PURPOSE: To study the CYP3A activity before and after docetaxel administration. Furthermore, it was investigated whether peroral midazolam could predict docetaxel exposure and adverse events. METHODS: Twenty patients with primary high risk breast cancer were given docetaxel as a 1-h infusion 80 mg/m(2) in a 21-day cycle in 3 cycles followed by 3 cycles of cyclophosphamide, epirubicin and fluorouracil. CYP3A activity was assessed a day before and a day after docetaxel by 7.5 mg oral midazolam. All patients were given peroral dexamethasone a total dose of 45 mg, of which 15 mg was given before docetaxel infusion and 30 mg before the latter assessment of CYP3A activity. All except one patient were given 11-19 mg of intravenous dexamethasone before docetaxel infusion. RESULTS: CYP3A activity was clearly induced when assessed a day after docetaxel administration as shown by lower midazolam AUC (P < 0.0001) and higher AUC ratio (1-OH-midazolam/midazolam, P = 0.018). The mean docetaxel AUC was about a half of that previously reported in the literature. Incidence of febrile neutropenia was smaller (15%) than reported in literature with comparable docetaxel doses and seemed to associate with slower metabolism. No correlation between pharmacokinetics of midazolam and docetaxel was found at baseline. CONCLUSIONS: We show here a markedly reduced docetaxel exposure followed by CYP3A induction by, most likely, dexamethasone. Peroral midazolam seemed not to predict docetaxel exposure. Slow CYP3A-mediated metabolism might predispose patients to adverse events of docetaxel.
PURPOSE: To study the CYP3A activity before and after docetaxel administration. Furthermore, it was investigated whether peroralmidazolam could predict docetaxel exposure and adverse events. METHODS: Twenty patients with primary high risk breast cancer were given docetaxel as a 1-h infusion 80 mg/m(2) in a 21-day cycle in 3 cycles followed by 3 cycles of cyclophosphamide, epirubicin and fluorouracil. CYP3A activity was assessed a day before and a day after docetaxel by 7.5 mg oral midazolam. All patients were given peroraldexamethasone a total dose of 45 mg, of which 15 mg was given before docetaxel infusion and 30 mg before the latter assessment of CYP3A activity. All except one patient were given 11-19 mg of intravenous dexamethasone before docetaxel infusion. RESULTS:CYP3A activity was clearly induced when assessed a day after docetaxel administration as shown by lower midazolam AUC (P < 0.0001) and higher AUC ratio (1-OH-midazolam/midazolam, P = 0.018). The mean docetaxel AUC was about a half of that previously reported in the literature. Incidence of febrile neutropenia was smaller (15%) than reported in literature with comparable docetaxel doses and seemed to associate with slower metabolism. No correlation between pharmacokinetics of midazolam and docetaxel was found at baseline. CONCLUSIONS: We show here a markedly reduced docetaxel exposure followed by CYP3A induction by, most likely, dexamethasone. Peroralmidazolam seemed not to predict docetaxel exposure. Slow CYP3A-mediated metabolism might predispose patients to adverse events of docetaxel.
Authors: Bodine P S Belderbos; Koen G A M Hussaarts; Leonie J van Harten; Esther Oomen-de Hoop; Peter de Bruijn; Paul Hamberg; Robbert J van Alphen; Brigitte C M Haberkorn; Martijn P Lolkema; Ronald de Wit; Robert J van Soest; Ron H J Mathijssen Journal: Br J Clin Pharmacol Date: 2019-03-21 Impact factor: 4.335
Authors: Marzia A Locatelli; Philippe Aftimos; E Claire Dees; Patricia M LoRusso; Mark D Pegram; Ahmad Awada; Bo Huang; Rossano Cesari; Yuqiu Jiang; M Naveed Shaik; Kenneth A Kern; Giuseppe Curigliano Journal: Oncotarget Date: 2017-01-10