Journal Article

No relation between docetaxel administration route and high‐grade diarrhea incidence

Song, Ji‐Ying, Marchetti, Serena, Schellens, Jan H. M., Stuurman, Frederik E., Beijnen, Jos H., Rosing, Hilde, Schinkel, Alfred H., Hendrikx, Jeroen J. M. A., Weger, Vincent A., Lagas, Jurjen S.

2020

Overview

Oral administration of docetaxel in combination with the CYP3A4 inhibitor ritonavir is used in clinical trials to improve oral bioavailability of docetaxel. Diarrhea was the most commonly observed and dose‐limiting toxicity. This study combined preclinical and clinical data and investigated incidence, severity and cause of oral docetaxel‐induced diarrhea. In this study, incidence and severity of diarrhea in patients were compared to exposure to orally administered docetaxel. Intestinal toxicity after oral or intraperitoneal administration of docetaxel was further explored in mice lacking Cyp3a and mice lacking both Cyp3a and P‐glycoprotein. In patients, severity of diarrhea increased significantly with an increase in AUC and Cmax (P = .035 and P = .025, respectively), but not with an increase in the orally administered dose (P = .11). Furthermore, incidence of grade 3/4 diarrhea after oral docetaxel administration was similar as reported after intravenous docetaxel administration. Intestinal toxicity in mice was only observed at high systemic exposure to docetaxel and was similar after oral and intraperitoneal administration of docetaxel. In conclusion, our data show that the onset of severe diarrhea after oral administration of docetaxel in humans is similar after oral and intravenous administration of docetaxel and is caused by the concentration of docetaxel in the systemic blood circulation. Mouse experiments confirmed that intestinal toxicity is caused by a high systemic exposure and not by local intestinal exposure. Severe diarrhea in patients after oral docetaxel is reversible and is not related to the route of administration of docetaxel.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Administration, Intravenous / Administration, Oral / Adult / Aged / Animals / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacokinetics / Antiretroviral drugs / Area Under Curve / ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics / Cytochrome / Cytochrome P-450 CYP3A - genetics / Diarrhea / Diarrhea - chemically induced / Diarrhea - physiopathology / Docetaxel - administration & dosage / Docetaxel - adverse effects / Docetaxel - pharmacokinetics / Drug dosages / Ethanol / Experiments / Female / Glycoproteins / Humans / Incidence / Injections, Intraperitoneal / Lung cancer / Male / Mice / Mice, Knockout / Middle Aged / Oral administration / oral docetaxel / Original / Pharmacokinetics / Pharmacology / Plasma / Rodents / Sample size / Severity of Illness Index / Studies / toxicity