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.