Oral paclitaxel with encequidar compared to intravenous paclitaxel in
patients with advanced cancer: a randomised crossover pharmacokinetic
study.
Abstract
Background and purpose: 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) 80mg/m2. Experimental approach: We conducted a multi-centre
randomised crossover study with two treatment periods. Patients (pts)
with advanced cancer received either oral paclitaxel 615mg/m2 divided
over three days and encequidar 15mg orally one-hour prior, followed by
IVP 80mg/m2, or the reverse sequence. PK blood samples were taken up to
day 9 for oPac+E and day 5 for IVP. Key Results: 42 pts 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 89.5% (90% CI 83.9-95.5). Mean absolute
bioavailability of oPac+E was 12%. PK parameters did not change
meaningfully after 4 weeks administration of oPac+E in an extension
study. G3 treatment emergent adverse events occurred in 7 (18%) pts
with oPac+E and 2 (5%) with IVP. 75% of pts preferred oPac+E over IVP.
Conclusion and Implications: 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 is a candidate to replace
IVP.