Comparative Pharmacokinetics and Pharmacodynamic Target Attainment of Ertapenem in Normal-Weight, Obese, and Extremely Obese Adults

Abstract

Little is known of the effects of obesity on ertapenem drug disposition and pharmacodynamics. Thirty healthy volunteers in three body mass index (BMI) groups (10 per group), normal weight (BMI, 18.5 to 24.9 kg/m 2 ), class I-II obesity (BMI, 30 to 39.9 kg/m 2 ), and class III obesity (BMI, >40 kg/m 2 ), were administered a 1-g dose of ertapenem. Serum concentrations were obtained over 24 h. Population pharmacokinetic data were obtained using a nonparametric adaptive grid followed by Monte Carlo simulation to determine the probability of obtaining the free drug exposure targets of the time that the free drug concentration remains above the MIC ( f T >MIC ) of 20% and 40% for bacteriostatic and maximal bactericidal activity, respectively. Compared to the subjects in the obese groups, area under the concentration-time curve from 0 h to infinity was significantly higher in the normal-weight subjects, whereas the total central compartment volume was higher in the class III obese subjects (P < 0.05). Achieving a bacteriostatic target of f T >MIC of 20% with a 90% probability was attained at MICs of <0.5 g/ml for normal-weight subjects. Class I-II and class III obese subjects were able to achieve this target only at a MIC of <0.25 g/ml. For maximal bactericidal activity ( f T >MIC , 40%), no group attained the target at the 90% probability level at any tested MIC. The results suggest that the standard 1-g ertapenem dose may not provide adequate drug exposure for any body mass index classification for MICs in excess of 0.25 to 0.5 g/ml.The prevalence of obesity is on the rise, and obesity has become an epidemic in many countries. In the United States alone, more than 44 million adults are obese (body mass index [BMI], Ն30 kg/m 2 ) (1), and some regional and ethnic groups of the population exhibit high rates of obesity. Recent data from the 1999 to 2002 National Health and Nutrition Examination Survey indicate that 65% of U.S. adults are either overweight or obese (2). Nevertheless, only a limited number of studies have been conducted that evaluate obesity-associated physiological changes and their pharmacokinetic (PK) ramifications. The effect of altered body composition on drug disposition and therapeutic outcome with increasing obesity is particularly pertinent in antimicrobial therapy. Suboptimal drug exposure can lead to clinical failure and increase the risk of drug resistance.Several studies that specifically examined drug disposition of ␤-lactam antibiotics in obesity found an increase in the volume of distribution and/or drug clearance in obese subjects (3,12,24). This suggests that such patients may require higher doses or more frequent administration in order to achieve adequate drug exposure.Ertapenem (Invanz) is a carbapenem antibiotic recommended for therapy (one gram once a day) of patients with appropriate renal function (creatinine clearance Ͼ30 ml/min/1.73 m 2 ) (19). Similar to other carbapenems, ertapenem demonstrates broadspectrum activity against gram-positive, gram-negative, and anaerobic pathogens...

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