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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,
  • C Hung,
  • Eva Segelov,
  • Paula Barlow,
  • Hans Prenen,
  • Blair McLaren,
  • Noelyn Hung,
  • Katriona Clarke,
  • Tsu-Yi Chao,
  • Ming-Shen Dai,
  • Hsien-Tang Yeh,
  • David Cutler,
  • Doug Kramer,
  • Jimmy He,
  • Jay Zhi,
  • Wing-Kai Chan,
  • Rudolf Kwan,
  • Sanjeev Deva
Christopher Jackson
University of Otago Medical School
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Eva Segelov
Monash University SCS at Monash Health
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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 Blood and Cancer Service
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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 Shuang Ho Hospital Ministry of Health and Welfare
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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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Doug 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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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:ACCEPTED

18 Dec 2020Submitted to British Journal of Clinical Pharmacology
21 Dec 2020Submission Checks Completed
21 Dec 2020Assigned to Editor
27 Dec 2020Reviewer(s) Assigned
25 Jan 2021Review(s) Completed, Editorial Evaluation Pending
25 Jan 2021Editorial Decision: Revise Major
08 Mar 20211st Revision Received
10 Mar 2021Assigned to Editor
10 Mar 2021Submission Checks Completed
10 Mar 2021Review(s) Completed, Editorial Evaluation Pending
11 Mar 2021Reviewer(s) Assigned
11 Apr 2021Editorial Decision: Revise Minor
20 Apr 20212nd Revision Received
21 Apr 2021Assigned to Editor
21 Apr 2021Submission Checks Completed
21 Apr 2021Review(s) Completed, Editorial Evaluation Pending
24 Apr 2021Editorial Decision: Accept