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. Similarly, time above a minimum inhibitory concentration may be relevant for both efficacy and toxicity. The time above a minimum inhibitory concentration may be different between IV and oral. The impact of this hypothesis on efficacy and toxicity cannot be established by the present study design and would require a randomised study comparing IV and oral administration, powered for efficacy and toxicity rather than PK exposure. Such studies are underway, and can be undertaken with confidence based on the present study results.
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. [25]
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.