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Oral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer: a randomised crossover pharmacokinetic study.
  • +15
  • Christopher Jackson,
  • Tak Hung,
  • Eva Segelov,
  • Paula Barlow,
  • Hans Prenen,
  • Blair McLaren,
  • Noelyn Hung,
  • Katriona Clarke,
  • Tsu-Yi Chao,
  • Ming-Shen Dai,
  • Hsien-Tang Yeh,
  • David Cutler,
  • Douglas Kramer,
  • Jimmy He,
  • Jay Zhi,
  • Wing-Kai Chan,
  • Rudolf Kwan,
  • Sanjeev Deva
Christopher Jackson
University of Otago Medical School
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Tak Hung
Zenith Technology Corporation Limited
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Eva Segelov
Monash University
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Paula Barlow
Auckland District Health Board
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Hans Prenen
University Hospital Antwerp
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Blair McLaren
Southern District Health Board
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Noelyn Hung
University of Otago
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Katriona Clarke
Capital and Coast District Health Board
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Tsu-Yi Chao
Taipei Medical University
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Ming-Shen Dai
Tri-Service General Hospital
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Hsien-Tang Yeh
Lo-Hsu Medical Foundation Lotung Poh-Ai Hospital
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David Cutler
Athenex Inc
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Douglas Kramer
Athenex Inc
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Jimmy He
Athenex Inc
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Jay Zhi
Athenex Inc
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Wing-Kai Chan
Athenex Inc
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Rudolf Kwan
Athenex Inc
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Sanjeev Deva
Auckland District Health Board
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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.

Peer review status:Published

07 May 2021Published in British Journal of Clinical Pharmacology. 10.1111/bcp.14886