title: Influence of amifostine on the toxicity and pharmacokinetics of docetaxel in metastatic breast cancer patients: a pilot study.
abstract: Preclinical studies suggest that amifostine could protect against toxicities induced by taxoids. We conducted a clinical and pharmacokinetic pilot study to assess the feasibility and toxicity of the docetaxel plus amifostine combination and the absence of influence of amifostine on docetaxel pharmacokinetics. We included 18 previously treated women with metastatic breast cancer (median age, 58.5 years; range, 34-74) in this single-center study. They were to receive a first course of docetaxel at 100 mg/m(2) i.v. as a 1-h infusion, then subsequent courses of docetaxel at 100 mg/m(2) preceded by amifostine at 910 mg/m(2) given as a 15-min i.v. infusion. Treatment was given every 3 weeks until disease progression or occurrence of unacceptable toxicity. We focused on neutrophils nadir (NN), time to nadir occurrence, and time to recovery of a neutrophil count >2 x 10(9)/liter, means of which were compared between cycle 1 and each of the other cycles by paired Student's t test. The total number of administered cycles was 84 (median number/patient, 4; range, 1-8). One patient received only the first course of docetaxel and was therefore not evaluable for amifostine effect. Neutropenia grade >2 occurred in 16 patients and was febrile in only 1. Other hematological and nonhematological toxicities were mild and manageable. Amifostine had no obvious influence on docetaxel-induced myelotoxicity as expressed by NN, time to nadir occurrence, and time to recovery. The mean NN (1 x 10(6)/liter) was 345 (18 patients) for cycle 1, then 318 (17 patients), 330 (13 patients), 340 (11 patients), 470 (8 patients), 200 (8 patients), 680 (5 patients), and 545 (4 patients) for cycles 2, 3, 4, 5, 6, 7, and 8, respectively (P >0.2). Individual pharmacokinetic (PK) parameters of docetaxel estimated in 11 patients undergoing blood sampling showed no influence of amifostine on the PK profile of docetaxel. Mean clearances (liter/h/m(2)) and peak concentration (C(peak); ng/ml) were 29.9 at cycle 1 versus 32.8 at cycle 2 (not significant) and 2849.9 at cycle 1 versus 2542.5 at cycle 2 (not significant), respectively. The population analysis including those 11 patients and 49 additional patients receiving docetaxel in other studies confirmed those findings. This study does not support evidence for amifostine cytoprotection against docetaxel-induced myelosuppression and shows that there is no major influence of amifostine on docetaxel PK parameters. For the other toxicities, which are usually cumulative, the present study has design limitations and further comparative trials are warranted.
authors.affiliation: Laboratoire d'Oncopharmacologie, Unité de chimiothérapie,Service de Médecine Interne et Laboratoire d'Investigation Clinique et d'Oncologie Expérimentale HJ Tagnon, Institut Jules Bordet, 1000, Brussels, Belgium.
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
authors.forename: Philippe
authors.initials: P
authors.lastname: Hennebert
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Thierry
authors.initials: T
authors.lastname: Gil
authors.forename: Joseph
authors.initials: J
authors.lastname: Kerger
authors.forename: Jean
authors.initials: J
authors.lastname: Selleslags
authors.forename: Christiane
authors.initials: C
authors.lastname: Brassinne
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.forename: Dominique
authors.initials: D
authors.lastname: de Valeriola
mesh_terms: D000328:Adult; D000368:Aged; D004999:Amifostine / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000077143:Docetaxel; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D010865:Pilot Projects; D015996:Survival Rate; D043823:Taxoids; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D004999:Amifostine; D017239:Paclitaxel