Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

Abdulaziz S. Alobaid, Steven C. Wallis, Paul Jarrett, Therese Starr, Janine Stuart, Melissa Lassig-Smith, Jenny Lisette Ordóñez Mejia, Michael S. Roberts, Jeffrey Lipman, Jason A. Roberts

Severe pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem in a cohort of critically ill patients including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into three body mass index (BMI) groups, non-obese (18.5-29.9 kg/m(2)); obese (30.0-39.9 kg/m(2)); and morbidly obese (BMI ≥ 40 kg/m(2)). Serial plasma samples were taken and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics®. Nineteen critically ill patients with different BMI categories were enrolled. The patient's mean ± SD age, weight and BMI were 49 ± 15.9 years, 95 ± 22.0 kg and 33 ± 7.0 kg/m(2), respectively. A two compartment model described the data adequately. The mean ± SD parameter estimates for the final covariate model were clearance (CL) 15.5 ± 6.0 L/h, volume of distribution of the central compartment (Vc) 11.7 ± 5.8 L, intercompartmental clearance from central to peripheral compartments 25.6 ± 35.1 L*h(-1) and intercompartmental clearance from peripheral to central compartment 8.32 ± 12.24 L*h(-1) Higher CLCR was associated with a lower probability of target attainment with BMI having little effect. Although obesity was found to be associated with an increased Vc, dose adjustment based on CLCR appears more important than patient BMI.