on the same day, consider administering Ibrutinib before. In case of a missed dose, take it as soon as possible on the same day and resume the regular schedule the following day. Do not take additional capsules or tablets to compensate for a missed dose.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Ibrutinib is available as an oral tablet.

420 mg PO qDay as monotherapy, in combination with rituximab, obinutuzumab, or bendamustine and rituximab (BR)

Continue until toxicity or disease progression becomes intolerable.

420 mg per day, PO

Proceed until the disease worsens or the level of toxicity is intolerable.

420 mg per day, PO

Continue until the progression of cGVHD, a recurrence of an underlying cancer, or the level of toxicity is intolerable.

Consider stopping therapy if it is no longer necessary, depending on the medical assessment of every individual.

While using Ibrutinib, refrain from consuming grapefruit or its juice to prevent potential drug metabolism issues. There are no specific dietary restrictions; maintain regular meals and emphasize adequate hydration. Quit smoking and alcohol consumption. Include green leafy vegetables, sweet potatoes, broccoli, tomatoes, carrots, mangoes, citrus fruits, berries, and cocoa. Prioritize hydration by drinking plenty of water, herbal tea, and vegetable and fruit juices. Avoid fast, fried, processed meats, refined carbs, and added sugar.

The dietary restriction should be individualized as per patient requirements.

Avoid grapefruit, maintain a healthy diet, quit smoking, and limit alcohol.

The adverse reactions related to Ibrutinib can be categorized as:

Hepatic failure, such as cirrhosis of the liver and/or acute and/or fatal events

Cardiac arrhythmias and cardiac failure, sudden death

Interstitial lung disease

Tumor lysis syndrome(TLS)

Anaphylactic shock, urticaria, and angioedema

Panniculitis, onychoclasis, Stevens Johnson Syndrome (SJS), and neutrophilic dermatoses

Hepatitis B reactivation

The clinically relevant drug interactions of Ibrutinib are briefly summarized here.

The common side effects of Ibrutinib include:

Nausea

Vomiting

Infection

Diarrhoea

Musculoskeletal (bone, muscle or joint) pain

Rash

Anaemia (low number of red blood cells)

Constipation

Headache

Fatigue

Dizziness

Mouth sores

Pregnancy Category D (FDA): Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.

Ibrutinib can cause fetal harm based on findings from animal studies; inform pregnant women of potential risk to the fetus; no data on use in pregnant women are available to inform a drug's association with a significant congenital disability and miscarriage risk.

In animal reproduction studies, Ibrutinib was administered to pregnant rats and rabbits during the organogenesis phase at exposures up to 3 to 20 times the clinical dose of 420 mg daily. This resulted in structural abnormalities in the embryofetal development.

Before starting treatment, test for pregnancy in reproductively capable females.

Females: Use reliable contraception during your course of treatment and for a month following your last dosage.

Males: Men should use effective contraception during treatment and for one month after the last dose if they have female partners who are capable of having children.

No information is available about the presence of ibrutinib or its metabolites in the human milk, the effects on a breastfed infant, or milk production. Women are advised not to breastfeed during treatment and for one week following the last dose due to the possibility of severe adverse reactions in breastfed children.

Studies on the effectiveness and safety of Ibrutinib in pediatric patients have shown both the drug's possible advantages and disadvantages in this demographic.

Recommended for patients aged one year or older with chronic graft versus host disease (cGVHD) who have not responded to more than one line of systemic therapy

For children aged 1 to under 12: 240 mg/m2 PO qDay (maximum 420 mg/dose)

12 years or older: 420 mg PO qDay

Continue until cGVHD worsens, an underlying cancer returns or the toxicity becomes intolerable.

If therapy is no longer necessary, consider stopping it per the patient's medical evaluation.

(eCrCl ≥25 mL/min): mild to moderate. No need to change the dosage

Patients on dialysis or those with severe (eCrCl <25 mL/min): Not studied

Unless the cause is non-hepatic or Gilbert's syndrome-related, adjust the dosage based on the subsequent ULN.

Total bilirubin (TB) level >1.5 to 3x ULN ≥1 to <12 years: Reduce to 80 mg/m2 PO qDay for children under 12 years old: Decrease to 140 mg PO qDay TB >3 times ULN: Do not use.

According to in vitro research, pro survival factors do not prevent CLL cells from undergoing apoptosis. Additionally, chemokine secretion, including CCL3 and CCL4, is reduced, cell migration is hampered, and CLL cell survival and proliferation are inhibited. The latter effect has been demonstrated to cause regression in xenograft mouse models.

In phase I and II clinical studies, the overall response rate for relapsed/refractory CLL was approximately 71%. About 70% of the patients who underwent testing had partial or complete responses in the case of relapsed or resistant mantle cell lymphoma. While a partial response was seen in over 75% of patients tested for Waldenstrom's macroglobulinemia, a partial response was found in 15-20% of patients studied in clinical trials for relapsed/refractory diffuse large B-cell lymphoma. Lastly, about 54% of patients with relapsed or resistant follicular lymphoma showed a partial to complete response to therapy.