Phase I and Pharmacokinetic Study of Sorafenib in Patients With Hepatic or Renal Dysfunction: CALGB 60301

Abstract

Purpose We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction. Patients and Methods Patients were assigned to one of nine cohorts: cohort 1, bilirubin ≤ upper limit of normal (ULN) and AST ≤ ULN and creatinine clearance (CC) ≥ 60 mL/min; cohort 2, bilirubin more than ULN but ≤ 1.5× ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5× ULN to ≤ 3× ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3× ULN to 10× ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8. Results Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found. Conclusion We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.

Refining Sorafenib Therapy: Lessons from Clinical Practice

“…In this context, it is insightful to consider a pharmacokinetic study of sorafenib by Miller and colleagues in solid-cancer patients with hepatic or renal dysfunction [30]. Despite corroborating the results of another trial by failing to show a significant difference in the pharmacokinetics of a 400-mg dose of sorafenib between Child-Pugh A and B patients [31], the authors did find that higher bilirubin concentrations were associated with lower areas under the curve of the main sorafenib metabolite, N-oxidesorafenib, but only in the hepatic and not the renal cohort.…”

Risk factors and model for predicting toxicity‐related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor–targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

“…Although VEGF-targeted therapies used for mRCC are not renally eliminated, there are some side effects that are more pronounced in patients with renal dysfunction. 44,45 Thus far, no significant pharmacokinetic differences have been observed with VEGF-targeted therapies in the context of renal insufficiency. 35,45,46 A more robust study of patients with severe renal dysfunction (GFR <30 mL/min/1.73 m 2 ) may clarify differences in mRCC patients treated with VEGF-targeted therapies.…”

Sorafenib and the medical treatment of hepatocellular carcinoma

“…Sorafenib pharmacokinetics is not altered in patients with moderate hepatic insufficiency (Child-Pugh B status), but these patients are at higher risk of hepatic decompensation and general complications. 9,10 For these patients, a protocol of dose escalation might be adequate to prevent potential complications. 10 While the introduction of sorafenib was a breakthrough in the treatment HCC, its overall efficacy remains modest, with a gain of survival of only a few months.…”

“…9,10 For these patients, a protocol of dose escalation might be adequate to prevent potential complications. 10 While the introduction of sorafenib was a breakthrough in the treatment HCC, its overall efficacy remains modest, with a gain of survival of only a few months. Furthermore, sorafenib essentially extends the survival of patients with HCC through its ability to slow tumor progression.…”