Nintedanib is predominantly metabolized via hydrolytic cleavage by esterases to its principle metabolite, BIBF 1202, which then undergoes glucuronidation via UGT enzymes in the intestines and liver (specifically UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10) to form BIBF 1202 glucuronide. The CYP450 enzyme system plays a minor role in nintedanib metabolism, with CYP3A4 believed to be the main contributor - the major CYP-dependent metabolite of nintedanib, a demethylated metabolite termed BIBF 1053, could not be detected in plasma during pharmacokinetic studies and was found only in small quantities in the feces (approximately 4% of total dose). CYP-dependent metabolism of nintedanib accounts for roughly 5% of total drug metabolism, as opposed to 25% for esterase cleavage. Other minor metabolites, M7 and M8, are found in very small quantities in the urine (0.03% and 0.01%, respectively), though their origin and relevance is currently unclear.
The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.
Experience with nintedanib overdose is limited, but patients who inadvertently received higher-than-intended doses during initial trials experienced adverse effects consistent with the known safety profile of nintedanib, for example elevated liver enzymes and significant gastrointestinal effects. There are no specific guidelines for the treatment of nintedanib overdose - in this case, therapy should be interrupted and general supportive measures employed as indicated.
IDENTIFICATION AND USE: Nintedanib is an antineoplastic agents and enzyme inhibitor used for the treatment of idiopathic pulmonary fibrosis (IPF) and cancer. HUMAN EXPOSURE AND TOXICITY: Adverse effects associated with nintedanib may include diarrhea, nausea, abdominal pain, elevated concentrations of hepatic enzymes, vomiting, decreased appetite, decreased weight, headache, and hypertension. Arterial thromboembolic events such as myocardial infarction have been reported in patients receiving nintedanib. In one case, a 64-year-old man with IPF had nintedanib added to his ongoing pirfenidone therapy. He developed dyspnea after 65 days and presented with hypoxemia after 68 days. He was diagnosed with an acute exacerbation of IPF. Nintedanib was temporarily discontinued and the acute exacerbation was successfully managed with intensive treatment. Nintedanib was safely and successfully restarted after treatment of the acute exacerbation. Based on findings from animal studies and its mechanism of action, the drug can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential. ANIMAL STUDIES: Two-year oral carcinogenicity studies of nintedanib in rats and mice have not revealed any evidence of carcinogenic potential. A study of male fertility and early embryonic development up to implantation in rats did not reveal effects on the male reproductive tract and male fertility. In female rats, nintedanib reduced fertility, including increases in resorption and post-implantation loss, at exposures below the maximum recommended human dose (MHRD) of 150 mg b.i.d. based on AUC. A decrease in the number and size of corpora lutea in the ovaries was observed in chronic toxicity studies in rats and mice. Nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits at less than and approximately 5 times the MRHD in adults. Nintedanib was negative for genotoxicity in the in vitro bacterial reverse mutation assay, the mouse lymphoma assay, and the in vivo rat micronucleus assay.
In large randomized controlled trials, serum enzyme elevations occurred in up to 14% of patients receiving nintedanib compared to 3% of controls. Aminotransferase values above 3 times the upper limit of normal (ULN) occurred in only 3% to 5% of patients (compared to
In a multiple dose study in Japanese patients with idiopathic pulmonary fibrosis (IPF), addition of nintedanib to ongoing pirfenidone therapy resulted in a 41 and 32% decrease in nintedanib peak plasma concentrations and area under the concentration-time curve (AUC), respectively, compared with nintedanib alone. Concomitant use of nintedanib and pirfenidone did not have an effect on the pharmacokinetics of pirfenidone. In this study, nausea and vomiting were reported more frequently with concomitant nintedanib and pirfenidone therapy compared with nintedanib alone; all adverse effects reported in the study were mild or moderate in severity.
Nintedanib may increase the risk of bleeding. The manufacturer states that patients receiving full-dose anticoagulation therapy should be monitored closely for bleeding; dosage adjustment of the anticoagulant may be necessary.
The absolute bioavailability of nintedanib is low at approximately 4.7%, likely owing to substantial first-pass metabolism and the effects of p-glycoprotein (P-gp) transporters. T<sub>max</sub> following oral administration is reached after approximately 2 hours in fasted patients and approximately 4 hours in fed patients, regardless of the food consumed. Administration of nintedanib following a high-fat, high-calorie meal resulted in an increase in C<sub>max</sub> by approximately 15% and an increase in AUC by approximately 20%. Age, body weight, and smoking status have been found to alter exposure to nintedanib, but these effects are not significant enough to warrant dose alterations.
Nintedanib is eliminated primarily via fecal and biliary excretion, with 93.4% of radio labelled nintedanib found in feces within 120 hours following administration. Renal clearance accounts for a small portion of nintedanib's elimination, approximately 0.65% of the total dose, and excretion of unchanged nintedanib 48 hours after oral and intravenous doses was 0.05% and 1.4%, respectively.
Nintedanib appears to follow biphasic disposition kinetics - the observed volume of distribution following intravenous administration is 1050 L, indicating extensive distribution into peripheral tissues. In rats, nintedanib was shown to rapidly and homogeneously distribute into peripheral tissues with the exception of the CNS, suggestive of an inability of nintedanib to cross the blood-brain barrier.
来源:DrugBank
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清除
Nintedanib的总血浆清除率大约为1390毫升/分钟，肾清除率为20毫升/分钟。
Nintedanib is has a high total plasma clearance of approximately 1390 mL/min and a renal clearance of 20 mL/min.
