Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.

No abstract

The oral bioavailability of many cytotoxic drugs is low and/or highly variable. This can be caused by high affinity for drug transporters and activity of metabolic enzymes in the gastrointestinal tract and liver. In this review, we will describe the main involved drug transporters and metabolic enzymes and discuss novel methods to improve oral treatment of affected substrate drugs. Results of preclinical and clinical phase I and II studies will be discussed in which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are given orally in combination with an inhibitor of drug transport or drug metabolism. Future randomized studies will, hopefully, confirm that this strategy for oral treatment is at least as equally effective and safe as standard intravenous administration of these drugs. The Oncologist 2002;7:516-530

Oral paclitaxel plus CsA is active and safe in advanced NSCLC, including in patients previously treated with chemotherapy.

Oral paclitaxel in combination with CsA is both active and safe in chemonaïve patients with advanced gastric cancer. Toxicities were mainly gastrointestinal.

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...

This case report describes the history of a patient with an aggressive course of a metastatic extra-adrenal pheochromocytoma (paraganglioma) who received different combination chemotherapy regimens with no or short-lasting clinical benefit. However, during treatment with single-agent paclitaxel, there was a significant clinical improvement, a partial biochemical response and a minor roentgenologic response, which was sustained for 1 year. In this report we present this case and also review the literature on the chemotherapy used for this rare disease over the past 15 years. To enable the activity of paclitaxel against this neoplasm to be determined, more patients need to be treated.

Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline pre-treated patients with advanced breast cancer.