Discussion and Conclusions
Paclitaxel is a widely used anti-neoplastic agent and weekly schedules
are now in common usage. This however results in considerable
consumption of health care resources, and precious patient time. Oral
formulations have several potential advantages but their development is
complex. Paclitaxel is poorly absorbed due to active extrusion by P-gp
and undergoes extensive first pass metabolism. The combination with a
gut-specific P-gp-inhibitor is a rational approach to improve
bioavailability. Previous work has shown saturation at doses of
paclitaxel above 300mg/m2 with once daily dosing.
Other P-gp inhibitors have been trialled, but have not progressed due to
either toxicity of the inhibitor, or failure to achieve comparable
exposure.
The classical MTD approach to drug development may not be ideal when
developing oral versions of agents with well-established dosing
schedules and known therapeutic effects. Several other studies have
taken an MTD approach but have achieved saturation which may compromise
therapeutic drug exposure.
We took a PK-directed approach to develop a schedule that could
potentially achieve similar exposure, measured by AUC, as IV paclitaxel
80mg/m2.
Unsurprisingly, the Cmax of paclitaxel with oPac+E is
lower than with IV. However, with multi-day dosing we were able to
demonstrate AUC of paclitaxel with oPac+E was comparable within the
prespecified bounds compared to IV administration, meeting the study
primary endpoint.
We found no difference in oral bioavailability between Asian and
European patients, and PK profile was consistent after 4 weeks exposure
to oPac+E suggesting that there is no clinically relevant induction of
P-gp or CYP enzymes. This implies that prolonged treatment will not
result in meaningful reductions in drug exposure.
The mean terminal half-life was longer with oral exposure than IV,
suggesting either ongoing oral absorption, or that IV clearance differs,
possibly mediated by cremophor.
Several challenges remain. This study was designed to measure PK profile
and it is not possible to determine, from this study, the safety profile
of prolonged administration. This is important as lower Cmax could
impact on toxicity profile such as the incidence of alopecia, or the
development of neuropathy. We found that oPac+E was adequately tolerated
in the three-day schedule but further study will be required to
establish the full safety profile with repeat dosing.
Our study used strict fasting requirements with patients fasting 8 hours
prior and 4 hours after administration. This provided ideal conditions
for studying PK parameters however is unlikely to be feasible in routine
clinical practice. Food studies are required.
The oral formulation also uses slightly less than 8 times the raw amount
of paclitaxel for oral dosing compared to IV administration. This does
have potential consequences for manufacture and supply for such a widely
used anti-neoplastic.
The schedule we devised in this study has been taken forward for further
study, which has recently completed. That study enrolled 402 patients
with metastatic breast cancer and randomised patients in a 2:1 ratio to
receive our schedule of oPac+E or IV Paclitaxel at the registration dose
of 175mg/m2 Q3W. The Oral schedule achieved higher
response rate (primary end-point) and numerically longer median OS (27.9
months v 16.9 months, study not powered for OS). Toxicities were much
less in oral group, with only 1% of patients experiencing grade 3
polyneuropathy (PNP), versus 8% in the IV group (all grades PNP 17%
versus 57%). The much lower incidence and severity of neuropathy could
be a major advantage in the treatment of cancer patients. Additionally,
fewer patients experienced alopecia, but slightly more patients had GI
disturbance or neutropenia. (Umanzor et
al., 2020)
In conclusion, we found that a combination of oral paclitaxel 205mg/m²
and encequidar 15mg in a three-day schedule is equivalent on AUC to
paclitaxel 80mg/m2 and provides advantages to cancer
patients over traditional IV weekly paclitaxel. PK parameters after 4
weeks exposure were unchanged, indicating no evidence of induction of
P-gp or CYP enzymes. There was no evidence of variation between Asian
and European ethnicity. There were no concerning safety signals.
Participants preferred oPac+E to IV paclitaxel. oPac+E may be a
candidate to replace weekly IV paclitaxel subject to confirmatory safety
and efficacy data.