Absorption of the orally active multikinase inhibitor axitinib as a therapeutic index to guide dose titration in metastatic renal cell carcinoma

Fukudo, Masahide; Tamaki, Gaku; Azumi, Makoto; Κakizaki, Hidehiro; Matsumoto, Seiji; Tasaki, Yoshikazu

doi:10.1007/s10637-020-01023-z

Cited by 7 publications

(2 citation statements)

References 36 publications

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“…This study identi ed no genetic determinants of interindividual variability regarding total exposure to regorafenib and M-2/M-5, a result that is comparable with the ndings of previous studies [12,13]. Recently, we demonstrated that poor absorption of axitinib, a multikinase inhibitor used to treat patients with metastatic renal cell carcinoma, was linked to higher glucuronidation of the drug, primarily by UGT1A1 in the liver [21]. The present study revealed that like axitinib, greater glucuronidation activity of UGT1A9 toward regorafenib (i.e., higher M-7/regorafenib metabolic ratio) was associated with decrease in the sum of the dose-adjusted C trough levels of regorafenib and M-2/M-5, probably due to a reduction in the relative contribution of CYP3A4-mediated regorafenib metabolism into M-2 (ESM Fig.…”

Section: Discussionsupporting

confidence: 88%

Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real‐world treatment outcomes

et al. 2021

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Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC), its toxicity pro le has limited clinical use. We aimed to evaluate the pharmacokinetics of regorafenib and its active metabolites M-2/M-5, and to clarify the relationships between total drug-related exposure and clinical outcomes in real-world practice.Methods Blood samples were obtained at steady state in Cycle 1 in patients treated with regorafenib.Plasma concentrations of regorafenib and its metabolites were measured by liquid chromatographytandem mass spectrometry. The e cacy and safety endpoints were progression-free survival (PFS) and dose-limiting toxicities (DLTs), respectively. The exposure-response relationships were assessed.Results Thirty-four Japanese patients with advanced cancers were enrolled (CRC, n = 26; GIST and HCC, each n = 4). Nine patients started regorafenib treatment at the recommended dose of 160 mg once daily (3 weeks on / 1 week off), while the other patients received a reduced starting dose to minimize toxicities. The median PFS was signi cantly longer in patients achieving total trough concentrations (C trough ) of regorafenib and M-2/M-5 ≥2.9 µg/mL than those who did not (112 vs. 57 days; p = 0.044). Furthermore, the cumulative incidence of DLTs during the rst 2 cycles was signi cantly higher in patients with summed C trough levels ≥4.3 µg/mL than in others (p = 0.0003).Conclusions Dose titration of regorafenib to achieve drug-related C trough levels in Cycle 1 between 2.9 and 4.3 µg/mL may improve the e cacy and safety, warranting further investigation in a larger patient population.

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Section: Discussionsupporting

confidence: 88%

Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real‐world treatment outcomes

et al. 2021

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“…For axitinib, the presence of an exposure-response (for AUC) and exposure-toxicity relationship (for hypertension, proteinuria, fatigue, and diarrhea) was clearly established in the approval reports ( n = 233) [ 172 , 173 ]. The finding of the exposure-response relationship was supported by multiple other studies, although the suggested targets ( C max ≥ 12.4ng/mL [ n = 20], AUC 0–12 150 ng*h/mL [ n = 26] and AUC ≥ 300 ng*h/mL [ n =168], respectively) are less convenient for TDM as these require several blood samples [ 174 – 176 ]. Two small studies proposed a target C min of 5 ng/mL, but this requires confirmation in more patients ( n = 24 and n = 35) [ 177 , 178 ].…”

Section: Introductionmentioning

confidence: 78%

Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

van der Kleij,

Guchelaar,

Mathijssen

et al. 2023

Clin Pharmacokinet

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Although kinase inhibitors (KI) frequently portray large interpatient variability, a ‘one size fits all’ regimen is still often used. In the meantime, relationships between exposure-response and exposure-toxicity have been established for several KIs, so this regimen could lead to unnecessary toxicity and suboptimal efficacy. Dose adjustments based on measured systemic pharmacokinetic levels—i.e., therapeutic drug monitoring (TDM)—could therefore improve treatment efficacy and reduce the incidence of toxicities. Therefore, the aim of this comprehensive review is to give an overview of the available evidence for TDM for the 77 FDA/EMA kinase inhibitors currently approved (as of July 1st, 2023) used in hematology and oncology. We elaborate on exposure-response and exposure-toxicity relationships for these kinase inhibitors and provide practical recommendations for TDM and discuss corresponding pharmacokinetic targets when possible.

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Therapeutic Drug Monitoring for Tyrosine Kinase Inhibitors in Metastatic Renal Cell Carcinoma

Henriksen,

Andersen,

Fristrup

2024

Clinical Genitourinary Cancer

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Absorption of the orally active multikinase inhibitor axitinib as a therapeutic index to guide dose titration in metastatic renal cell carcinoma

Cited by 7 publications

References 36 publications

Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real‐world treatment outcomes

Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real‐world treatment outcomes

Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Therapeutic Drug Monitoring for Tyrosine Kinase Inhibitors in Metastatic Renal Cell Carcinoma

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