Abstract
BackgroundPhenoxodiol 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.MethodsThe 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.ResultsFollowing 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.ConclusionsPhenoxodiol 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 registrationAustralian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000
Highlights
Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer
This paper presents data derived from that first-in-human, pharmacokinetic study, and our aim at the time was to determine the pharmacokinetic parameters of phenoxodiol in order to inform us further about the design of Phase I and other studies
The patient who missed out on continuous intravenous infusion had developed progression of her disease and was advised by her oncologist to proceed with other treatments; there was no evidence that the single administration of phenoxodiol had contributed to her disease progression
Summary
Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. Phenoxodiol is a synthetic analogue of genistein with unknown mechanism of action. It appears to have pleiotropic actions such as inhibition of tyrosine kinases, inhibition of topoisomerase II in a dose-dependent manner and inhibition of the X-linked inhibitor of apoptosis [2,10,11,12] but the predominant mode of action remains to be elucidated. At the time this study was performed in 2000, we had no information regarding the behaviour of phenoxodiol in humans, so the first study undertaken was a pharmacokinetic study to investigate both bolus and continuous intravenous administration. This paper presents data derived from that first-in-human, pharmacokinetic study, and our aim at the time was to determine the pharmacokinetic parameters of phenoxodiol in order to inform us further about the design of Phase I and other studies
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