Pharmacokinetics Of Nintedanib Research Articles

Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Nintedanib in Healthy Subjects.

BackgroundNintedanib is a substrate for p-glycoprotein which can impact bioavailability. We investigated the effects of ketoconazole, a p-glycoprotein inhibitor, and rifampicin, a p-glycoprotein inducer, on the pharmacokinetics of nintedanib.MethodsIn the ketoconazole study, 34 healthy subjects received nintedanib 50 mg orally alone and 1 h after the last dose of ketoconazole given orally at a dose of 400 mg once daily for 3 days in 1 of 2 randomized sequences. In the rifampicin study, 26 subjects received nintedanib 150 mg orally alone and the morning after the last dose of rifampicin given orally at a dose of 600 mg once daily for 7 days. The primary objective was to determine the relative bioavailability of nintedanib administered following multiple doses of ketoconazole or rifampicin versus alone, based on AUC from time 0 extrapolated to infinity (AUC0–∞) and maximum concentration (Cmax) calculated using an analysis of variance. Geometric mean ratios and 2-sided 90% CIs were calculated.ResultsExposure to nintedanib increased when it was administered following ketoconazole versus alone (AUC0–∞: geometric mean ratio, 160.5% [90% CI, 148.2–173.7]; Cmax: geometric mean ratio, 179.6% [90% CI, 157.6–204.8]) and decreased when it was administered following rifampicin versus alone (AUC0–∞: geometric mean ratio, 50.1% [90% CI, 47.2–53.3]; Cmax: geometric mean ratio, 59.8% [90% CI, 53.8–66.4]). The time to reach Cmax (tmax) and half-life (t½) of nintedanib were unaffected by co-administration of ketoconazole or rifampicin.ConclusionsExposure to nintedanib is increased by co-administration of ketoconazole and decreased by co-administration of rifampicin, likely due to effects on bioavailability of the absorbed fraction.ClinicalTrials.govidentifiers:NCT01679613, NCT01770392.

Population pharmacokinetics of nintedanib, an inhibitor of tyrosine kinases, in patients with non-small cell lung cancer or idiopathic pulmonary fibrosis

PurposeA population pharmacokinetic model was developed for nintedanib in patients with non-small cell lung cancer (NSCLC) or idiopathic pulmonary fibrosis (IPF). The effects of intrinsic and extrinsic patient factors on exposure of nintedanib and its main metabolite BIBF 1202 were studied.MethodsData from 1191 patients with NSCLC (n = 849) or IPF (n = 342) treated with oral nintedanib (once- or twice-daily, dose range 50–250 mg) in 4 Phase II or III studies were combined. Plasma concentrations of nintedanib (n = 5611) and BIBF 1202 (n = 5376) were analyzed using non-linear mixed-effects modeling.ResultsPharmacokinetics of nintedanib were described by a one-compartment model with linear elimination, first-order absorption, and absorption lag time. For a typical patient, the absorption rate was 0.0827 h−1, apparent total clearance was 897 L/h, apparent volume of distribution at steady state was 465 L, and lag time was 25 min. Age, weight, smoking, and Asian race were statistically significant covariates influencing nintedanib exposure, but no individual covariate at extreme values (5th and 95th percentiles of baseline values for continuous covariates) resulted in a change of more than 33% relative to a typical patient. Pharmacokinetics and covariate effects for BIBF 1202 were similar to nintedanib. Mild or moderate renal impairment and mild hepatic impairment (classified by transaminase or bilirubin increase above the upper limit of normal) or underlying disease had no significant effects on nintedanib pharmacokinetics.ConclusionsThis model adequately described the pharmacokinetic profile of nintedanib in NSCLC and IPF populations and can be used for simulations exploring covariate effects and exposure–response analyses.

A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients

BackgroundThis randomised, open-label, phase I/II study evaluated the efficacy and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with chemotherapy, relative to bevacizumab plus chemotherapy as first-line therapy in patients with metastatic colorectal cancer (mCRC). Patients and methodsPatients with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative Oncology Group performance status ≤2 and adequate organ function were included. Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.i.d. plus mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2 or d,l-leucovorin 400 mg/m2, 5-fluoruracil bolus 400 mg/m2 followed by 2400 mg/m2, every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks) plus mFOLFOX6. During phase I, patients underwent a 3 + 3 dose-escalation schema to determine the maximum tolerated dose (MTD) of nintedanib in combination with mFOLFOX6. The primary end point was progression-free survival (PFS) rate at 9 months. Objective response (OR) was a secondary end point. ResultsThe nintedanib recommended phase II dose was 200 mg b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients randomised in the phase II part, 126 received treatment (nintedanib plus mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% with nintedanib and 70.2% with bevacizumab [difference: -8.1% (95% confidence interval -27.8 to 11.5)]. Confirmed ORs were recorded in 63.5% and 56.1% of patients in the nintedanib and bevacizumab groups, respectively. The incidence of adverse events (AEs) considered related to treatment was 98.8% with nintedanib and 97.6% with bevacizumab; the incidence of serious AEs was 37.6% with nintedanib and 53.7% with bevacizumab. The pharmacokinetics of nintedanib and the components of mFOLFOX6 were unaffected by their combination. ConclusionsNintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in patients with mCRC with a manageable safety profile and further studies in this population are warranted.

Open-label, phase I/randomized, phase II trial of the triple angiokinase inhibitor, nintedanib, versus sorafenib in previously untreated patients with advanced hepatocellular carcinoma (HCC).

TPS4160 Background: While sorafenib is established as the standard first-line treatment for patients with advanced HCC, its use can be complicated by the occurrence of drug-related adverse events (AEs). Nintedanib, a potent, oral triple angiokinase inhibitor that targets VEGF, PDGF and FGF signaling (as well as Flt3 and RET), has demonstrated clinical activity in various advanced solid tumors with a relatively low incidence of AEs typically associated with angiogenesis inhibitors (e.g. skin toxicity, hypertension, hemorrhage, and hematologic toxicity) and is currently in phase III for non-small cell lung cancer and ovarian cancer. In the Phase I, dose-finding stage of this ongoing, multicenter, open-label Phase I/II trial (NCT01004003), 200mg twice daily (bid) was established as the maximum tolerated dose of nintedanib in previously untreated patients with advanced HCC (Palmer D, et al. Ann Oncol 2012;23(Suppl 9):ix245[Abs 740P]). Nintedanib had an acceptable liver AE profile; the most common AEs were mild/moderate gastrointestinal toxicities. Methods: The randomized Phase II stage of the trial aims to assess the efficacy, safety, and pharmacokinetics of nintedanib in comparison with sorafenib. Eligible patients have pathologically confirmed, measurable HCC that is not amenable to local therapy, ECOG Performance Status of ≤2, Child-Pugh score of 5–6 (Class A), AST/ALT levels ≤2× upper limit of normal, and no prior systemic therapy. Patients are being stratified by macrovascular invasion and/or extrahepatic spread and then randomized 2:1 to receive nintedanib 200mg bid or sorafenib 400mg bid in continuous 28-day cycles until progression or unacceptable toxicity. Overall, 93 patients were randomized between Sept 2011 and Nov 2012. The primary endpoint is time to progression (TTP) by independent review, according to RECIST 1.0. TTP will be estimated in the treated set by Kaplan–Meier methodology with treatment effects compared using a Cox proportional hazards model. Secondary endpoints include overall survival, tumor response, progression-free survival, safety and pharmacokinetics. Results are due late 2013. Clinical trial information: NCT01004003.

740P - Phase I Study of Nintedanib (BIBF 1120) in European Patients with advanced Hepatocellular Carcinoma

ABSTRACT Background Caucasian and Asian patients (pts) with hepatocellular carcinoma (HCC) tolerate anticancer drugs differently. This open-label, multicentre, phase I/randomised phase II study (NCT01004003; phase II in progress) evaluated the efficacy, safety and pharmacokinetics of nintedanib (a triple angiokinase inhibitor targeting VEGFRs, PDGFRs and FGFRs) versus sorafenib in pts with advanced HCC from Europe. Initial phase I results are reported. Methods Pts (ECOG performance status ≤2, Child-Pugh [CP] score ≤7) with histologically/cytologically confirmed HCC and no prior systemic therapy were enrolled in the phase I trial and stratified into two groups: (I) AST and ALT ≤2 x upper limit of normal (ULN), and CP 5–6; (II) AST or ALT >2 to ≤5 x ULN, or CP 7. Utilising a 3 + 3 design, cohorts received oral nintedanib continuously in 28-day courses, starting at 50mg bid (group II) or 100mg bid (group I) and escalating up to 200mg bid in 50mg bid intervals. Therapy was continued until no clinical benefit or undue toxicity. The phase I primary endpoint was the maximum tolerated dose (MTD) of nintedanib in Course 1. Results A total of 28 pts (71% Caucasian) have been treated: 13 in group I (median [range] days: 345 [2–757]; 100/150/200mg bid, n = 6/3/4) and 15 in group II (median [range] days: 74 [17–428]; 50/100/150/200mg bid, n = 3/4/4/4). No dose-limiting toxicities (DLTs) were seen in group I or II during Course 1 at doses up to 200mg bid, which was the MTD of nintedanib. After the dose-escalation phase and determination of MTD, seven pts reported DLTs at various dose levels (CTCAE Grade [G]3 bilirubin increase, G3 AST increase, G4 amylase increase, G3 hypertension/ALP increase, G3 amylase increase, G5 multi-organ failure, G3 bilirubin increase). The most frequent adverse events (AEs) in both groups, by system organ class, were gastrointestinal (89%) and general/administration site (39%) disorders. Class-related AEs (any grade) were uncommon (hypertension [n = 2], rash [n = 3]). Hepatic enzyme data will be presented. Conclusions Nintedanib has an acceptable safety profile in pts with advanced HCC at the same dose used in other cancers (200 mg bid). Disclosure D. Palmer: Daniel Palmer: research funding from Boehringer Ingelheim. A.B. Loembe: Arsene-Bienvenu Loembe: employee of Boehringer Ingelheim. M. Studeny: Matus Studeny: employee of Boehringer Ingelheim. J. Hocke: Julia Hocke: employee of Boehringer Ingelheim. T. Meyer: Tim Meyer: research funding from Boehringer Ingelheim