Page 247 - Vitamin D and Cancer

234 C.M. Barnett and T.M. Beer

clinical setting, and therefore illustrate the need for a control arm to interpret
these results, nevertheless the observation is suggestive of a treatment effect.
Dose escalation was not carried out in the Gross et al. study beyond doses of
2.5 mg/day due to concern about hypercalciuria.

Every Other Day Subcutaneous Administration

The hypotheses that an alternative route of administration and dosing schedule may
allow greater dose escalation by reducing the calcemic toxicity of calcitriol was
examined in a clinical trial of subcutaneous administration every other day.
Significant escalation was indeed possible with doses of 10 mg reached and peak
calcitriol concentrations of approximately 0.7 nM at the 8 mg dose. Hypercalcemia
precluded further dose escalation [129].

Weekly Oral Dosing

In the initial phase I study, weekly oral dosing demonstrated both significant potential
with regard to dose escalation and revealed a formulation-specific absorption ceiling.
Doses as high as 2.8 mg/kg were examined. In this study, peak blood calcitriol con-
centrations (C ) of 3.7–6.0 nM were observed without dose limiting toxicity, but
max
above 0.48 mg/kg, C and the area under the concentration curve (AUC) did not
max
increase linearly [130]. Mundi et al. later confirmed that the commercially available
formulation of calcitriol had non-linear pharmacokinetics [131] and later showed a
similar pattern with a liquid calcitriol formulation [132].
A new formulation of calcitriol has been developed to overcome the limitation
of the pharmacokinetics and the large quantity of pills required for treatment
(calcitriol is only commercially available as 0.25 and 0.5 mg capsules). DN-101
(Novacea, Inc. South San Francisco), given as a single dose capsule, demonstrated
dose-proportional increases in both C and AUC when studied over a range of
max
doses (15–165 mg). Peak calcitriol concentrations (14.9 nM at the 165 mg dose)
were higher than any previously reported [133]. While single dose administration
was free from dose-limiting toxicity, grade 2 hypercalcemia was seen with repeat
weekly dosing in the 60 mg group [134]. It is likely that a higher weekly dose would
have been achievable if a more conventional grade 3 toxicity criterion were utilized
or if DN-101 had been co-administered with agent(s) that have potential to reduce
hypercalcemia (i.e., bisphosphonates or steroids).

10.6.2.2 Early Stage Studies of Calcitriol in Combination
with Other Agents

Daily Administration

One study examined daily calcitriol, dosed at 0.5 mg daily with daily dexamethasone
and weekly carboplatin in 34 patients with androgen independent prostate cancer