Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of calcitriol, in patients with cancer.

Background: Intermittent administration allows substantial dose escalation of calcitriol but limited bioavailability of the commercially available formulations at high doses is limiting. In this dose escalation study, we sought to evaluate the tolerability and pharmacokinetics of a single oral dose of DN-101, a high-dose calcitriol formulation.

Methods: DN-101 doses were escalated in sequential groups of three to six patients with advanced solid tumors. Dose-limiting toxicity was defined as grade > or =2 hypercalcemia or grade > or =3 persistent treatment-related toxicities. Single-dose administration of 15, 30, 60, 75, 90, 105, 135, and 165 mug was tested.

Results: Thirty-eight patients were enrolled in 2002 and 2003. The median age was 70 years (range, 44-91 years). Dose escalation was stopped at the 165 microg level when the number of capsules required at one time reached 11. No dose-limiting toxicities occurred. Transient and self-limited grade 3 toxicities were hyponatremia (2) and proteinuria (1). A dose-proportional increase in peak concentration (C(max)) and area under the concentration curve (AUC) was seen across the full range of DN-101 doses tested. At the 165 microg dose, C(max) was 6.21 +/- 1.99 ng/mL, AUC(0-24) was 41.3 +/- 9.77 ng h/mL, AUC(0-infinity) was 55.4 +/- 8.44, and half-life (T(1/2)) was 16.2 hours.

Conclusions: At doses between 15 and 165 microg, DN-101 exhibits linear pharmacokinetics. At 165 microg, DN-101 achieves systemic exposure that is 5- to 8-fold higher than that achieved with commercial formulations of calcitriol, which makes DN-101 comparable to that required for antitumor activity in vivo in a murine squamous cell carcinoma model.