Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients

• Published in: Journal of clinical pharmacology 2017-03, Vol.57 (3), p.356-368
• Main Authors: Chung, Eun Kyoung, Cheatham, S. Christian, Fleming, Megan R., Healy, Daniel P., Kays, Michael B.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Body Height; Body Mass Index; Body Weight; Creatinine - blood; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; meropenem; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Monte Carlo simulation; NONMEM; obesity; Obesity - metabolism; Obesity, Morbid - metabolism; Patients; pharmacokinetics; Thienamycins - administration & dosage; Thienamycins - pharmacokinetics
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.812

The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients—11 nonobese (body mass index [BMI] < 30 kg/m2), 9 obese (30 kg/m2 ≤ BMI < 40 kg/m2), and 20 morbidly obese (BMI ≥ 40 kg/m2)—received meropenem 500 mg every 6 hours (q6h), q8h, or q12h or 1 g q6h or q8h, infused over 0.5 hour. Population pharmacokinetic modeling was performed using NONMEM, and 5000‐patient Monte‐Carlo simulations were performed to calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2‐compartment linear‐elimination model best described the serum concentration‐time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary.