Oral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer: A randomised crossover pharmacokinetic study

Aims Paclitaxel is a widely used anti‐neoplastic agent but has low oral bioavailability due to gut extrusion by P‐glycoprotein (P‐gp). Oral paclitaxel could be more convenient, less resource intensive, and more tolerable than intravenous administration. Encequidar (HM30181A) is a novel, minimally absorbed gut‐specific P‐gp inhibitor. We tested whether administration of oral paclitaxel with encequidar (oPac+E) achieved comparable AUC to intravenous paclitaxel (IVP) 80 mg/m2. Methods We conducted a multi‐centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615 mg/m2 divided over 3 days and encequidar 15 mg orally 1 hour prior, followed by IVP 80 mg/m2, or the reverse sequence. PK blood samples were taken up to Day 9 for oPac+E and Day 5 for IVP. Results Forty‐two patients were enrolled; 35 completed both treatment periods. AUC0‐∞was 5033.5 ± 1401.1 ng.h/mL for oPac+E and 5595.9 ± 1264.1 ng.h/mL with IVP. The geometric mean ratio (GMR) for AUC was 89.50% (90% CI 83.89–95.50). Mean absolute bioavailability of oPac+E was 12% (CV% = 23%). PK parameters did not change meaningfully after 4 weeks administration of oPac+E in an extension study. G3 treatment‐emergent adverse events occurred in seven (18%) pts with oPac+E and two (5%) with IVP. Seventy‐five per cent of patients preferred oPac+E over IVP. Conclusions GMR for AUC was within the predefined acceptable range of 80–125% for demonstrating equivalence. oPac+E is tolerable and there is no evidence of P‐gp induction with repeat administration. With further study, oPac+E could be an alternative to IVP.