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

Tomasz (Tom) Beer, Milind Javle, Gilbert N. Lam, W. David Henner, Alvin Wong, Donald L. Trump

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    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 formulatbn. 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 ≥2 hypercalcemia or grade ≥3 persistent treatment-related toxicities. Single-dose administration of 15, 30, 60, 75, 90, 105, 135, and 165 μg 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 μg 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 μg dose, Cmax was 6.21 ± 1.99 ng/mL, AUC(0-24) was 41.3 ± 9.77 ng h/mL, AUC(0-∞) was 55.4 ± 8.44, and half-life (T1/2) was 16.2 hours. Conclusions: At doses between 15 and 165 μg, DN-101 exhibits linear pharmacokinetics. At 165 μg, 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.

    Original languageEnglish (US)
    Pages (from-to)7794-7799
    Number of pages6
    JournalClinical Cancer Research
    Volume11
    Issue number21
    DOIs
    StatePublished - Nov 1 2005

    Fingerprint

    Calcitriol
    Area Under Curve
    Pharmacokinetics
    Neoplasms
    Hyponatremia
    Hypercalcemia
    Proteinuria
    Biological Availability
    Capsules
    Half-Life
    Squamous Cell Carcinoma
    Therapeutics

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of catcitriol, in patients with cancer. / Beer, Tomasz (Tom); Javle, Milind; Lam, Gilbert N.; Henner, W. David; Wong, Alvin; Trump, Donald L.

    In: Clinical Cancer Research, Vol. 11, No. 21, 01.11.2005, p. 7794-7799.

    Research output: Contribution to journalArticle

    Beer, Tomasz (Tom) ; Javle, Milind ; Lam, Gilbert N. ; Henner, W. David ; Wong, Alvin ; Trump, Donald L. / Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of catcitriol, in patients with cancer. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 21. pp. 7794-7799.
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    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 formulatbn. 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 ≥2 hypercalcemia or grade ≥3 persistent treatment-related toxicities. Single-dose administration of 15, 30, 60, 75, 90, 105, 135, and 165 μg 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 μg 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 μg dose, Cmax was 6.21 ± 1.99 ng/mL, AUC(0-24) was 41.3 ± 9.77 ng h/mL, AUC(0-∞) was 55.4 ± 8.44, and half-life (T1/2) was 16.2 hours. Conclusions: At doses between 15 and 165 μg, DN-101 exhibits linear pharmacokinetics. At 165 μg, 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.",
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    T1 - Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of catcitriol, in patients with cancer

    AU - Beer, Tomasz (Tom)

    AU - Javle, Milind

    AU - Lam, Gilbert N.

    AU - Henner, W. David

    AU - Wong, Alvin

    AU - Trump, Donald L.

    PY - 2005/11/1

    Y1 - 2005/11/1

    N2 - 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 formulatbn. 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 ≥2 hypercalcemia or grade ≥3 persistent treatment-related toxicities. Single-dose administration of 15, 30, 60, 75, 90, 105, 135, and 165 μg 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 μg 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 μg dose, Cmax was 6.21 ± 1.99 ng/mL, AUC(0-24) was 41.3 ± 9.77 ng h/mL, AUC(0-∞) was 55.4 ± 8.44, and half-life (T1/2) was 16.2 hours. Conclusions: At doses between 15 and 165 μg, DN-101 exhibits linear pharmacokinetics. At 165 μg, 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.

    AB - 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 formulatbn. 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 ≥2 hypercalcemia or grade ≥3 persistent treatment-related toxicities. Single-dose administration of 15, 30, 60, 75, 90, 105, 135, and 165 μg 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 μg 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 μg dose, Cmax was 6.21 ± 1.99 ng/mL, AUC(0-24) was 41.3 ± 9.77 ng h/mL, AUC(0-∞) was 55.4 ± 8.44, and half-life (T1/2) was 16.2 hours. Conclusions: At doses between 15 and 165 μg, DN-101 exhibits linear pharmacokinetics. At 165 μg, 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.

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