Nintedanib

Mechanism of Action

Nintedanib is a small molecule indolinone derivative that binds the tyrosine kinase receptors. The proposed mechanism of action is the restriction of neo-angiogenesis by inhibiting a number of growth factors such as *FGFR, VEGFR, PDGFR, CSF1R, and FLT3.[7] It was initially planned for use in non-small lung cancer treatment. Due to similarities in the growth factors involved in the pathogenesis of this cancer and pulmonary fibrosis, it was considered a potential treatment for IPF and studied.[8] Nintedanib competitively binds to the intracellular adenosine triphosphate (ATP) binding site of the growth factor receptors, preventing autophosphorylation and blocking downstream signaling cascades. In addition, nintedanib blocks non-receptor tyrosine kinases like Src and Lck directly, thereby preventing the activation of fibroblasts. As a result, Nintedanib ultimately inhibits fibroblast proliferation and migration, effectively attenuating angiogenesis within the lungs. This reduction in fibrosis and angiogenesis helps to impede the advancement of ILD, IPF, and associated complications such as pulmonary hypertension.

*FGFR: Fibroblast growth factor receptor; VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet-derived growth factor receptor; CSF1R: Colony-stimulating factor-1-receptor; FLT3: Fms-like tyrosine kinase-3.

Administration

Nintedanib therapy is available in soft capsules with 100 mg and 150 mg dosages. 

The manufacturer's recommendation is for the capsule to be taken whole with food and fluids. Chewing, crushing, or splitting the capsules can cause a bitter taste. The typical recommended dosage is 150 mg twice daily. 

In cases of mild hepatic impairment (Child-Pugh class A), low body mass index (BMI), or persistent gastrointestinal side effects, a dose reduction to 100 mg twice daily is recommended.[9] If a dose is missed or skipped, continuing the routine schedule is advised. It is not recommended to take extra capsules to make up for the missed dose.

The drug should be kept tightly closed in the same container it came in and out of reach from children. Nintedanib should be stored at room temperature, away from moisture and excessive heat. Disposal of nintedanib should be done safely, ensuring that children, pets, or other people do not have access to the disposed-of capsules. The best way of drug disposal is through a medication take-back program at a local pharmacy. 

Precaution should be taken when nintedanib is co-administered with medications metabolized by CYP3A4 and P-glycoprotein enzymes due to altered bioavailability and metabolism.[10] Some commonly used drugs that may potentially affect nintedanib metabolism include but are not limited to omeprazole, barbiturates, phenytoin, amoxicillin, azithromycin, ketoconazole, carbamazepine, amiodarone, rifampin, and St. John's wort.

Adverse Effects

Nintedanib has been reported to have the following side effects in clinical studies:

• Gastrointestinal-related side effects were most common, including nausea (31%), vomiting (23%), diarrhea (76%), abdominal pain (10%), and decreased appetite (10%).
• Hepatic impairment was commonly seen with elevation in liver enzymes.
• Endocrinological - decreased weight (7%)
• Respiratory - nasopharyngitis (7%), cough (14%), upper respiratory tract infection (14%)
• Nervous system - headache (12%), fatigue (14%)
• Dermatological - dermal ulcer (16%)
• Genitourinary - urinary tract infection (12%)[11]

The majority of diarrheal events were classified as mild to moderate and occurred mainly within the first three months of therapy. Patient education and supportive treatment such as adequate hydration, antidiarrheals, and antiemetics should be provided when appropriate. A dose reduction or treatment interruption should be considered in patients with persistent gastrointestinal symptoms despite being on supportive treatment, or treatment should be discontinued.[9] The major risk factor for diarrhea is a low BMI, and adding prednisolone was found to be beneficial. In addition, low BMI and poor performance status were also significant risk factors for nausea.[12][13] Elevated alanine transaminase (ALT), aspartate transaminase (AST), and bilirubinemia were more commonly seen in patients with low BMI. These side effects are particularly common in females, Asians, and those who weigh less than 65 kilograms. The risk of hepatotoxicity is reduced when treated with a lower dose of 100 mg twice daily.[14] When taken together, before the initiation of nintedanib, careful consideration and assessment of these risk factors should be made.

Post-marketing adverse events that have been reported include gastrointestinal perforation, proteinuria, and pancreatitis. In several clinical trials, nintedanib was also found to be associated with an increased risk of bleeding, likely secondary to VEGFR inhibition. Although severe bleeding and arterial thromboembolic events such as myocardial infarction (MI) and stroke were rare, bleeding events with serious and fatal outcomes have been reported in the post-marketing surveillance of the drug.[15] As a result, patients on nintedanib therapy receiving full anticoagulation require close monitoring for adverse bleeding events.[16]

The inhibition of VEGFR and its downstream signaling pathways were also associated with renal dysfunction, including proteinuria and hypertension. Several cases of proteinuria and thrombotic microangiopathy have been described in the literature related to the chronic use of nintedanib.[17] The proteinuria was reversible with the discontinuation of nintedanib only in some cases. Interruption of therapy should be considered in cases of new, worsening, or persistent proteinuria.

Contraindications

The use of nintedanib during pregnancy and lactation is not recommended.[15]

Nintedanib is pregnancy category D, and females of reproductive age should be counseled to use highly effective contraception (for example, reversible implantable contraceptive device) before starting the medication and during therapy. Contraception should be continued for at least three months after the last dose of nintedanib. A Pregnancy test should be performed before and at regular intervals during treatment. 

The excretion of the drug in breast milk is not defined, but breastfeeding while on this therapy is not recommended. 

Moderate to severe hepatic impairment (Child-pugh class B and C) is also a relative contraindication to nintedanib therapy.[15] Nintedanib is not well studied in cases of severe hepatic disease population. Tobacco use is associated with reduced efficacy of nintedanib, so patients should be advised to stop smoking before initiating treatment. 

Caution should be exercised in female patients over 65 years of age with low body mass index(BMI) and in those patients with coronary artery disease, thromboembolic events, anticoagulation, recent abdominal surgery, and a history of gastrointestinal perforation. The safety profiles of nintedanib therapy in adolescents, children, or infants have not been established.

Monitoring

Pregnancy testing before the initiation of therapy and periodically during the therapeutic course is recommended in females of the reproductive age group. 

A liver function test is necessary at baseline and within the first three months of therapy initiation. After which, regular monitoring should be performed at least every 6 to 12 months or as clinically indicated.[9] Physicians should take precautionary measures in patients at high risk of bleeding and those with a history of arterial thromboembolism. Patients with signs and symptoms of acute coronary syndrome should undergo treatment interruption.[18]

The optimal time to assess treatment response is not well defined. Clinicians should perform routine monitoring with pulmonary function tests (PFT), 6-minute walk tests (6MWT), home spirometry, as well as subjective exercise tolerance and physical exam findings.[19] 

Changes in the patient's clinical condition may reflect superimposed infection, malignancy, or even the development of pulmonary artery hypertension and not just the progression of the underlying ILD.[20] Reevaluation of patients should occur if there are changes in the clinical status, which may involve repeating tests such as high-resolution computed tomography (HRCT), other imaging tests, and PFT. 

Quantitative HRCT is also a sensitive tool used to quantify the disease progression and response to treatment in SSc-ILD.

Toxicity

The standard dose of nintedanib therapy is 150 mg every 12 hours. There are no recommended guidelines for managing overdose. Any patient with a suspected overdose should undergo close monitoring in a healthcare facility. Nintedanib has a high protein binding ability (approximately 98%), predominantly to albumin, with a bioavailability of around 5%.[10] The nintedanib molecule is primarily metabolized by hydrolytic ester cleavage, resulting in subsequent glucuronidation by the liver and excreted mainly in the feces, with around <1% excreted in the urine. It is also a substrate and weak inhibitor of P-glycoprotein and a minor substrate of CYP3A4. The tolerability of nintedanib therapy should be closely monitored in patients receiving concomitant P-gp and CYP3A4 inhibitors.[10]

Nintedanib therapy is frequently associated with elevated liver enzymes and bilirubin, but this is usually reversible with dose reduction or treatment interruption. For patients with ALT/AST elevation less than 3 to 5 times the upper limit without signs of hepatotoxicity, it is recommended to hold the therapy and resume at a lower dose of 100 mg twice daily once the liver enzymes normalized. Treatment should be discontinued in patients who develop signs and symptoms of hepatotoxicity with AST/ALT elevation more than 3 to 5 times the normal upper limit.[16] No dose adjustment is needed for creatinine clearance (CrCl) of less than 30 ml/min. However, safety and efficacy have not been evaluated in patients with CrCl of less than 30 ml/min.[21] 

Female patients with low BMI, low body surface area (BSA), and Asian ethnicity are at higher risk of hepatotoxicity when treated with doses of 150 mg twice daily. This is reversible with treatment interruption or dose reduction.[14] Such patients may also benefit from starting at 100 mg twice daily, with dose titration, if there is no hepatotoxicity.

Enhancing Healthcare Team Outcomes

Treatment of progressive fibrosing ILD remains challenging for healthcare providers, and these patients have significant unmet needs. ILD can lead to the continued deterioration of lung function, reduced exercise tolerance, worsening dyspnea, and cough. These changes can result in reduced health-related quality of life (HR-QOL), increased morbidity and mortality, and some diseases with ILD have a median survival rate as low as 4.5 years.[22][23][24] 

Over the last decade, anti-fibrotic drugs such as nintedanib and pirfenidone have become the emerging therapy for IPF. Other conditions associated with progressive ILD have also shown promising results in slowing the progression of the disease. When used alone or in combination, the safety and tolerability of these medications are well established, although more studies are needed to determine the degree of the potential synergistic effect.[25] Nintedanib is an anti-fibrotic drug that has been proven to slow the course of progressive ILD, IPF, and SSc-ILD in well-designed clinical trial settings. In real-world studies, nintedanib's efficacy and safety profile are acceptable, and the FDA approved its use in the disease pattern mentioned above.[26]

Patient education is crucial and should be included in the provider's management tool kit. The pros and cons of this therapy, as well as supportive care, should be discussed with patients in detail. Adjunctive treatments, including oxygen therapy, should be prescribed to maintain daily activity and prevent or delay the onset of secondary pulmonary hypertension. Pulmonary rehabilitation has been shown to have long-term benefits as it emphasizes the importance of a comprehensive therapeutic approach to fibrotic lung disease.[27] 

A multidisciplinary team, including a pulmonologist, rheumatologist, cardiologist, and pulmonary rehabilitation medicine specialist, should be involved in patient care to prevent long-term complications. Although more studies are needed, such an approach may delay disease progression and reduce the need for lung transplantation. ILD is also a risk factor for ischemic heart disease.[28] Studies have shown that nintedanib can lower oxidative LDL-triggered inflammation and senescence, making it a potential therapy for treating atherosclerosis.[29]

Interprofessional teamwork is also essential to optimal patient management and care. In addition to the multidisciplinary physician team, mid-level practitioners (NPs and PAs), nursing staff, respiratory therapists, and pharmacists can all contribute from various areas of expertise to manage cases using nintedanib. All interprofessional team members must maintain meticulous records of their interactions and observations with the patient so all team members operate from the same accurate, updated information. If any caregiver notes any concerns or changes in status, they should reach out to the appropriate team member(s) for further evaluation and possible interventions. This interprofessional approach will drive optimal patient outcomes. [Level 5]

Patients should be encouraged to get approved vaccines against coronavirus, age-appropriate pneumococcal vaccine, and annual influenza vaccine. Continuous exposure to first-hand and second-hand smoking is detrimental and should be discouraged. There is also a strong association between ILD and depression is independently related to sleep quality, pain, and forced vital capacity.[30] Patients with ILD should routinely have screening for depression during follow-up visits. Recent observations suggest that nintedanib may improve functional ability in patients with pulmonary fibrosis secondary to COVID-19 infection.[31] 

In patients with progressive IPF not amenable to pharmacological therapy, the introduction of advance directives and palliative care should be considered as the prognosis remains guarded.[32] Prompt initiation of nintedanib from the time of diagnosis of IPF may result in reduced medical costs and hospitalization risk.[33] Additional studies are needed to fully understand the early initiation of anti-fibrotic therapy in patient outcomes.