Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers

Stopfer, Peter; Rathgen, Karin; Bischoff, Daniel; Lüdtke, Silke; Marzin, Kristell; Kaiser, Rolf; Wagner, Klaus; Ebner, Thomas

doi:10.3109/00498254.2010.545452

Cited by 72 publications

(116 citation statements)

References 18 publications

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“…BIBF 1202 ZW is subsequently glucuronidated by various uridine diphosphate glucuronosyltransferases (UGTs) in the intestine and by UGT1A1 in the liver to form BIBF 1202 glucuronide. Both nintedanib metabolites are excreted via the biliary system into the faeces [13]. This phase II study was conducted to determine the safety, tolerability and pharmacokinetics of nintedanib and its metabolites, alone and when added to ongoing pirfenidone therapy, in Japanese patients with IPF.…”

Section: Introductionmentioning

confidence: 99%

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis

et al. 2014

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A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis.50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo.Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone.In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. @ERSpublications Nintedanib had acceptable safety and tolerability in Japanese patients with IPF

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Section: Introductionmentioning

confidence: 99%

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis

et al. 2014

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“…Encouraging PFS data in OC have been reported (Table 2), and OS data for this indication are awaited [92]. Nintedanib is an orally available angiokinase inhibitor of VEGFR-1 to -3, PDGFR-a and -b, and FGFR-1 to -3, in addition to FLT-3 and Src [82,114,138]. Human tumor model studies show that nintedanib can reduce vessel density, vessel integrity, and tumor growth via effects on endothelial and smooth muscle cells, pericytes, and tumor cells [82].…”

Section: Current and Emerging Multitargeting Antiangiogenic Agentsmentioning

confidence: 99%

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

2015

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Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR‐2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet‐derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti‐VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors. Implications for Practice: Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF‐targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.

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“…The renal excretion plays a negligible role in Nintedanib elimination, as preclinical data showed that the major route of elimination of [C 14 ] Nintedanib is via fecal and biliar excretion, amounting to 93.4% of dose [31].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Nintedanib for Advanced Epithelial Ovarian Cancer: A Change of Perspective? Summary of Evidence from a Systematic Review

Barra

Laganà

Ghezzi

et al. 2018

Gynecol Obstet Invest

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Background/Aims: Epithelial ovarian cancer (EOC) is the sixth most commonly diagnosed cancer among women. Results with available therapies are far from being satisfactory and, therefore, current research is focusing on new anticancer drugs to improve the clinical response of these patients. Nintedanib is an oral multiple tyrosine kinases inhibitor, which targets angiogenesis. Considering the current scenario, the aim of this systematic review is to highlight the prevailing knowledge about pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of Nintedanib for the treatment of advanced EOC. Methods: We performed a systematic review of the literature, screening all available articles about the treatment of advanced EOC with Nintedanib, including phase I, II, and III trials. Results: Although in early phase clinical trials, Nintedanib has demonstrated anticancer activity and tolerability as monotherapy or in combination with carboplatin and paclitaxel. In the phase III trial AGO-OVAR 12, it obtained a modest improvement in progression-free survival (PFS) as first-line combination therapy for patients with advanced EOC. Interestingly, a PFS increase was observed in patients with non-high progression risk or low tumor burden. Conclusion: Despite the promising results, further studies are needed to evaluate Nintedanib efficacy in women affected by EOC.

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Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers

Cited by 72 publications

References 18 publications

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

Nintedanib for Advanced Epithelial Ovarian Cancer: A Change of Perspective? Summary of Evidence from a Systematic Review

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