Although activated HSCs may produce the factors that regulate liver regeneration, the de novo NGF production by regenerating hepatocytes may induce the death of activated HSCs via p75NTR, leading to termination of hepatic regeneration.

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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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