Fospropofol assay: issues and impact on pharmacokinetic and pharmacodynamic evaluation

Abstract

Following i.v. administration, fospropofol is rapidly metabolized by alkaline phosphatase enzymes, releasing propofolFP. Several pharmacokinetic and pharmacodynamic studies have shown that propofolFP demonstrated differences in pharmacokinetic and pharmacodynamic profiles compared with propofol in a lipid solution [1–5]. We have recently discovered an assay problem that may have affected the measurement of propofolFP plasma concentrations in previously published studies. In the earlier studies [1–4,6], blood samples were collected in tubes containing sodium orthovanadate (SOV; 60 mg added as a solid powder to maintain 10 mg ml 1 concentration) to prevent further in-vitro conversion of fospropofol to propofol by alkaline phosphatase enzymes. This was found to result in incomplete dissolution of the SOV powder and variable concentrations of SOV that affected plasma pH and caused haemolysis of many samples, leading to changes in propofol extraction recovery and storage stability. As a result, the propofolFP concentrations obtained in previous studies [1–4,6] could possibly be inconsistent and unreliable as the impact of the above-mentioned factors was neither known nor controlled, and, therefore, the originally reported propofol pharmacokinetic and pharmacodynamic results and the derived conclusions could be inaccurate. It was shown that the assay and stability problem was limited to quantitation of propofolFP and that it did not affect the fospropofol concentrations. The new drug application for fospropofol disodium was submitted to the Food and