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Title
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Oral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer : a randomised crossover pharmacokinetic study
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Author
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Abstract
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| 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/m(2). Methods We conducted a multi-centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615 mg/m(2) divided over 3 days and encequidar 15 mg orally 1 hour prior, followed by IVP 80 mg/m(2), 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. AUC(0-infinity)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. |
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Language
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English
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Source (journal)
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British journal of clinical pharmacology. - London
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Publication
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Hoboken
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Wiley
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2021
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ISSN
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0306-5251
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DOI
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10.1111/BCP.14886
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Volume/pages
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87
:12
(2021)
, p. 4670-4680
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ISI
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000663086000001
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Pubmed ID
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33960504
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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