Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer

Abstract

Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor ciclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m À2 combined with CsA 10 mg kg À1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m À2 week À1 . Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter-and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer. British Journal of Cancer (2006) As the incidence of breast cancer rises with advancing age, the total number of women with breast cancer will increase (Feigelson et al, 1997). Paclitaxel is widely used in advanced breast, lung and ovarian cancer. In breast cancer, paclitaxel has demonstrated activity as a single agent in first-and second-line treatment and in combination schedules (Van Poznak et al, 2002). Tumour response rates of 20 -30% have been observed in several phase III studies in second-line treatment (Di Leo and Piccart, 1999). Weekly infusions of paclitaxel have gained wide popularity because of the favourable toxicity profile allowing dose intensifications (Seidman et al, 1997;Perez et al, 2001). Seidman et al (1997) reported in a phase II study using weekly 100 mg m À2 an overall response rate (ORR) of 53% in 30 breast cancer patients who had failed first-line chemotherapy (Perez et al, 2001). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3 sensory neuropathy was observed in 10% of patients receiving doses of less than 100 mg m weekly  2 q3wks (Green et al, 2005). There is also evidence that weekly paclitaxel can be effective as rescue in patients who have failed paclitaxel administered every 3 weeks (Perez et al, 2001). Oral administration of paclitaxel is convenient and practical for patients and circumvents systemic exposure to the vehicle Cremophor EL, which is held responsible for hypersensitivity reactions (Meerum Terwogt et al, 1998). Moreover, oral administration enables the development of chronic treatment schedules, resulting in sustained plasma...

Cytotoxic and antiangiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles

“…Long-term uses of these inhibitors that are immunosuppressive and calcium channel blockers may present safety concerns. The oral paclitaxel formulation (Paxoral ® ) developed by IVAX Research needs cyclosporine co-administration to increase bioavailability [41] and thus faces the same dilemma. Loading paclitaxel in lipid nanoparticles and subsequently solubilized by Solutol ® HS15 increased oral bioavailability 3-fold over Taxol ® but huge inter-animal variability exists [9].…”

Oral paclitaxel chemotherapy for brain tumors: Ideal combination treatment of paclitaxel and P-glycoprotein inhibitor

“…Oral administration of paclitaxel was planned to maximize the chemotherapeutic effects of paclitaxel (18). However, because P-gp is expressed on the luminal side of plasma membrane of gut epithelial cells (15), paclitaxel cannot be absorbed from gut lumen. In addition, P-gp on the endothelial cells in melanoma brain metastasis (Fig.…”

“…Metronomic chemotherapy uses antiangiogenic effects of cytotoxic agents and shows better therapeutic results in several tumor types (13,14). However, P-gp expressed in the luminal side of plasma membrane of gut epithelial cells prevents P-gp substrate chemotherapeutic agents from adsorption in the gut (15). In addition, metronomic chemotherapy is expected to be ineffective on tumors in the brain because P-gp expression on the brain endothelial cells extruded cytotoxic agents out of endothelial cells.…”

“…These properties of paclitaxel create expectations that paclitaxel could be a good therapeutic agent in the treatment of brain tumors. But as paclitaxel is one of the P-gp substrates (21)(22)(23), it cannot reach tumor cells in the brain parenchyma (24), which makes it hard to absorb orally administered paclitaxel from the gut lumen (15). Therefore, inhibition of P-pg activity is essential.…”

Simultaneous LC–MS–MS Determination of HM30181A, [2-(2-{4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl]amide, as a new P-Glycoprotein Inhibitor and Its Two Metabolites, M1 and M2, in Human Plasma: Application to a Pharmacokinetic Study

“…The presence of P-gp in the luminal side of gut enterocytes as well as the luminal side of the brain capillaries inhibits the influx of P-gp substrates such as chemotherapeutic agents in the gut or brain parenchyma [3][4][5]. Thus, oral co-administration of P-gp inhibitor with chemotherapeutic agent as a P-gp substrate is expected to be effective on brain tumors, because inhibition of P-gp activity improves the absorption of P-gp substrate in the gastrointestinal tract and passage into the brain.…”