Pharmacokinetics and Tolerability of a Single Dose of DN-101, a New Formulation of Calcitriol, in Patients with Cancer

Abstract

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 z2 hypercalcemia or grade z3 persistent treatment-related toxicities. Single-dose administration of 15,30, 60, 75, 90, 105, 135, and 165 Ag 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 Ag level when the number of capsules required at one time reached 11. No dose-limiting toxicities occurred. Transient and selflimited 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-101doses tested. At the 165 Ag dose, C max was 6.21 F1.99 ng/mL, AUC(0-24) was 41.3 F 9.77 ng h/mL, AUC(0-1) was 55.4 F 8.44, and half-life (T 1/2 ) was 16.2 hours. Conclusions: At doses between 15 and 165 Ag, DN-101 exhibits linear pharmacokinetics. At 165 Ag, 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.Numerous studies have shown that calcitriol, the natural ligand of the vitamin D receptor, potently inhibits cell proliferation in vitro and in vivo in many cell types, including carcinomas of the breast, prostate, colon, skin, and brain, myeloid leukemia cells, and others (1, 2). Recently, calcitriol has also been shown to induce apoptosis and to inhibit angiogenesis, tumor invasion, and metastases (reviewed in ref. 3). Calcitriol or its analogues have been shown to produce additive or synergistic antineoplastic activity with a broad range of agents including dexamethasone (4, 5), retinoids (6, 7), tamoxifen (8 -10), and radiation (11, 12), and several cytotoxic chemotherapy drugs, including docetaxel (13), paclitaxel (14), platinum compounds (15, 16), mitoxantrone (17), doxorubicin (18), and etoposide (19), are enhanced by calcitriol or its analogues. These preclinical data have stimulated interest in developing calcitriol for cancer treatment. Antineoplastic effects of calcitriol occur at supraphysiologic concentrations. In in vitro models of human prostate (LNCaP and DU145), pancreas (CaPAN-1), lung (MV522), breast (MCF-7), myeloma (H929), leukemia (HL-60), rat prostate (Dunning), and murine squamous cell carcinoma (SCC), IC 50 values of 1 to 50 nmol/L have been reported (14, 20 -22). Johnson and Trump also confirm these findings.5 Kumagai et al. found that the 1,25 dihydroxychole...

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

“…calcitriol (achieved half way through infusion; ref. 33). The lack of significant hypercalcemia at DN101 doses of 165 to 180 Ag/wk contrasts with the dose-limiting hypercalcemia noted in our study (33,34).…”

“…C max achieved at our MTD of 74 Ag/wk i.v. calcitriol was comparable with the C max achieved with 165 Ag/wk of oral DN101 (33). Higher C max levels with i.v.…”

“…calcitriol (6.68 ng/mL; C max 16 nmol/L) was also markedly higher than the C max achieved at 75 Ag of a novel weekly oral formulation of calcitriol (DN101, C max 3.8 nmol/L); however, AUC was similar for both formulations (35.6 and 38.4 for calcitriol and DN101, respectively; ref. 33). C max achieved at our MTD of 74 Ag/wk i.v.…”

Phase II trial of high‐dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen‐independent prostate cancer

“…Hypercalcemia can cause clinical symptoms; however, the health consequences of intermittent, mild hypercalcemia are uncertain. In the current study, as well as those of other authors, [21][22][23][24][25][26][27][28] it is unusual for serum calcium levels Ͼ11.0 mg/dL to occur; furthermore, such increases are transient and often do not recur despite continued calcitriol administration.…”

“…Phase I studies of larger size formulation are complete and this agent has completed a phase III evaluation with docetaxel in patients with prostate cancer that clearly demonstrates that weekly calcitriol (at a dose of 0.5 g/kg ϫ 1) plus docetaxel is safe. 27,28 The PSA response rate (19%) for this well-tolerated regimen is interesting, but it is not possible to determine the extent to which this response rate was related to calcitriol, dexamethasone, or their combination. To our knowledge, there are no data with respect to the PSA response rate after the use of dexamethasone on this schedule (4 mg every day ϫ 4, weekly).…”