Measurement of sorafenib plasma concentration by high-performance liquid chromatography in patients with advanced hepatocellular carcinoma: is it useful the application in clinical practice? A pilot study

Abstract

Pharmacokinetics and dose-finding studies on sorafenib were conducted on heterogeneous groups of patients with solid tumors. Portal hypertension, gut motility impairment and altered bile enterohepatic circulation may explain different sorafenib toxicological profile in cirrhotic patients. This study evaluated sorafenib plasma concentration in a homogeneous group of cirrhotic patients with hepatocellular carcinoma (HCC). Sorafenib concentrations were determined by liquid chromatography in 12 consecutive patients. Data have been evaluated by the generalized estimating equations method (p value statistical level was set at α = 0.05). (1) There were not significant differences between sorafenib concentrations in patients who tolerate the full dose versus patients with reduced dose due to toxicity; (2) the average sorafenib concentrations measured 3 h after the morning dosing were lower than those measured 12 h after the evening dosing (p = 0.005); (3) sorafenib concentrations decrease overtime (p < 10(-4)); (4) it has been found an association between the development of severe adverse reactions and sorafenib concentrations (p < 10(-5)). The relationship between dose and concentration of sorafenib in HCC patients is poor and not clinically predictable, confirming the variability both in the maximum tolerated dose and in plasma concentrations. Several factors may influence the pharmacokinetics in patients with liver disease. This may explain the inter-patient variability of concentrations and the lack of differences in concentration at different dosages. It could be interesting to extend the series of HCC patients to enhance information on the kinetics of the drug; furthermore, to establish a threshold of plasma sorafenib concentrations to predict severe adverse reactions would be clinically useful.

Growth factor receptor signaling inhibition prevents SARS-CoV-2 replication

“…Both compounds inhibited 195 cytopathic effects during infection and the viral replication ( Figure 4B, C, D, S5, and S6). Overall, five compounds, inhibiting downstream signaling of GFRs, prevented SARS-CoV-2 replication at clinically achievable concentrations ( Figure 4B and 5) (Eskens et al, 2001;Fucile et al, 2014;Martinez-Garcia et al, 2012;Munster et al, 2016;Sarker et al, 2015), emphasizing the importance of GFR signaling during SARS-CoV-2 infection and revealing clinically available 200 treatment options as drug candidates for COVID-19.…”

Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma

“…Sorafenib suppresses the serine/threonine kinase subtypes of Raf, which are well known to regulate the Raf/MEK/ERK signaling pathway and inhibit tyrosine kinase receptors, including VEGFR2, PDGFR and IGFR. For this reason, sorafenib inhibits angiogenesis and tumor growth (52). Sorafenib has demonstrable preclinical and clinical activity against certain types of cancer (for example, HCC, and ovarian, breast and pancreatic cancer).…”

Influence of OATP1B1 Function on the Disposition of Sorafenib‐β‐D‐Glucuronide

“…The high degree of interindividual pharmacokinetic variability observed with sorafenib has important toxicological ramifications. For example, it was recently demonstrated that levels of sorafenib in plasma are correlated with the incidence of skin rash, with dose reduction and study withdrawal due to adverse effects, and with the development of severe adverse reactions …”