Nintedanib

Nintedanib is an tyrosine kinase inhibitor belonging to anticancer and antifibrotic agent

Nintedanib is used in the treatment of Idiopathic pulmonary fibrosis, Progressive pulmonary fibrosis and systemic sclerosis associated fibrosis

Food increases exposure and delays absorption. Absolute bioavailability: Approx 5%. Volume of distribution is about 1,050 L. Plasma protein binding: Approx 98%, mainly to albumin.

Nintedanib get initially metabolized in the liver via hydrolytic cleavage by esterases to a free acid moiety, BIBF 1202, then undergoes glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) enzymes; metabolized by CYP3A4 enzymes (minor) and get excreted Mainly via faeces (approx. 93%); urine (<1%). Terminal elimination half-life: 9-15 hours.

The onset of action of Nintedanib was Within 5 to 10 minutes.

The Duration of time for Nintedanib was within 12 hours.

The Tmax of Nintedanib is approximately 2-4 hours.

the Cmax of Nintedanib ranges from 0.7 to 1.4 mg/L or 0.7 to 1.4 µg/mL after oral administration.

Nintedanib shows common side effects like burning. stinging. increased nasal discharge. dryness inside the nose. sneezing. nervousness. nausea. dizziness.

Nintedanib is available in the form of capsules

Nintedanib is available in India, Germany, Canada, Italy, USA

Nintedanib inhibits multiple receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases (nRTKs), including platelet-derived growth factor (PDGFR alpha and PDGFR beta); fibroblast growth factor receptor (FGFR1, FGFR2, FGFR3); vascular endothelial growth factor (VEGFR1, VEGFR2, and VEGFR3); colony-stimulating factor 1 receptor (CSF1R); and Fms-like tyrosine kinase-3 (FLT3). Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts.

Nintedanib is available in the form of capsules.

Nintedanib is used in the treatment of Idiopathic pulmonary fibrosis, Progressive pulmonary fibrosis and systemic sclerosis associated fibrosis.

Nintedanib is an inhibitor of multiple receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases (nRTKs). It binds competitively to the ATP binding pocket of these receptors and blocks the intracellular signaling which is vital for the proliferation, migration, and transformation of fibroblasts involved in the pathology of pulmonary fibrosis.

Nintedanib is approved for use in the following clinical indications

• Idiopathic pulmonary fibrosis: Treatment of idiopathic pulmonary fibrosis.
• Progressive pulmonary fibrosis : Treatment of chronic progressive fibrosing interstitial lung diseases.
• Systemic sclerosis-associated interstitial lung disease: Indicated to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease.

• Idiopathic pulmonary fibrosis: Oral: 150 mg every 12 hours; maximum daily dose: 300 mg/day.
• Progressive pulmonary fibrosis: Oral: 150 mg every 12 hours; maximum daily dose: 300 mg/day.
• Systemic sclerosis-associated interstitial lung disease :

Missed dose: If a dose is missed, the next dose should be taken at the next scheduled time. Do not make up a missed dose.

Nintedanib is available in various strengths as 100 mg, 150 mg.

Nintedanib is available in the form of capsule.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute: No initial dosage adjustment necessary.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

ESRD: There are no dosage adjustments provided in the manufacturer's labeling .

• Dosage Adjustment in Hepatic impairment Patient

Hepatic impairment at baseline:

Mild impairment (Child-Pugh class A): Oral: 100 mg every 12 hours. If a patient does not tolerate 100 mg every 12 hours, consider treatment interruption or discontinue treatment to manage adverse reactions.

Moderate to severe impairment (Child-Pugh class B or C): Oral: Use is not recommended (exposure is increased in moderate impairment; has not been studied in severe impairment).

Hepatotoxicity during treatment:

AST or ALT >3 times to <5 times ULN (without signs of liver damage): Interrupt treatment or reduce dosage to 100 mg every 12 hours. Once liver enzymes have returned to baseline values after treatment interruption, reintroduce therapy at 100 mg every 12 hours; may be subsequently increased to 150 mg every 12 hours.

AST or ALT >5 times ULN or >3 times ULN with signs or symptoms of liver damage: Discontinue therapy.

Concerns related to adverse effects:

• Bleeding: May increase the risk of bleeding, especially epistaxis. Use in patients with known risk of bleeding only if the benefit outweighs the risk. Serious and non-serious bleeding events (some fatal) have been reported during post-marketing.

• Cardiovascular effects: Arterial thromboembolic events, including MI, have been reported. Use caution in patients at high cardiovascular risk, including in patients with known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.
• GI effects: Diarrhea, nausea, and vomiting may occur. Diarrhea occurred in over 50% of nintedanib-treated patients, and was generally of mild to moderate intensity and occurred within the first 3 months of treatment. Treat with appropriate supportive care (eg, adequate hydration, antidiarrheals, antiemetics); dose reduction and/or treatment interruption may be required. If GI effects do not resolve, discontinue treatment. In addition, nintedanib may increase the risk of GI perforation; cases of GI perforation (some fatal) have been reported during postmarketing. Use caution when treating patients who have had recent abdominal surgery, previous history of diverticular disease or who are receiving concomitant corticosteroids or NSAIDs; only use in patients at risk of perforation if the benefit outweighs the risk. It has been recommended to wait at least 4 weeks following abdominal surgery before initiating therapy (OFEV Canadian product monograph). Discontinue if perforation develops.
• Hepatic effects: Serious and non-serious cases of drug-induced liver injury (including severe liver injury with fatal outcome) have been reported. Hepatic effects usually occurred within the first 3 months of treatment. Elevations of ALT, AST, GGT, alkaline phosphatase, and bilirubin were usually reversible with dose modification or interruption. Risk may be increased in patients with a low body weight (<65 kg), Asian patients, female patients, and older patients. Obtain LFTs prior to initiation of treatment, at regular intervals during the first 3 months of treatment, and periodically thereafter or as clinically indicated. Monitor for clinical signs/symptoms of liver injury (eg, fatigue, right upper abdominal discomfort, dark urine, jaundice); if reported, promptly obtain LFTs. Dosage modifications or interruption may be necessary.
• Nephrotic range proteinuria: Proteinuria within the nephrotic range has been reported. Histological findings were consistent with glomerular microangiopathy with or without renal thrombi. Usually improved when treatment was discontinued; some cases of residual proteinuria did persist. Consider treatment interruption in patients with new or worsening proteinuria.

• Common Adverse effects:

Dermal ulcer, Weight loss, Abdominal pain, decreased appetite, diarrhea, nausea, vomiting, Increased liver enzymes, Fatigue.

• Less Common Adverse effects:

Acute myocardial infarction, arterial thrombosis, hypertension, Hypothyroidism, Urinary tract infection, Hemorrhage, Dizziness (6%), headache, Neuromuscular & skeletal: Back pain.

• Rare Common Adverse effects:

Pruritus, Skin rash, pancreatitis, proteinuria, thrombocytopenia, hepatoxicity.

Increased risk of gastrointestinal adverse effect with corticosteroids and NSAIDs. Increased plasma concentration with strong P-gp inhibitors (e.g. ketoconazole, erythromycin, ciclosporine). Decreased plasma concentration with strong P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin).

The common side effects of Nintedanib include the following Dermal ulcer, Weight loss, Abdominal pain, decreased appetite, diarrhea, nausea, vomiting, Increased liver enzymes, Fatigue.

Symptoms: Nasopharyngitis, gastrointestinal symptoms, increased liver enzymes.

Management: Supportive treatment.

Pharmacodynamic

Nintedanib is a small molecule kinase inhibitor that inhibits upstream kinase activity to ultimately inhibit lung fibroblast proliferation and migration, as well as signalling pathways that promote the proliferation and survival of endothelial and perivascular cells in tumour tissues.

Nintedanib poses a risk of drug-induced liver injury, especially within the first three months of therapy. Liver function tests should be conducted at baseline prior to beginning therapy, at regular intervals for the first three months of therapy, and as indicated thereafter in patients exhibiting symptoms of hepatic injury such as jaundice or right upper quadrant pain.

Pharmacokinetics

• Absorption: Food, increases exposure and delays absorption. Absolute bioavailability: Approx 5%. Time to peak plasma concentration: 2-4 hours.
• Distribution: Volume of distribution: 1,050 L. Plasma protein binding: Approx 98%, mainly to albumin.
• Metabolism: Initially metabolised in the liver via hydrolytic cleavage by esterases to a free acid moiety, BIBF 1202, then undergoes glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) enzymes; metabolised by CYP3A4 enzymes (minor).
• Excretion: Mainly via faeces (approx 93%); urine (<1%). Terminal elimination half-life: 9-15 hours.

• https://www.rxlist.com/dopram-drug.htm
• https://www.mims.com/india/drug/info/Nintedanib?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00561
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003846/