¹Center for Clinical Pharmacology and Cancer Institute, University of Pittsburgh.

Correspondence: Josephia R. Muindi, MD, PhD, Center for Clinical Pharmacology, 200 Lothrop St, University of Pittsburgh, Pittsburgh, PA 15213. E-mail: muindi@msx.dept-med.pitt.edu

^*Supported by National Cancer Institute grants RO1 CA 67267 and CA 85142; grant DOD PC 970578, US Army Medical Research and Materiel Command; the CaPCURE Award; The Mary Hillman Jennings Foundation; Bristol Myers Squibb; National Cancer Institute core grant P30 CA 47904; and General Clinical Research Center grant MO1-RR00056-40.

Received 21 March 2002; Accepted 9 August 2002.

Abstract

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 g for 3 consecutive days each week, and the maximum dose administered was 38 g for 3 consecutive days each week. The preparation of calcitriol used in this trial was a commercially available caplet (0.5 g 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 (C_max), time to reach C_max, 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 g was only 4 times that at 4 g, 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.