Pharmacokinetic Properties of Nintedanib in Healthy Volunteers and Patients With Advanced Cancer

Dallinger, Claudia; Trommeshauser, Dirk; Marzin, Kristell; Liesener, André; Kaiser, Rolf; Stopfer, Peter

doi:10.1002/jcph.752

Cited by 42 publications

(59 citation statements)

References 16 publications

(40 reference statements)

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“…The small percentage of Nintedanib absorbed in the gut is partially due to transport proteins activity (such as P-glycoprotein) and the first-pass hepatic metabolism. Nintedanib is rapidly absorbed and it achieves the maximum plasma concentration (Cmax) within 1-3 h after oral administration [29]. After food intake, Nintedanib exposure increases by approximately 20% compared to administration under fasting conditions (90% CI 95.3-152.5%).…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Nintedanib is available as soft gelatin capsules of 100 and 150 mg. As summarized in Table 1, in a PK profile study in healthy volunteers, Nintedanib demonstrated a relative oral bioavailability of 4.7% (90% CI 3.62-6.08) [29]. The small percentage of Nintedanib absorbed in the gut is partially due to transport proteins activity (such as P-glycoprotein) and the first-pass hepatic metabolism.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Only a minor extent of the biotransformation of Nintedanib consisted of cytochrome (CYP) pathways, with CYP 3A4 being the predominant enzyme involved. Dallinger et al [29] demonstrated that Nintedanib metabolites after oral administration are higher than after IV administration probably because of hepatic first-pass metabolism. The glucuronidated form of the free acid has different PK characteristics compared with Nintedanib, presenting a late C max and a t 1/2 of 10 h. The free acid moiety has comparable PK characteristics compared with Nintedanib.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…The serum albumin is considered its major binding protein [30]. Following intravenous (IV) administration in healthy volunteers, this drug showed a total clearance of geometric mean (gMean) 1,390 mL/min and a volume of distribution of 1,050 L. The decline during the distribution phase was slower after oral administration than after IV administration [29].…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…It is noticeable that Nintedanib has limited drug-drug interaction potential, due to the minor role of CYP450 in its metabolism and the lack of induction or inhibition of this group of enzymes (IC50 > 50 μmol/L) by the drug [29]. In the phase I study by du Bois et al [25], authors investigated the effect of Nintedanib at 200 mg BID on the PK parameters of paclitaxel or carboplatin.…”

Section: Safety Tolerability and Toxicitymentioning

confidence: 99%

See 4 more Smart Citations

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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Section: Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Section: Safety Tolerability and Toxicitymentioning

confidence: 99%

See 3 more Smart Citations

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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Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases

Ferguson

Myerson

et al. 2023

Advanced NanoBiomed Research

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Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from alveoli due to their high perfusion. To solve this problem, the mechanisms by which nano‐scale drug carriers dramatically improve lung pharmacokinetics using an inhalable liposome formulation containing nintedanib, an antifibrotic for pulmonary fibrosis, are studied. Direct instillation of liposomes in murine lung increases nintedanib's total lung delivery over time by 8000‐fold and lung half life by tenfold, compared to oral nintedanib. Counterintuitively, it is shown that pulmonary surfactant neither lyses nor aggregates the liposomes. Instead, each lung compartment (alveolar fluid, alveolar leukocytes, and parenchyma) elutes liposomes over 24 h, likely serving as “drug depots.” After deposition in the surfactant layer, liposomes are transferred over 3–6 h to alveolar leukocytes (which take up a surprisingly minor 1–5% of total lung dose instilled) in a nonsaturable fashion. Further, all cell layers of the lung parenchyma take up liposomes. These and other mechanisms elucidated here should guide engineering of future inhaled nanomedicine for alveolar diseases.

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Why Collecting Pharmacokinetic Information After Intravenous Drug Administration Is Important

Hinderling¹,

Papoian²

2020

Clinical Pharm in Drug Dev

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Keywords absolute bioavailability, alternative study design, intravenous drug administration, micro-dose, model predictions, true PK parameters A new drug application (NDA) for a systemically active, new therapeutic entity (NTE) may contain clinical studies that administered a small molecule or a biologic only by the intended route. This may be self-evident for NTEs given intravenously, but less so for NTEs whose intended route of administration is not intravenous. Because the US Food and Drug Administration (FDA) accepts apparent pharmacokinetic (PK) parameters of NTEs determined after nonintravenous administration, sponsors decide whether studies with additional intravenous treatment arms are included in the development plan of an NTE, and thus, whether the true PK parameters, clearance, (CL), volume of distribution, (Vd), and derived parameters such as nonrenal clearance (CLnr), terminal elimination phase half-life (t 1/2z ), and absolute bioavailability (F) of NTEs will or will not be known.Detailed information on methods and results of the PK studies performed by sponsors are submitted as part of the NDA. After approval of an NTE, information on the PK parameters is provided in the publicly available Clinical Pharmacology reviews of the NDAs. Sponsors of NTEs may also publish results of PK studies in the scientific literature.The goals of this commentary are to investigate how many recently approved NTEs intended for nonintravenous administration performed additional PK studies with intravenous drug administration and to discuss the implications of the findings. A newer method is highlighted that facilitates obtaining information on the PK of drugs after intravenous administration.The Clinical Pharmacology reviews of the NDA submissions available from the FDA website (Drugs@FDA) were screened for PK studies with intravenous drug administration. Small molecules were selected for this review because they represent the largest group among the newly and previously approved NTEs. Additionally, PubMed sources using key words such as "absolute bioavailability," "pharmacokinetics," "micro-dose," and "tracer kinetics" were employed.As shown in Table 1, only 31 (39%) of the 80 NDA submissions of small molecules with systemic activity intended exclusively for oral administration and approved by the FDA during the 5-year period between 2013 and 2017 contained information on at least 1 of the 5 PK parameters that can be obtained only after intravenous administration. For 22 of the 31 small-molecule NTEs, information on the true PK parameters was reported also in the indexed biomedical literature. The PK of all 31 drugs is reportedly dose proportional.For the large majority of the small-molecule NTEs, information on the true parameters was obtained from absolute bioavailability studies in which the NTE is administered by the intended route and the intravenous route that serves as the 100% bioavailable control. The information provided by the NDAs and the published literature for the 31 small-molecule NTEs that conducted ...

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Pharmacokinetic Properties of Nintedanib in Healthy Volunteers and Patients With Advanced Cancer

Cited by 42 publications

References 16 publications

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

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

Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases

Why Collecting Pharmacokinetic Information After Intravenous Drug Administration Is Important

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