Subacute toxicity and toxicokinetics study of DHP107, an oral paclitaxel formulation with once-weekly dosing in mice

Highlights

• DHP107 is an oral cancer therapy containing paclitaxel as a single active ingredient.

• The target organs of DHP107 were reproductive and hematopoietic organs.

• The systemic exposure was increased dose-dependently.

• The NOAEL of DHP107 was under 25 mg/kg for males, and 50 mg/kg for females.

Abstract

DHP107, an oral formulation of paclitaxel, is effectively and systemically absorbed in intestinal endothelial cells. Although the in vivo efficacy of DHP107 has been reported, the potential toxicity of DHP107 has not been evaluated. Therefore, this study was conducted to evaluate the toxicity and toxicokinetics of DHP107 orally administered to ICR mice at 25, 50, and 100 mg/kg via once-weekly dosing for six weeks. DHP107-related clinical signs were observed in both sexes at 100 mg/kg. There were significant increases in the number of platelets and percentages of reticulocytes and basophils in male mice. Also in males, there was a significant decrease in the absolute and relative weights of testes, epididymides, kidneys, and heart. Relative spleen weights were significantly increased in males treated with doses ≥50 mg/kg which had histopathological correlates. These changes were reversible after a two-week recovery period with the exception of the findings in the reproductive organs. Systemic exposure to paclitaxel increased with DHP107 doses in single and multiple dosing with no marked differences between sexes. In conclusion, the target organs were determined to be the reproductive and hematopoietic organs in male mice, suggesting of sex difference and the NOAEL of DHP107 was established to be < 25 mg/kg for males and 50 mg/kg for females.

Introduction

Paclitaxel is a prototypic taxane anticancer drug for solid tumors such as ovarian, breast, and non-small cell lung carcinomas (Sandler et al., 2006; Vergote et al., 2010; Di Leo et al., 2008). It induces the polymerization of tubulin to stable microtubules and inhibits depolymerization by low temperature and calcium; thus, it can interfere with the mitotic phase and inhibit cell replication.⁴ Paclitaxel is insoluble in water, so the current commercial formulation uses polyoxyethylated castor oil (Cremophor EL) as a vehicle for intravenous administration (Lim et al., 2015). However, Cremophor EL induces hypersensitivity reactions and neuropathy, and also has a nonlinear pharmacokinetic profile in humans (Kim et al., 2004; Ryu et al., 2017). For this reason, an oral formulation of paclitaxel without Cremophor EL was developed as a more convenient and safer option for patients and to prevent unnecessary hospitalization (Hahn et al., 2014). Oral administration of paclitaxel has low bioavailability because of P-glycoprotein (P-gp), cytochrome P450, and other membrane proteins in the gastrointestinal mucosa (Ryu et al., 2017). Therefore, the oral formulation of paclitaxel was combined with a P-gp inhibitor to enhance its bioavailability (van Asperen et al., 1998). However, this combination has the potential to interact with concomitant medications (Balayssac et al., 2005).

DHP107 is a lipid-based oral paclitaxel formulation, which was developed for absorption without P-gp inhibitors or Cremophor EL (Ryu et al., 2017; Jang et al., 2017). It exhibited strong antitumor efficacies in female Balb/c nude mice and an orthotopic mouse model of ovarian cancer (Hahn et al., 2014; Hong et al., 2007). The absorption mechanisms of DHP107 were evaluated in mice and rats (Jang et al., 2017; Shin et al., 2009). After the oral administration of DHP107, paclitaxel was effectively absorbed through the intestinal lipid transport system and distributed in most organs, including the liver, spleen, lungs, kidneys, and gastrointestinal tract in a time-dependent manner (Hong et al., 2007). The efficacy and safety of DHP107 were demonstrated to be equivalent to intravenous paclitaxel in Phase IIa and Phase III studies in patients with advanced gastric cancer (Ryu et al., 2017; Kang et al., 2018). However, the potential toxicity of DHP107 was not evaluated in non-clinical studies. We investigated the toxicity and toxicokinetics of DHP107 by repeated oral administration to ICR mice for six weeks, in compliance with the Good Laboratory Practice (GLP) guidelines of the Organization for Economic Cooperation and Development (OECD, 1998).