The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel

• Published in: Anti-cancer drugs Vol. 12; no. 4; pp. 351 - 358
• Main Authors: Malingré, Mirte M, Beijnen, Jos H, Rosing, Hilde, Koopman, Franciska J, van Tellingen, Olaf, Duchin, Ken, ten Bokkel Huinink, Wim W, Swart, Martha, Lieverst, Jan, Schellens, Jan HM
• Format: Journal Article
• Language: English
• Published: England Lippincott Williams & Wilkins, Inc 01-04-2001
• Subjects: Adenocarcinoma - drug therapy; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - toxicity; Area Under Curve; Breast Neoplasms - drug therapy; Carcinoma, Small Cell - drug therapy; Cyclosporine - administration & dosage; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Diseases - chemically induced; Hematologic Diseases - chemically induced; Humans; Infusions, Intravenous; Lung Neoplasms - drug therapy; Male; Middle Aged; Neoplasms - drug therapy; Neoplasms - pathology; Paclitaxel - administration & dosage; Premedication; Stomach Neoplasms - drug therapy; Uterine Cervical Neoplasms - drug therapy; Uterine Neoplasms - drug therapy
• ISSN: 0959-4973; 1473-5741
• DOI: 10.1097/00001813-200104000-00008

The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.1 μM (T>0.1 μM) of oral paclitaxel. The mean (±SD) AUC and T>0.1 μM values of oral paclitaxel with CsA 10 mg/kg were 4.29±0.88 μM·h and 12.0±2.1 h, respectively. With CsA 5 mg/kg these values were 2.75±0.63 μM·h and 7.0±2.1 h, respectively (p = 0.028 for both parameters). In conclusion, dose reduction of CsA from 10 to 5 mg/kg resulted in a significant decrease in the AUC and T>0.1 μM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC and T>0.1 μM values compared to CsA 15 mg/kg (data which we have published previously), the minimally effective dose of CsA is determined at 10 mg/kg.