¹ Guilford Pharmaceuticals Inc., Metrum Research Group LLC, Baltimore, MD

Abstract

Background: AQUAVAN® Injection (AI) is a water-soluble prodrug of propofol. AI population PK/PD model was developed earlier using PK and MOAA/S (Modified Observer's Assessment of Alertness/Sedation) data from a colonoscopy study.

Methods: Model-based simulations were used to design a new study: (i) Choose initial bolus doses that produce deep sedation (MOAA/S than 5 min) in < 5% of patients; (ii) Choose titration regimens that provide sedation to most patients without sedating them too deeply; (iii) Optimize weight adjustment of dosing to maximize % of sedated patients while minimizing % of deeply sedated patients; (iv) Assess power and choose sample size with respect to sedation success.

Results: The following dosing paradigm should balance efficacy and safety outcomes: weight-proportional dosing with boundaries at 60 and 90 kg (patients weighing < 60 or > 90 kg are dosed as 60 or 90 kg patients), initial doses of 5-8 mg/kg, and supplemental doses of 25% of the initial administered at 4 and 8 min. Initial doses should sedate patients who are more responsive while avoiding deep sedation. Supplemental doses should sedate most patients who are less responsive to sedation. With 25 patients per group, 5 mg/kg group is differentiated from 2 and 8 mg/kg groups with 99% and 79% power, respectively.

Conclusions: The model-based simulations optimized the design with initial doses of 2, 5, 6.5, and 8 mg/kg with boundaries at 60 and 90 kg. The validity of the predictions will be tested upon completion of the study.