Chemical formula: C₃₁H₃₃N₅O₄ Molecular mass: 539.625 g/mol PubChem compound: 9809715
Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth muscle cells). In addition Fms-like tyrosine-protein kinase (Flt)-3, lymphocyte-specific tyrosine-protein kinase (Lck) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.
Tumour angiogenesis is an essential feature contributing to tumour growth, progression and metastasis formation and is predominantly triggered by the release of pro-angiogenic factors secreted by the tumour cell (i.e. VEGF and bFGF) to attract host endothelial as well as perivascular cells to facilitate oxygen and nutrient supply through the host vascular system. In preclinical disease models nintedanib, as single agent, effectively interfered with the formation and maintenance of the tumour vascular system resulting in tumour growth inhibition and tumour stasis. In particular, treatment of tumour xenografts with nintedanib led to a rapid reduction in tumour micro vessel density, pericytes vessel coverage and tumour perfusion.
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) measurements showed an anti-angiogenic effect of nintedanib in humans. It was not clearly dose dependent, but most responses were seen at doses of ≥200 mg. Logistic regression revealed a statistically significant association of the anti-angiogenic effect to nintedanib exposure. DCE-MRI effects were seen 24-48 h after the first intake of the medicinal product and were preserved or even increased after continuous treatment over several weeks. No correlation of the DCE-MRI response and subsequent clinically significant reduction in target lesion size was found, but DCE-MRI response was associated with disease stabilization.
In in vitro studies using human cells nintedanib has been shown to inhibit processes assumed to be involved in the initiation of the fibrotic pathogenesis, the release of pro-fibrotic mediators from peripheral blood monocytic cells and macrophage polarisation to alternatively activated macrophages. Nintedanib has been demonstrated to inhibit fundamental processes in organ fibrosis, proliferation and migration of fibroblasts and transformation to the active myofibroblast phenotype and secretion of extracellular matrix. In animal studies in multiple models of IPF, SSc/SSc-ILD, rheumatoid arthritis-associated-(RA-)ILD and other organ fibrosis, nintedanib has shown anti-inflammatory effects and anti-fibrotic effects in the lung, skin, heart, kidney, and liver. Nintedanib also exerted vascular activity. It reduced dermal microvascular endothelial cell apoptosis and attenuated pulmonary vascular remodelling by reducing the proliferation of vascular smooth muscle cells, the thickness of pulmonary vessel walls and percentage of occluded pulmonary vessels.
Nintedanib reached maximum plasma concentrations approximately 2-4 hours after oral administration as soft gelatin capsule under fed conditions (range 0.5-8 hours). The absolute bioavailability of a 100 mg dose was 4.69% (90% CI: 3.615-6.078) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism. Nintedanib exposure increased dose-proportionally in the dose range of 50-450 mg once daily and 150-300 mg twice daily. Steady state plasma concentrations were achieved within one week of dosing at the latest.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (CI: 95.3-152.5%) and absorption was delayed (median tmax fasted: 2.00 hours; fed: 3.98 h).
In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolate pudding for up to 15 minutes did not have any impact on the pharmaceutical quality. Swelling and deformation of the capsules due to the water uptake of the gelatin capsule shell was observed with longer exposure time to the soft food. Therefore, taking the capsules with soft food would not be expected to alter the clinical effect when taken immediately.
Nintedanib follows at least bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution (Vss: 1 050 L, 45.0% gCV) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.869.
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 ADME study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.
In preclinical in vivo experiments, BIBF 1202 did not show efficacy despite its activity at target receptors of the substance.
Total plasma clearance after intravenous infusion was high (CL: 1 390 mL/min, 28.8% gCV). Urinary excretion of the unchanged active substance within 48 h was about 0.05% of the dose (31.5% gCV) after oral and about 1.4% of dose (24.2% gCV) after intravenous administration; the renal clearance was 20 mL/min (32.6% gCV). The major route of elimination of drug related radioactivity after oral administration of [14C] nintedanib was via faecal/biliary excretion (93.4% of dose, 2.61% gCV). The contribution of renal excretion to the total clearance was low (0.649% of dose, 26.3% gCV). The overall recovery was considered complete (above 90%) within 4 days after dosing. The terminal half-life of nintedanib was between 10 and 15 h (gCV% approximately 50%).
The pharmacokinetics of nintedanib can be considered linear with respect to time (i.e. single-dose data can be extrapolated to multiple-dose data). Accumulation upon multiple administrations was 1.04-fold for Cmax and 1.38-fold for AUCτ. Nintedanib trough concentrations remained stable for more than one year.
Drug-drug interactions between nintedanib and CYP substrates, CYP inhibitors, or CYP inducers are not expected, since nintedanib, BIBF 1202, and BIBF 1202 glucuronide did not inhibit or induce CYP enzymes in preclinical studies nor was nintedanib metabolized by CYP enzymes to a relevant extent.
Nintedanib is a substrate of P-gp. Nintedanib was shown to be not a substrate or inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2 in vitro. Nintedanib was also not a substrate of BCRP. Only a weak inhibitory potential on OCT-1, BCRP, and P-gp was observed in vitro which is considered to be of low clinical relevance. The same applies for nintedanib being a substrate of OCT-1.
In exploratory pharmacokinetic adverse event analyses, higher exposure to nintedanib tended to be associated with liver enzyme elevations, but not with gastrointestinal adverse events. PK-efficacy analyses were not performed for clinical endpoints. Logistic regression revealed a statistically significant association between nintedanib exposure and DCE-MRI response.
The pharmacokinetic properties of nintedanib were similar in healthy volunteers, cancer patients, and patients of the target population. Exposure to nintedanib was not influenced by gender (body weight corrected), mild and moderate renal impairment (estimated by creatinine clearance), liver metastases, ECOG performance score, alcohol consumption, and P-gp genotype.
Population PK analyses indicated moderate effects on exposure to nintedanib depending on age, body weight, and race (see below). Based on the high inter-individual variability of exposure observed in the clinical LUME-Lung-1 trial these effects are not considered clinically relevant. However, close monitoring is recommended in patients with several of these risk factors.
Exposure to nintedanib increased linearly with age. AUCτ,ss decreased by 16% for a 45-year old patient (5th percentile) and increased by 13% for a 76-year old patient (95th percentile) relative to a patient with the median age of 62 years. The age range covered by the analysis was 29 to 85 years; approximately 5% of the population were older than 75 years.
Based on the analysis of pharmacokinetic data of study InPedILD (1199.337), oral administration of nintedanib according to the weight-based dosing algorithm resulted in exposure within the range observed in adult patients. The observed geometric mean AUCτ,ss (geometric coefficient of variation) exposures were 175 ng/mL·hr (85.1%) and 167 ng/mL·hr (83.6%) in 10 patients aged 6 to 11 years old and 23 patients aged 12 to 17 years old, respectively.
An inverse correlation between body weight and exposure to nintedanib was observed. AUCτ,ss increased by 25% for a 50 kg patient (5th percentile) and decreased by 19% for a 100 kg patient (95th percentile) relative to a patient with the median weight of 71.5 kg.
The population mean exposure to nintedanib was 33-50% higher in Chinese, Taiwanese, and Indian patients and 16% higher in Japanese patients while it was 16-22% lower in Koreans compared to Caucasians (body weight corrected). Based on the high inter-individual variability of exposure these effects are not considered clinically relevant. Data from black individuals was very limited but in the same range as for Caucasians.
In a dedicated single dose phase I trial and compared to healthy subjects, exposure to nintedanib based on Cmax and AUC was 2.2-fold higher in volunteers with mild hepatic impairment (Child Pugh A; 90% CI 1.3-3.7 for Cmax and 1.2-3.8 for AUC, respectively). In volunteers with moderate hepatic impairment (Child Pugh B), exposure was 7.6-fold higher based on Cmax (90% CI 4.4-13.2) and 8.7-fold higher (90% CI 5.7-13.1) based on AUC, respectively, compared to healthy volunteers. Subjects with severe hepatic impairment (Child Pugh C) have not been studied.
In a dedicated pharmacokinetic study, concomitant treatment of nintedanib with pirfenidone was investigated in patients with IPF. Group 1 received a single dose of 150 mg nintedanib before and after uptitration to 801 mg pirfenidone three times a day at steady state (N=20 patients treated). Group 2 received steady state treatment of 801 mg pirfenidone three times a day and had a PK profiling before and after at least 7 days of co-treatment with 150 mg nintedanib twice daily (N=17 patients treated).
In group 1, the adjusted geometric mean ratios (90% confidence interval (CI)) were 93% (57% – 151%) and 96% (70% – 131%) for Cmax and AUC0-tz of nintedanib, respectively (n=12 for intraindividual comparison). In group 2, the adjusted geometric mean ratios (90% CI)) were 97% (86% – 110%) and 95% (86% – 106%) for Cmax,ss and AUCτ,ss of pirfenidone, respectively (n=12 for intraindividual comparison). Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when administered in combination.
In a dedicated pharmacokinetic study, concomitant treatment of nintedanib with bosentan was investigated in healthy volunteers. Subjects received a single dose of 150 mg nintedanib before and after multiple dosing of 125 mg bosentan twice daily at steady state. The adjusted geometric mean ratios (90% confidence interval (CI)) were 103% (86% – 124%) and 99% (91% – 107%) for Cmax and AUC0-tz of nintedanib, respectively (n=13), indicating that co-administration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.
In a dedicated pharmacokinetic study, female patients with SSc-ILD received a single dose of a combination of 30 μg ethinylestradiol and 150 μg levonorgestrel before and after twice daily dosing of 150 mg nintedanib for at least 10 days. The adjusted geometric mean ratios (90% confidence interval (CI)) were 117% (108% - 127%; Cmax) and 101% (93% - 111%; AUC0-tz) for ethinylestradiol and 101% (90% - 113%; Cmax) and 96% (91% - 102%; AUC0-tz) for levonorgestrel, respectively (n = 15), indicating that co-administration of nintedanib has no relevant effect on the plasma exposure of ethinylestradiol and levonorgestrel.
Exposure-response analyses of patients with IPF and other chronic fibrosing ILDs with a progressive phenotype, indicated a weak relationship between nintedanib plasma exposure and ALT and/or AST elevations. Actual administered dose might be the better predictor for the risk of developing diarrhoea of any intensity, even if plasma exposure as risk determining factor could not be ruled out.
Single dose toxicity studies in rats and mice indicated a low acute toxic potential of nintedanib. In repeat dose toxicology studies in rats, adverse effects (e.g. thickening of epiphyseal plates, lesions of the incisors) were mostly related to the mechanism of action (i.e. VEGFR-2 inhibition) of nintedanib. These changes are known from other VEGFR-2 inhibitors and can be considered class effects.
Diarrhoea and vomiting accompanied by reduced food consumption and loss of body weight were observed in toxicity studies in non-rodents.
There was no evidence of liver enzyme increases in rats, dogs, and Cynomolgus monkeys. Mild liver enzyme increases, which were not due to serious adverse effects such as diarrhoea, were only observed in Rhesus monkeys.
A study of male fertility and early embryonic development to implantation in rats did not reveal effects on the male reproductive tract and male fertility.
In rats, embryofoetal lethality and teratogenic effects were observed at exposure levels below human exposure, at the maximum recommended human dose (MRHD) of 200 mg b.i.d. Effects on the development of the axial skeleton and on the development of the great arteries were also noted at subtherapeutic exposure levels.
In rabbits, embryofoetal lethality was observed at an exposure approximately 8 times higher than at the MRHD. Teratogenic effects on the aortic arches in combination with the heart and the urogenital system were noted at an exposure 4 times higher than at the MRHD and on the embryofoetal development of the axial skeleton at an exposure 3 times higher than at the MRHD.
In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into the milk (≤0.5% of the administered dose).
Genotoxicity studies indicated no mutagenic potential for nintedanib.
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