Sorafenib exposure and its correlation with response and safety in advanced hepatocellular carcinoma: results from an observational retrospective study

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study

“…Third, multiple studies have shown a relationship between sorafenib exposure and the dose limiting toxicity HFSR. 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21 Additionally, published data show that efficacy is related to sorafenib exposure. 20 , 21 , 25 Finally, several studies have demonstrated that longer continuous exposure to sorafenib, even when lower doses were used to manage toxicities, led to improved outcomes.…”

“… 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21 Additionally, published data show that efficacy is related to sorafenib exposure. 20 , 21 , 25 Finally, several studies have demonstrated that longer continuous exposure to sorafenib, even when lower doses were used to manage toxicities, led to improved outcomes. 22 , 23 Specifically, these studies showed that sorafenib exposure of less than 2 months related to worse survival (hazard ratio [HR] = 4, p < 1e‐4), sorafenib dosage reductions used to manage tolerability in those with grade 2 or greater adverse events improved disease control relative to those with grade 0 or 1 (78% vs. 48%; p < 1e‐4) including time to progression (9.5 vs. 3 months; p < 1e‐4) and survival (12.5 vs. 5.7 months; p < 1e‐4), and sorafenib related dermatologic adverse events in patients with HCC related to a better outcome ( p = 0.022).…”

“…The rationale for the lower limit of the sorafenib AUC 0‐12 h range was related to previously reported sorafenib exposure versus efficacy relationships, which have shown trends to increased efficacy with sorafenib steady‐state AUC 0–12 h exposures ranging from ~ 17 to 54 h µg/ml. 20 , 21 , 25 However, these studies were in adults with a variety of diseases (HCC, renal cell carcinoma, and sarcoma), differing demographics (both from Japan and the United States), and underpowered and not statistically significant most likely due to their small sample sizes. Other studies have suggested that sorafenib exposures that cause adverse effects, along with continuous exposure even with lower doses (which can provide higher overall exposure compared to higher doses that are intermittent due to dose limiting toxicities), may be more efficacious.…”

“…Using pharmacokinetically guided dosing to individualize sorafenib doses to a desired systemic exposure instead of a fixed sorafenib dosage, which has been previously used, 5 has been motivated by several reasons. These include the pharmacokinetics (PKs) of sorafenib have large interindividual variability and relatively smaller interoccasion variability [5][6][7][8][9][10][11][12][13] ; sorafenib systemic exposure decreases over time 14 ; the dose limiting toxicity hand foot skin reaction (HFSR) is sorafenib exposure dependent 13,[15][16][17][18][19][20][21] ; and, longer continuous exposure to sorafenib, even at lower doses can manage toxicities and lead to improved outcomes. 22,23 Designing clinical studies to evaluate whether pharmacokinetically guided dosing can improve therapy is challenging for TKIs due to the large number of individuals needed to sufficiently power the analysis.…”

Living donor liver transplantation for patients with advanced hepatocellular carcinoma

“…A recent publication evaluating the role of Sorafenib on HCC recurrence and survival in 45 patients with advance HCC on explant pathology after LT found that adjuvant treatment with sorafenib in LT recipients with high-risk features does not improved HCC recurrence-free or overall survival [56] . When used, it is crucial to be aware of reported early and severe toxicities such as hepatotoxicity, thrombocytopenia, anorexia, fatigue, hand-foot syndrome, and diarrhea [57] .…”