Pharmacokinetics of Total and Unbound Ertapenem in Healthy Elderly Subjects

Ertapenem (INVANZ; Merck & Co., Inc.) is a parenteral β-lactam. It has excellent in vitro activity against gram-positive and gram-negative, aerobic and anaerobic bacteria generally associated with community-acquired and mixed infections (2). The antibiotic is approved for the treatment of complicated intra-abdominal infections, complicated skin and skin structure infections, community-acquired pneumonia, acute pelvic infections, and complicated urinary tract infections. It is a carbapenem with an anionic side chain and a 1-β-methyl group that provides stability against human renal dehydropeptidase I. Its major metabolite is the open-lactam form via dehydropeptidase I. Its protein binding in rat, monkey, and human plasma (about 96%) is nonlinear with increasing concentrations (7). The objectives of this study were to investigate the pharmacokinetics of single and multiple intravenous (i.v.) doses of ertapenem in healthy elderly subjects and compare and contrast them with previously determined values from healthy young adults (4). The elderly respond differently than the young to some drugs and are often more susceptible to adverse effects. The greater sensitivity of the elderly may be due to altered disposition of the drug and result in higher concentrations (1). The pharmacokinetics of this study was assessed with the concentrations of total and unbound ertapenem in plasma. The plasma protein binding of ertapenem in the elderly and differences between female and male elderly subjects were also evaluated. Except for age and clinical site, the clinical, analytical, and pharmacokinetic aspects of the investigation in elderly subjects were nearly identical to those in the young. On the basis of both total and unbound ertapenem, the pharmacokinetics of ertapenem in healthy young subjects (4) are nearly dose proportional over a 0.5- to 2-g dose range. The area under the concentration-time curve (AUC) of total ertapenem increases slightly less than dose proportionally, consistent with the plasma protein binding properties of ertapenem (7). The plasma clearance (CLP) of the total drug varies from 27.6 to 36.3 ml/min with doses of 0.5 to 3 g, and the mean apparent half-life (t1/2) is about 3.5 to 4 h. The fraction unbound is ∼5 to 6% at a total concentration of <50 μg/ml of plasma, ∼8% at a total concentration of approximately 150 μg/ml of plasma, and ∼15 to 18% at a total concentration of approximately 300 μg/ml of plasma. Following multiple dosing, the mean plasma profiles on day 8 are comparable to those on day 1, indicating little accumulation in young adults.