Introduction
Taxanes are a class of commonly used chemotherapy compounds, originally
identified from Taxus plants. The classical taxanes docetaxel and
paclitaxel are widely used anti-neoplastic agents with activity in
multiple solid tumours including breast
(Ghersi et al., 2015), ovarian
(Clamp et al., 2019), lung
(Masters et al., 2015), and gastric
cancer (Lu et al., 2018), as well as
Kaposi and angiosarcoma (Rowinsky, 1997).
Newer taxanes include cabazitaxel (De Bono
et al., 2010) and the nanoparticle-bound nab-paclitaxel
(H. Lee et al., 2020). The principal
mechanism of action is thought to be disruption of microtubule function.
Microtubules are essential for cell division and taxanes stabilize the
GDP-bound tubulin in the microtubule, causing inhibition of cell
division. Paclitaxel was first discovered in 1963 as part of an National
Cancer Institute funded drug candidate screening programme, with
activity in mouse models noted in 1978
(Walsh & Goodman, 2002;
Wani, Taylor, Wall, Coggon, & McPhail,
1971). Its wide utility has resulted in it being listed on the WHO
essential medicines list. The development of paclitaxel was initially
hindered by insolubility in water, thus it is administered with the
formulation vehicle cremophor EL (in a 1:1 mixture with dehydrated
ethanol), which greatly increases the rate of hypersensitivity
reactions. Paclitaxel is administered in a variety of dosage regimens as
monotherapy or combination, frequently as a weekly infusion at a dose of
80mg/m2 (Joerger, 2016).
Patients are required to have repeated venepuncture, and the schedule
uses expensive and often scare hospital infusion resources as well as
valuable patient time.
Oral administration may improve convenience and have the potential to
reduce costs. During COVID-19 global pandemic, oncologists are
substituting oral for intravenous agents to reduce the number of
patients’ clinic visits and the inherent risks of exposure to
SARS-CoV-2, without compromising oncological
outcome(Schrag, Hershman, & Basch, 2020)
(Hence, whenever possible, utilization of oral therapy regimens is
recommended instead of intravenous anticancer therapies, if considered
equivalent(Gosain et al., 2020).
Paclitaxel has low oral bioavailability due to structural instability in
the gastrointestinal tract, active extrusion from enterocytes by
p-glycoprotein (P-gp) and first pass metabolism by the liver enzymes
CYP3A4 and CYP2C8(Jibodh, Lagas, Nuijen,
Beijnen, & Schellens, 2013) (Schellens
et al., 2000) (Kartner, Riordan, & Ling,
1983) (Helgason et al., 2006). Paclitaxel
absorption is enhanced in P-gp and CYP knockout mice. Preclinical
studies have evaluated combinations of Cyclosporine A, a known P-gp
inhibitor and substrate for CYP3A4, and oral paclitaxel and showed a 13
fold increase in the oral bioavailability in
mice(van Asperen, van Tellingen, van der
Valk, Rozenhart, & Beijnen, 1998). Subsequently, Phase 1 and 2 studies
investigated oral paclitaxel combination with cyclosporine A and showed
promising results(Helgason et al., 2006;
Malingré et al., 2000), however repeated
use of cyclosporine A could also lead to serious adverse events such as
hypertension and nephrotoxicity Investigation into other P-gp inhibitors
such as elacridar and GF120918 have been commenced but not developed for
routine use in the clinical setting.
Therefore more specific P-gp inhibitors have been developed such as
HM30181A (encequidar; Hanmi Pharmaceutical; Seoul, Korea)
(I. B. Paek, H. Y. Ji, M. S. Kim, G. Lee,
& H. S. Lee, 2006; I. B. Paek, H. Y. Ji,
M. S. Kim, G. S. Lee, & H. S. Lee, 2006). Encequidar is a novel,
poorly absorbed, potent, selective gut specific p-glycoprotein
inhibitor. Due to low oral bioavailability, the effects of Encequidar
are limited to the intestinal enterocyte. In healthy volunteer studies,
encequidar was well tolerated with no serious adverse effects at doses
ranging from 180mg to 900mg in a single dose, and 60mg to 360mg doses
daily for 5 days, with the maximum tolerated dose not reached.(Kim et
al., 2012)
In a phase 1 study 24 patients received escalating doses of oral
paclitaxel with encequidar (oPac+E, previously also known as Oraxol) to
determine the maximum tolerated dose
(DLTs)(H. J. Lee et al., 2014). In this
study, the dose of paclitaxel was escalated from 60 to 420 mg/m² and the
dose of encequidar from 30 to 210 mg/m² (half the dose of paclitaxel).
The drugs were administered on days 1, 8 and 15 of each 28 day cycle. No
premedication for hypersensitivity was delivered. Only one patient
experienced a DLT (grade 3 neutropenia) at 240mg/m² of paclitaxel. The
MTD was not reached in this study but maximum plasma concentration of
paclitaxel was obtained at a dose level of 300 mg/m².
In another phase I / II study with oPac+E, paclitaxel was orally
administered at escalating doses (90, 120 or 150 mg/m²) with a fixed
dose (15 mg/day) of encequidar(K. W. Lee
et al., 2015). oPac+E was administered 6 times per cycle (day 1, 2, 8,
9, 15 and 16) every 4 weeks. In the phase 1 component of the study
(n=10), the MTD could not be determined but based on toxicity and
pharmacokinetic data, the recommended phase 2 dose of oral paclitaxel in
this 2 consecutive day schedule was determined to be 150 mg/m² per day.
In contrast to a dose escalation approach to determining optimal dosing
schedule, we adopted a pharmacokinetic (PK) driven approach comparing
the PK profile of sequential oral doses of oPac+E to the profile of IV
paclitaxel. In a pilot pharmacokinetic study, we enrolled patients with
advanced cancer who were scheduled to receive oPac+E and compared IV
administration of paclitaxel with
oPac+E(Jackson et al., 2016). Three
cohorts were enrolled with escalating oral paclitaxel doses of 270mg/m²
(6 patients), 274mg/m2 (2 patients) or
313mg/m2 (2 patients) daily over two consecutive days,
preceded by Encequidar 15mg (fixed dose). With a two-day dosing schedule
saturation at 274mg/m2 was observed. PK modelling
predicted a three-day schedule of 205mg/m2 per day
could achieve bioequivalence between oPac+E and IV paclitaxel
80mg/m2
To test this hypothesis, we undertook a multicenter, open label, 2 stage
study with a 2-treatment period crossover design to test whether oPac+E
achieved comparable exposure by AUC to IV paclitaxel
80mg/m2. We also undertook an extension study to test
safety of repeated administration of oPac+E, with repeat PK after 4
weeks administration to test whether potential accumulation or P-gp/CYP
induction occurred that may affect systemic concentrations and
potentially diminish efficacy.