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
[1], ovarian
[2], lung
[3], and gastric cancer
[4], as well as Kaposi and
angiosarcoma [5]. Newer taxanes
include cabazitaxel [6] and the
nanoparticle-bound nab-paclitaxel [7].
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
[8, 9].
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 [10].
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[11] (Hence, whenever
possible, utilization of oral therapy regimens is recommended instead of
intravenous anticancer therapies, if considered
equivalent[12].
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[13]
[14]
[15]
[16]. 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[17]. Subsequently, Phase 1 and 2
studies investigated oral paclitaxel combination with cyclosporine A and
showed promising results[16,
18], 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)
[19,
20]. 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.[21]
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)[22]. 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[23].
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[24]. 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.