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Summary and Introduction
Summary
Background: An effective agent is needed that provides rapid onset of sedation and quick recovery for patients undergoing colonoscopy.
Aim: To assess the efficacy and safety of fospropofol disodium in providing sedation in patients undergoing colonoscopy.
Methods: A randomized, double-blind, multicentre trial evaluated 127 adult patients who received fospropofol (2, 5, 6.5 or 8 mg/kg) or midazolam 0.02 mg/kg following pre-treatment with fentanyl. Supplemental doses of study medication were allowed to reach a Modified Observer's Assessment of Alertness/Sedation scale score ≤4. Efficacy end points included sedation success, measures of clinical benefit, sedation, and recovery as well as patient- and doctor-rated satisfaction.
Results: Fospropofol produced a significant dose-dependent increase in sedation success from 24% (2 mg/kg), 35% (5 mg/kg) and 69% (6.5 mg/kg) to 96% (8 mg/kg; P < 0.001). There were also dose-dependent trends for time to sedation, requirements for alternative sedative medication, supplemental doses of sedative and fentanyl, time to ready for discharge and doctor-rated satisfaction scores. Fospropofol was well tolerated, with most adverse events mild-to-moderate in severity.
Conclusion: The 6.5 mg/kg dose of fospropofol provides the ideal balance of efficacy and safety for patients undergoing colonoscopy and has been selected for phase 3 clinical development.
Introduction
Gastroenterologists commonly use benzodiazepines and opioids to produce moderate sedation with analgesia during colonoscopy. Not all patients are readily sedated with commonly used doses of midazolam (1-2 mg) combined with opioids, and these drugs are not suitable for certain patients undergoing endoscopy who are at a higher risk for sedation-related complications, e.g. morbid obesity, short thyromental distance ('short neck'), alcohol or substance abuse, unstable cervical spines and those with psychiatric illnesses who may require evaluation and sedation care under the direction of an anaesthesiologist. Lipid emulsion propofol, used as a rate-controlled infusion for procedures, has pharmacokinetic (PK) and pharmacodynamic (PD) properties, such as rapid attainment of maximum plasma concentration (Cmax), that can induce levels of deep sedation, and occasionally even general anaesthesia. Although propofol can be highly effective for moderate sedation during procedures such as endoscopy, it may require the presence of an anaesthesia specialist. Therefore, a sedative agent that provided the benefits of propofol, but which could more readily, reliably and safely be titrated to target a moderate level of sedation on individual patient basis, would be useful for patients undergoing diagnostic and therapeutic procedures performed by a variety of medical and surgical specialists, including gastroenterologists.
Fospropofol disodium (AQUAVAN Injection; MGI PHARMA, Inc., Bloomington, MN, USA) is a water-soluble prodrug of propofol that is undergoing evaluation as a sedative agent for diagnostic and therapeutic procedures. Fospropofol disodium is rapidly hydrolysed by alkaline phosphatases to release propofol, as well as phosphate and formaldehyde (which is rapidly converted to formate). These metabolites do not accumulate above endogenous levels. The safety profile and PK/PD properties of fospropofol disodium have been evaluated in preliminary clinical trials and support its use as a sedative during diagnostic procedures such as colonoscopy. Following intravenous (i.v.) administration of fospropofol, the plasma concentration profile of fospropofol-derived propofol is characterized by a smooth and predictable rise and decline, rather than a rapid spike similar to that observed following administration of the lipid-emulsion formulation of propofol (Diprivan, AstraZeneca SpA, Caponago, Italy). The elimination kinetics of propofol are similar, regardless of whether propofol is derived from fospropofol or Diprivan. The purpose of this dose-ranging trial was to determine the efficacy and safety of various dosing regimens of fospropofol disodium intended to target moderate sedation, to avoid deep levels of sedation and to provide an acceptable safety profile for patients undergoing colonoscopy.
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