Fospropofol Assay Issues and Impact on Pharmacokinetic and Pharmacodynamic Evaluation

Abstract

To the Editor:— Fospropofol disodium (GPI 15715 or Aquavan® Injection; MGI Pharma, Inc., Bloomington, MN) is a water-soluble, phosphono-O -methyl prodrug of propofol for intravenous injection. It has been evaluated for sedation during diagnostic and routine therapeutic procedures. The early evaluation studies were published mostly in Anesthesiology between 2003 and 2005.After intravenous administration, fospropofol is rapidly metabolized by alkaline phosphatase enzymes, releasing propofolFP. Several pharmacokinetic and pharmacodynamic studies have shown that propofolFPdemonstrated differences in pharmacokinetic and pharmacodynamic profiles compared with propofol in a lipid solution.1–5We have recently discovered an assay problem that may have affected the measurement of propofolFPplasma concentrations in previously published studies. In the earlier studies,1–4,6blood samples were collected in tubes containing sodium orthovanadate (SOV; 60 mg added as a solid powder to maintain 10 mg/ml 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 hemolysis of many samples, leading to changes in propofol extraction recovery and storage stability. As a result, the propofolFPconcentrations obtained in previous studies1–4,6could possibly be inconsistent and unreliable, because the impact of the aforementioned 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 propofolFPand that it did not affect the fospropofol concentrations. The new drug application for fospropofol disodium was submitted to the US Food and Drug Administration in September 2007. The propofol assay problem was reported in detail in the New Drug Application, as were details of the revised assay methodology. Subsequent to the discovery of the problem, the sample handling procedure was standardized to reduce variation in SOV concentration (e.g. , SOV was added as a solution), and improved sample handling and processing techniques that resolved the problems were developed and validated. Additional studies were then conducted using an appropriate assay to assess the pharmacokinetics and pharmacodynamics of fospropofol in healthy volunteers and patients. We plan to publish these results shortly, along with an estimate of the degree of error from the previously published studies that reported results using the old assay. We very much regret the magnitude of the originally published incorrect information and the confusion that it has and will cause in the pharmacokinetics of propofol from the use of fospropofol.*MGI Pharma, Inc., Bloomington, Minnesota. ajit.shah@mgipharma.com