Pharmacokinetics of oral cyclosporin A when co-administered to enhance the absorption of orally administered docetaxel.
OBJECTIVE
To evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the absorption of orally administered docetaxel.


METHODS
Patients (n = 9) with histological proof of solid cancer received oral docetaxel 75 mg/m2 in combination with oral CsA 15 mg/kg.


RESULTS
The area under the blood concentration-time curve (AUC) of CsA when combined with docetaxel 75 mg/m2 was 31.0+/-9.3 mg/l h (mean +/- SD). Compared with literature data of the same dose of CsA, AUC values in our study appear to be substantially higher. In addition, compared with the AUC values of CsA in combination with oral paclitaxel (previously published data), AUC values in this study are approximately 1.5-fold higher.


CONCLUSIONS
The higher AUC values of CsA obtained in this study compared with literature data may be explained by competitive inhibition of cytochrome P450 (CYP) 3A4-mediated metabolism of CsA by docetaxel. In addition, the higher levels of CsA with docetaxel than with paclitaxel co-administration may be explained by the fact that docetaxel is almost exclusively metabolised by CYP 3A4, whereas paclitaxel is predominantly metabolised by CYP 2C8 and to a lesser extent by CYP 3A4.
Malingré
M M
MM
Department of Medical Oncology, The Netherlands, Cancer Institute/antoni van Leeuwenhoek Hospital, Amsterdam. apmmg@slz.nl
Ten Bokkel Huinink
W W
WW
Mackay
M
M
Schellens
J H
JH
Beijnen
J H
JH
D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077143:Docetaxel; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D043823:Taxoids
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D043823:Taxoids; D000077143:Docetaxel; D016572:Cyclosporine; D017239:Paclitaxel