Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib

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 (AUC_{0-12 h}) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC_{0-12 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.

Keywords: OAT6; hand-foot skin reaction (HFSR); pharmacokinetics; probenecid; sorafenib.

Figure 1

Pharmacokinetic results are displayed for (a) sorafenib-glucuronide concentration, (b) sorafenib concentration, (c) sorafenib-glucuronide (SG) to sorafenib ratio.

Figure 2

Inhibition of OATP1B1 function by probenecid in vitro. HEK293 cells expressing OATP1B1 or VC were pre-incubated with probenecid at the indicated concentrations for 15 min before incubation with probenecid and [3H]estradiol-17b-d-glucuronide for 15 min. Data represent uptake of OATP1B1-expressing cells at each concentration compared against vehicle after subtracting uptake by VC cells (mean ± SEM). Each concentration consists of 3–9 technical replicates across 1–3 biological replicates.