Pharmacokinetics and Side Effect Profile of Pirfenidone and Nintedanib
Metabolism of pirfenidone occurs primarily in the liver through the cytochrome (CYP) 450 CYP1A2 enzyme. Strong CYP1A2 inhibitors, such as the selective serotonin reuptake inhibitor fluvoxamine, should be avoided when taking pirfenidone. Concurrent use of moderate inhibitors of CYP1A2, including ciprofloxacin and amiodarone, should prompt consideration of a reduction in the dose of pirfenidone. Inducers of CYPA12, including cigarette smoking and omeprazole, may reduce effective levels of pirfenidone and should be avoided. Patients with mild or moderate hepatic dysfunction may be treated with pirfenidone, but require careful monitoring. Use of pirfenidone is contraindicated in severe (Child Pugh Class C) hepatic dysfunction. US prescribing information for pirfenidone states the drug can be used in those with renal dysfunction, but use is contraindicated in end-stage renal disease. No dose adjustments are required for age, sex, race, or body size. Patients being treated with pirfenidone require liver function testing prior to starting therapy, monthly for the first 6 months, and every 3 months thereafter.
Although generally well tolerated, pirfenidone may be associated with side effects, particularly gastrointestinal and skin-related adverse events. It is recommended that the drug be taken with meals to reduce the rate of absorption and possibly ameliorate gastrointestinal side effects. Spacing the ingestion of the three tablets between courses and use of pro-kinetic agents and proton-pump inhibitors may also help control adverse gastrointestinal side effects. Skin-related adverse events include photosensitivity reactions and skin rash. Patients taking pirfenidone should minimize direct exposure to sunlight, use sunscreen, and wear protective clothing when outdoors.
Nintedanib is metabolized by hepatocytes via ester cleavage to the metabolite BIBF 1202. This metabolism is largely independent of the CYP450 enzymes, although CYP3A4 has a minor role in the drug metabolism. Nintedanib is also a substrate of P-glycoprotein (P-gp), and drugs with effects on both P-gp and CYP3A4 activity may alter levels of the drug. Patients taking P-gp and CYP3A4 inhibitors (e.g. ketoconazole, erythromycin) should monitor for evidence of increased exposure to nintedanib and dose adjust or discontinue the drug if found. P-gp and CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, and St John's Wort) should be avoided as they decrease exposure to nintedanib. Patients with mild hepatic impairment (Child Pugh Class A) can be treated with nintedanib with close monitoring. Use is not recommended in moderate or severe (Child Pugh Class B or C) liver disease. No dose adjustment is required in mild or moderate renal insufficiency. The safety and efficacy of nintedanib in severe renal insufficiency has not been established.
Gastrointestinal side effects, including diarrhea, nausea, abdominal pain, and vomiting, were the most commonly reported side effects in the RCTs of nintedanib. Diarrhea affected over 60% of the patients in INPULSIS 1 and 2 receiving nintedanib. Most cases were mild to moderate, and less than 5% of patients discontinued the study drug due to diarrhea. Diarrhea can be addressed with antimotility drugs when it occurs, and is primarily limited to the first 3 months of treatment. Elevated liver transaminases occurred in 5% of patients in clinical trials of the drug. The majority (94%) had elevations less than 5× upper limit of normal and no cases of hepatic failure occurred. It is recommended that liver enzymes be checked prior to starting therapy, then monthly for 3 months, and every 3 months thereafter.
Arterial thromboembolic events occurred in 2.5% of patients treated with nintedanib versus 0.8% of placebo patients in clinical trials. Caution should be exercised if treating patients with known cardiovascular disease or significant risks factors. Drug discontinuation should be considered if patients have an acute myocardial infarction while on therapy. Increased bleeding was also reported in patients treated with nintedanib (10%) versus placebo (7%). The manufacturer recommends using nintedanib in patients at risk for bleeding only if the risks outweigh the benefits. We recommend avoiding nintedanib in patients on therapeutic anticoagulation or with a history of significant bleeding. Table 3 summarizes the recommended dosing and pharmacokinetics of each drug.