title: Therapeutic index by combination of adriamycin and docetaxel depends on dosing time in mice.
abstract: Although the combination of adriamycin and docetaxel showed a better cure rate against metastatic breast cancer, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule, based on a chronopharmacologic approach, to relieve severe adverse effects. In experiment 1, adriamycin or docetaxel was injected i.p. at 2, 6, 10, 14, 18, or 22 hours after light onset (HALO) to estimate toxicities. In experiment 2, the dosing time dependency of toxicity and pharmacokinetics were assessed in the combination of adriamycin and docetaxel. In addition, G2-M phase in myelocyte cells was determined in nontreated mice. Adverse effects caused by adriamycin were shown to be the worst at 2 HALO and the best at 14 HALO. On the other hand, docetaxel-induced adverse effects were more severe at 14 HALO than at 2 HALO. In the combination study, the D(2)-A(1)4 group, in which docetaxel was administered at 2 HALO followed by adriamycin at 14 HALO, showed the most toxicity relief of all the treated groups. In the pharmacokinetic study, the dosing time dependency of toxicities was not related to the daily variation of pharmacokinetics of adriamycin and docetaxel. A significant 24-hour rhythm of G2-M phase distribution was found in myelocyte cells of nontreated mice. The daily variation of leukopenia caused by docetaxel corresponded to the 24-hour rhythm of G2-M phase distribution. These findings reveal that the therapeutic index of the combined chemotherapy can be improved by administering adriamycin and docetaxel at the time when the most adverse effects are relieved in each drug.
authors.affiliation: Clinical Pharmacokinetics and Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tabuchi
authors.forename: Hideto
authors.initials: H
authors.lastname: To
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakaguchi
authors.forename: Naho
authors.initials: N
authors.lastname: Goto
authors.forename: Ayako
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Shun
authors.initials: S
authors.lastname: Higuchi
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D016195:G2 Phase / Q000187:drug effects; D007958:Leukocyte Count; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin