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

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

The withdrawal of torcetrapib from drug development: implications for the future of drugs that alter HDL metabolism

In December 2006, Pfizer withdrew torcetrapib, a cholesterol ester transferase protein (CETP) that elevates plasma HDL levels, from further development following an excess in mortality in the active treatment arm of the study. Although torcetrapib successfully elevated HDL levels, significant increases in blood pressure were observed in three surrogate outcome studies that were conducted over the approximate same time period. Two of these studies examined carotid intima-medial thickness and one examined coronary artery atheroma load and none of the studies found a significant benefit in favour of torcetrapib therapy. It is likely that the torcetrapib-induced increase in blood pressure contributed to the apparent adverse effect of the drug on mortality and further studies are needed to determine why this occurred and whether it is a class effect of CETP inhibitors. in addition, further research is needed to determine whether the manner which CETP alters vascular biology and, in particular, the effect that it has on vascular inflammation associated with denuded endothelium. Despite disappointing results so far, CETP inhibitors should not be abandoned as much remains to be learnt from them and they may yet prove to be a valuable class of lipid-modifying drug

Lipoproteins and cardiovascular reactivity

The observation that relatively short periods of cholesterol lowering therapy can reduce the incidence of coronary artery disease events has prompted interest in the short term effects of lipoproteins on cardiovascular responsiveness. Numerous studies in animals and humans have demonstrated that oxidized LDL-cholesterol can impair endothelial dependent vasodilation in coronary arteries and peripheral resistance vessels. Reduction of plasma LDL-cholesterol levels in hypercholesterolaemic patients improves nitric oxide mediated vasodilator responses in the coronary and peripheral circulation. LDL-cholesterol also potentiates responses to vasoconstrictors such as noradrenaline and endothelin-1 in the absence of endothelium, possibly by enhancing calcium influx into vascular smooth muscle cells. Pharmacological reduction of plasma LDL-cholesterol levels has been shown to reduce blood pressure responses to intravenous infusions of pressor hormones and to stress. However, the relative contribution of changes in endothelial dependent vasodilation and vasoconstrictor or inotropic responses remains to be established. Short term changes in LDL-cholesterol produce changes in cardiovascular responsiveness that may influence the development of ischaemic events