Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib.

Koen G A M Hussaarts,Roelof W F Van Leeuwen,Karel Eechoute,Jeffrey Damman,Stijn L W Koolen,Ron H J Mathijssen,Alex Sparreboom,Sharyn D Baker,Esther Oomen-De Hoop,Alice A Gibson,Eric D Eisenmann,Nadia Van Doorn,Leni Van Doorn,Qiang Fu,Peter De Bruijn,Teun Van Gelder,Sander Bins

doi:10.3390/pharmaceutics12090788

Abstract

Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0–12 h) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC0–12 h decreased by 27% (90% CI: −38% to −14%; P < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-N-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.

Highlights

Over the last two decades, systemic anti-cancer treatment options have been expanded from traditional cytotoxic chemotherapy to targeted agents, including tyrosine kinase inhibitors (TKIs)
Previous in vitro and in vivo research showed that sorafenib can accumulate in human epidermal keratinocytes mediated by the organic anion transporter 6 (OAT6) [11], and that sorafenib-induced skin toxicity can be prevented by cotreatment with the OAT6 inhibitor probenecid without negatively influencing the antitumor properties of sorafenib [11]
We investigated the influence of the OAT6 and organic anion transporting polypeptides 1B1 (OATP1B1) inhibitor probenecid on sorafenib pharmacokinetics and toxicity in patients, and found a significant decrease in the geometric mean of sorafenib plasma exposure and a nearly significant decrease in intracutaneous sorafenib exposure during concomitant probenecid administration making sorafenib concomitantly with probenecid not bioequivalent to sorafenib monotherapy

Summary

Introduction

Over the last two decades, systemic anti-cancer treatment options have been expanded from traditional cytotoxic chemotherapy to targeted agents, including tyrosine kinase inhibitors (TKIs). The clinical incidence of HFSR varies among TKIs with a high incidence (20% ≥ grade 3) being observed with sorafenib [5], an orally administered multikinase inhibitor, registered for treatment of advanced hepatocellular carcinoma and advanced renal cell carcinoma as well as iodine-refractory advanced thyroid cancer [3,4,6,7]. It is investigated as a treatment option for acute myeloid leukemia [8]. As part of an ongoing project to develop translationally useful prevention strategies for sorafenib-induced HFSR, in the current study, we evaluated the pharmacokinetics (PK) and safety of sorafenib when concomitantly used with probenecid

Objectives

Methods

Conclusion