A Phase 1 Dose‐Escalation Study of Low‐Dose Metronomic Treatment With Novel Oral Paclitaxel Formulations in Combination With Ritonavir in Patients With Advanced Solid Tumors

Abstract

ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low-dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open-label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice-daily 30-mg paclitaxel combined with twice-daily 100-mg ritonavir (MP5/r 30-30/100-100) in 9 dose levels. Dose-limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20-20/100-100, the maximum paclitaxel plasma concentration and area under the concentration-time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng • h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20-20/100-100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted.

Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies

“…Three different oral paclitaxel formulations were previously investigated in various clinical studies [ 16 , 20 , 27 ]. Registered IV formulations of paclitaxel (6 mg/mL dissolved in ethanol and Cremophor EL1:1 w/v, Mayne Pharma, Melbourne Australia or Paxene, Norton Healthcare Ltd., London, United Kingdom) were used as a drinking solution [ 16 , 27 ].…”

“…The PK data originated from three clinical studies which included a total of 58 patients [ 16 , 20 , 27 ]. A summary of applied doses, dosing, and sampling times is shown in Supplementary Table 1.…”

“…The daily doses studied for ModraPac capsule formulation included 5, 10, 15, 20, 30, and 40 mg; and for the ModraPac tablet formulation 40, 50, and 60 mg. Ritonavir was administered at a daily dose of 200 mg in all dose levels. This study was registered in the Dutch trial registry (NTR3632) and European Union Drug Regulating Authorities Clinical Trials (EudraCT) Database (2010-021,525-13) [ 20 ].…”

“…Additionally, the bioavailability was boosted by inhibiting gastrointestinal and hepatic CYP3A4 and P-gp through co-administration with the potent CYP3A4 inhibitor, and moderate P-gp inhibitor, ritonavir [ 18 , 19 ]. Several early phase clinical studies have shown that clinically relevant paclitaxel plasma concentrations could be achieved using these strategies [ 20 , 21 ].…”

Boosting the oral bioavailability of anticancer drugs through intentional drug–drug interactions

“…Inhibitors of P‐gp and/or CYP3A4 have been found to boost the oral bioavailability of paclitaxel and docetaxel 33 . These findings led to promising clinical trials testing the ability of encequidar, a selective P‐gp inhibitor, to boost the oral bioavailability of paclitaxel 45 or the ability of ritonavir, an inhibitor of P‐gp and CYP3A, to boost the oral bioavailability of solid dispersion formulations of paclitaxel (ModraPac) and docetaxel (ModraDoc) 46,47 ; the clinical development of these formulations is ongoing and is likely to result in the eventual commercial approval of an oral, boosted taxane formulation.…”