Fospropofol pharmacokinetics
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Introduction
Fospropofol is a new water-soluble prodrug of propofol. The water-soluble formulation aims to bypass the disadvantages of propofol’s lipid emulsion: pain on injection (1, 2), risk of infection from decreased bacterial clearance(3), high lipid intake during long-term administration (4, 5), and dose-related cardiac and respiratory depression (5).
Based on a review of the literature, propofol is modeled using a three-compartment model with peripheral, central, and slow compartments (6, 7). The conversion of the fospropofol prodrug introduces two additional compartments leading to a five-compartment model (7).
Case Simulation
Due to the delay in conversion of prodrug to propofol, time to peak propofol concentration after a bolus administration of fospropofol is noticeably longer than after bolus administration of propofol in lipid emulsion. Administering the highest-recommended fospropofol dosage of 12.5 mg/kga single administration does not reach levels sufficient for loss of consciousness (LOC) until four minutes, compared to LOC after one circulatory time with the highest-recommended dosing with propofol of 2.5mg/kg(8).
Onset of sedation with fospropofol is reported to have a median time of two minutes from administration (8). Administering half-initial dose of fospropofol after two minutes, as might occur by an anxious clinician wishing to proceed with sedation, results in no appreciable improvement in onset time,but return of levels to LOC threshold takes 20 minutes. This may lead to prohibitive delays and prolonged periods of loss of consciousness during quick procedures, such as colonoscopies, for which fospropofol is intended (9).
Conclusion
We present a user-friendly on-line computer simulation based on pharmacokinetic and pharmacodynamic data available in the scientific literature. This simulation helps illustrate potential unanticipated problems that may be encountered in clinical use of new drugs.
References
1. Picard P, Tramer MR. Prevention of Pain on Injection with Propofol: A Quantitative Systematic Review. Anesthesia Analgesia. 2000;90(4):963-969
2. Nakane M, Iwama H. A potential mechanism of propofol-induced pain on injection based on studies using nafamostat mesilate. British Journal of Anaesthesia. 1999;83(3):397-404
3. Kelbel I, Koch T, Weber A, Schiefer HG, Van Ackern K, Neuhof H. Alterations of bacterial clearance induced by propofol. Acta Anaesthesiologica Scandinavica. 1999;43(1):71-76
4. Fulton B, Sorkin E. Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation. Drugs. . 1995 50(4):636-57
5. McKeage K, Perry C. Propofol: a review of its use in intensive care sedation of adults. CNS Drugs. . 2003;17(4):235-72
6. Gepts E, Camu F, Cockshott I, Douglas E. Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg. . 1987 66(12):1256-63
7. Fechner J, Ihmsen H, Hatterscheid D, et al. Pharmacokinetics and clinical pharmacodynamics of the new propofol prodrug GPI 15715 in volunteers. Anesthesiology. . 2003 99(2):303-13
8. Gan T. Pharmacokinetic and pharmacodynamic characteristics of medications used for moderate sedation. Clin Pharmacokinet. 2006;45(9):855-69
9. Group TAI-CW. Procedural Sedation with AQUAVAN® Injection during Colonoscopy: A Randomized, Open-Label, Multicenter, Dose-Ranging Phase II Study of Safety and Efficacy for Endoscopic Procedures. Anesthesiology 2004;101: A20.
