Abstract
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.
Highlights
IntroductionNintedanib is a kinase inhibitor targeting VEGFR (vascular endothelial growth factor receptor) 1, 2, and 3, PDGFR (platelet-derived growth factor receptor) α and β, and FGFR (fibroblast growth factor receptor) 1, 2, and 3 [1,2,3]
Nintedanib is a kinase inhibitor targeting VEGFR 1, 2, and 3, PDGFR α and β, and FGFR 1, 2, and 3 [1,2,3]
The pharmacokinetic profile of nintedanib was adequately described by a one-compartment model with first-order absorption and linear elimination
Summary
Nintedanib is a kinase inhibitor targeting VEGFR (vascular endothelial growth factor receptor) 1, 2, and 3, PDGFR (platelet-derived growth factor receptor) α and β, and FGFR (fibroblast growth factor receptor) 1, 2, and 3 [1,2,3]. These kinase receptors have been shown to play an important role in angiogenesis and in tumor growth and metastasis [4]. Based on results of one Phase II trial (TOMORROW) [11] and two identically designed Phase III trials (INPULSIS-1 and INPULSIS-2), which demonstrated a significant reduction in the rate of decline in forced vital capacity over a 52-week treatment period [12], nintedanib is approved for the treatment of IPF in various countries, including the US, Canada, Japan, and Europe [13, 14]
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