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Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer.

Howes JB, de Souza PL, West L, Huang LJ, Howes LG - BMC Clin Pharmacol (2011)

Bottom Line: The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively.The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg.The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology and Therapeutics, Griffith University, Gold Coast Hospital, Southport, Queensland, Australia.

ABSTRACT

Background: Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer.

Methods: The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection.

Results: Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 ± 0.14 μg/ml after 0.87 ± 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h.

Conclusions: Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion.

Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000.

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Related in: MedlinePlus

Total phenoxodiol levels following the bolus intravenous administration of 5 mg/kg of phenoxodiol over 5 minutes.
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Figure 2: Total phenoxodiol levels following the bolus intravenous administration of 5 mg/kg of phenoxodiol over 5 minutes.

Mentions: Summaries of the pharmacokinetic data for free and total phenoxodiol following the single intravenous bolus dose are presented in Tables 1 and 2. Plasma concentration versus time plots for free and total phenoxodiol for these patients are presented in Figures 1 and 2. Linear regression of log plasma concentration versus time plots indicate that phenoxodiol appeared to follow first order kinetics in all patients (that is, a single phase of elimination from plasma). This was the case for both free and total phenoxodiol. Total phenoxodiol had a longer plasma elimination half-life than free phenoxodiol, but both were relatively short (mean values 3.19 ± 1.93 h and 0.67 ± 0.53 h, respectively). These short half-lives were associated with relatively high mean total plasma clearance rates of 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h respectively. The apparent volumes of distribution (Vd) at steady state for free and total phenoxodiol were relatively low (1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg, for free and total phenoxodiol, respectively) and total phenoxodiol had a lower volume of distribution than free phenoxodiol. The area under the plasma concentration versus time curves for (AUC) total phenoxodiol following the bolus intravenous dose in Part 1 of the study was approximately 15 times greater than for free phenoxodiol.


Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer.

Howes JB, de Souza PL, West L, Huang LJ, Howes LG - BMC Clin Pharmacol (2011)

Total phenoxodiol levels following the bolus intravenous administration of 5 mg/kg of phenoxodiol over 5 minutes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3045896&req=5

Figure 2: Total phenoxodiol levels following the bolus intravenous administration of 5 mg/kg of phenoxodiol over 5 minutes.
Mentions: Summaries of the pharmacokinetic data for free and total phenoxodiol following the single intravenous bolus dose are presented in Tables 1 and 2. Plasma concentration versus time plots for free and total phenoxodiol for these patients are presented in Figures 1 and 2. Linear regression of log plasma concentration versus time plots indicate that phenoxodiol appeared to follow first order kinetics in all patients (that is, a single phase of elimination from plasma). This was the case for both free and total phenoxodiol. Total phenoxodiol had a longer plasma elimination half-life than free phenoxodiol, but both were relatively short (mean values 3.19 ± 1.93 h and 0.67 ± 0.53 h, respectively). These short half-lives were associated with relatively high mean total plasma clearance rates of 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h respectively. The apparent volumes of distribution (Vd) at steady state for free and total phenoxodiol were relatively low (1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg, for free and total phenoxodiol, respectively) and total phenoxodiol had a lower volume of distribution than free phenoxodiol. The area under the plasma concentration versus time curves for (AUC) total phenoxodiol following the bolus intravenous dose in Part 1 of the study was approximately 15 times greater than for free phenoxodiol.

Bottom Line: The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively.The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg.The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology and Therapeutics, Griffith University, Gold Coast Hospital, Southport, Queensland, Australia.

ABSTRACT

Background: Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer.

Methods: The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection.

Results: Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 ± 0.14 μg/ml after 0.87 ± 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h.

Conclusions: Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion.

Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000.

Show MeSH
Related in: MedlinePlus