Exploring different body-size metric based dosing strategies for propofol in morbidly obese versus healthy weight subjects by modelling and simulation approach
Sarah C McLeay (1), Glynn A Morrish (1), Carl MJ Kirkpatrick (1) & Bruce Green (2)
(1) School of Pharmacy, University of Queensland, Brisbane, Australia; (2) Model Answers Pty Ltd., Brisbane, Australia
Objectives: Propofol is an intravenous anaesthetic that is dosed based upon the subject’s body weight. Although effective for subjects of healthy weight (BMI<25kg/m2), use of total body weight (TBW) dosing in morbidly obese subjects (BMI≥40kg/m2) can result in overdose due to a nonlinear increase in clearance (CL) with TBW[1]. The aims of this study were to identify a linear body-size based dosing strategy to normalize pharmacodynamic (PD) response across a large weight range and compare PD outcomes to those from TBW label dosing.
Methods: A population pharmacokinetic (PK) and PD analysis was performed using NONMEM VI on data from 419[2,3] adults who received propofol. Two PD models were developed: a binary model for hypnosis (awake/asleep) and a categorical model describing stages of awakening (asleep/disoriented/awake). An adverse event model describing the inhibitory effect of propofol on ventilation[4] was also linked to the PK model. Stochastic simulations were performed using the best optimised dose (based upon the identification of the best PK model) and label dosing. PD responses for the different dosing strategies and different weight groups were compared.
Results: A 3-compartment model with lean body weight[5] (LBW) and age on CL best described propofol PK. The hypnosis model was described by an Emax function in the logit with predicted concentration in the effect-site compartment[6] as the exposure variable. The awakening model was described by an Emax function using predicted concentration in the central compartment. The optimised dose based on LBW of a 140mg bolus followed by a 7.6mg/kgLBW/h infusion resulted in similar PD between morbidly obese and healthy weight subjects. For healthy weight subjects, TBW dosing resulted in similar responses to LBW dosing. For morbidly obese subjects however, TBW dosing resulted in faster induction and longer awakening, with the median subject taking 7min longer to reach 50% probability of being awake and oriented than the median healthy weight subject. TBW dosing also resulted in earlier and greater ventilatory depression in the morbidly obese group with a maximum decrease to 7% of normal ventilation at 1.7min for the median subject versus 16% at 2min for the median healthy weight subject.
Conclusion: A fixed induction dose of propofol followed by a maintenance dose scaled by LBW may be appropriate to normalize subject responses across all weights and minimize ventilatory depression on induction in the morbidly obese.
References:
[1] Schuttler J. et al., Anesthesiology 2000; 92:727-38.
[2] The WorldSIVA Open TCI Initiative 2009, http://opentci.org.
[3] Servin F. et al., Anesthesiology 1993; 78: 657-65.
[4] Bouillon T. et al., Anesthesiology 2004; 100: 240-50.
[5] Janmahasatian S. et al., Clin Pharmacokinet 2005; 44: 1051-65.
[6] Bjornsson M. et al., PAGE 18, 2009 Abstr 1590.