title: Investigating the relationship between serum thrombopoietin kinetics and the platelet-sparing effect: A clinical pharmacological evaluation of combined paclitaxel and carboplatin in patients with non-small cell lung cancer.
abstract: We conducted a clinical pharmacological evaluation of paclitaxel/carboplatin combination in Japanese patients with non-small cell lung cancer. The purpose of this study was to identify the optimal dose of this combination and to investigate the relationships between the pharmacokinetic profiles of these 2 drugs, serum thrombopoietin (TPO) kinetics and the platelet-sparing effect. Patients received paclitaxel at 180-225 mg/m(2) by intravenous infusion over 3 h, followed by carboplatin at a target area under the concentration-time curve (AUC) of 6 mg/ml x min as a 1-h infusion. Serum paclitaxel, free platinum and TPO concentrations were measured using high-performance liquid chromatography, atomic absorption spectrometry and a double-sandwich enzyme-linked immunosorbent assay, respectively. Thirteen patients were enrolled. Neutropenia was the most frequent hematological toxicity and was significantly related to the time for which paclitaxel concentrations remained above 0.05 micro mol/ml. The prominent non-hematological toxicities were myalgia and sensory-dominant neuropathy. In this study, platelet and serum TPO kinetics were clearly different from those in our previous study of single-agent carboplatin (21). The platelet counts at the nadir were significantly higher (p<0.0001) in patients treated with paclitaxel/carboplatin combination (161,000+/-38,000/ micro l) compared with single-agent carboplatin (92,000+/-28,000/ micro l). The early increase in TPO (the percentage increase in TPO at day 4) was significantly greater (p=0.0345) in patients treated with paclitaxel/carboplatin combination (57.8+/-44.5%) compared with single-agent carboplatin (21.3+/-34.1%). The recommended doses are paclitaxel 210 mg/m(2) and carboplatin at an AUC of 6 mg/ml x min every 3 weeks. The observed platelet-sparing effect of the paclitaxel/carboplatin might be related to the early increase in circulating TPO levels, although the precise mechanism remains to be elucidated.
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Daga
authors.forename: Takeshi
authors.initials: T
authors.lastname: Isobe
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujitaka
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001792:Blood Platelets / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D013054:Spectrophotometry, Atomic; D013926:Thrombopoietin / Q000097:blood*
chemical_list: D013926:Thrombopoietin; D016190:Carboplatin; D017239:Paclitaxel