Pharmacokinetics of high-dose oral calcitriol: Results from a phase 1 trial of calcitriol and paclitaxel

骨化三醇 药代动力学 最大值 医学 紫杉醇 药理学 泌尿科 内科学 内分泌学 化疗 维生素D与神经学
作者
Josephia R. Muindi,Yibing Peng,Douglas M. Potter,Pamela A. Hershberger,Jil S. Tauch,M.J. Capozzoli,Merrill J. Egorin,Candace S. Johnson,Donald L. Trump
出处
期刊:Clinical Pharmacology & Therapeutics [Wiley]
卷期号:72 (6): 648-659 被引量:127
标识
DOI:10.1067/mcp.2002.129305
摘要

Objectives The data reported are from a trial designed to determine, in patients with advanced cancer, the maximum tolerated dose and pharmacokinetics of calcitriol when administered with paclitaxel, an agent whose antitumor activity in in vitro and in vivo studies has been shown to be enhanced by calcitriol. An additional goal was to evaluate the relationship between calcitriol dose and hypercalcemia. Methods Calcitriol was given orally for 3 consecutive days each week, and paclitaxel (80 mg/m2) was given intravenously weekly. Thirty-six patients were treated in cohorts composed of 3 to 9 patients, at escalating dose levels of calcitriol. The starting dose of calcitriol was 4 μg for 3 consecutive days each week, and the maximum dose administered was 38 μg for 3 consecutive days each week. The preparation of calcitriol used in this trial was a commercially available caplet (0.5 μg per caplet). Serum calcitriol concentrations were measured by radioimmunoassay. Detailed assessments of calcitriol pharmacokinetics were performed in 26 patients. Results There was substantial interpatient variation in peak serum calcitriol concentrations (Cmax), time to reach Cmax, and area under the concentration versus time curve (AUC). Serum calcitriol AUC was not proportional to calcitriol dose (P = .0014). AUC for the 24-hour period after calcitriol administration [AUC (0–24)] at 38 μg was only 4 times that at 4 μg, instead of the 9.5-fold increase expected for a proportional relationship. Calcitriol plasma concentrations of 600 to 1440 pg/mL were achieved. No dose-limiting toxicity occurred in this trial. Conclusions Despite variability in absorption, very high doses of calcitriol can be safely administered with paclitaxel. The high calcitriol serum concentrations achieved in this study approach those that, both in vitro and in vivo, potentiate the cytotoxicity of taxanes and platinum analogs. Clinical Pharmacology & Therapeutics (2002) 72, 648–659; doi: 10.1067/mcp.2002.129305

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