Journal Article

Pharmacokinetic properties and stability of continuous-infusion meropenem in adults with cystic fibrosis

Nightingale, Charles H, Nicolau, David P, Kuti, Joseph L, Knauft, R.Frederic

2004

Overview

Background: Meropenem is commonly used to treat lung infections in adults with cystic fibrosis (CF). Although continuous infusion is the ideal method to maximize the pharmacodynamic properties of this betalactam antibiotic, meropenem is stable for only ∼4 to 6 hours at room temperature, and its pharmacokinetic (PK) properties, when administered by continuous infusion to patients with CF, are largely unknown. Objective: This study was undertaken to determine the PK properties and stability of meropenem when administered to adults with CF by a continuous ambulatory drug-delivery infusion pump stored in a cold pouch between 2 freezer packs. Methods: This open-label, multidose, randomized, crossover PK study was conducted at the Clinical Research Center at Hartford Hospital (Harford, Connecticut). Adults aged ≥ 18 years with CF were eligible. Study participants were randomized to receive meropenem 125 mg/h or 250 mg/h (equivalent to 3 g and 6 g, respectively, over 24 hours) by continuous IV infusion for 12 hours. Serum samples were collected throughout the infusion and then for 6 hours after infusion to determine the PK properties (volume of distribution [V d], elimination rate constant, total body clearance [CL], terminal half-life [ t 1 2 ], and steady-state concentration [C ss]). Serum meropenem concentrations were assayed using high-performance liquid chromatography, and PK profiles were determined using compartmental analysis. Meropenem stability was ascertained by sampling the drug directly from the infusion pump at prespecified time points. Meropenem tolerability was assessed throughout the study by questioning subjects on how they felt. In addition, laboratory values of serum chemistries and liver enzymes were compared with baseline values. Results: Seven adult volunteers with CF (4 women, 3 men; mean [SD] age, 27 [10] years [range, 19–46 years]) participated in the study. Mean (SD) C ss values were 8.31 (0.68) mg/L and 18.50 (3.31) mg/L for the 125-mg/h and 250-mg/h infusion rates, respectively. V d, CL, and t 1 2 were dose independent and similar between the 2 infusion rates. Meropenem stability was maintained over 12 and 24 hours. Meropenem by continuous infusion was well tolerated. One patient complained of a headache during the study. Conclusions: In this study of adults with CF, meropenem infusion rates of 125 mg/h and 250 mg/h provided serum drug concentrations greater than the minimum inhibitory concentration for pathogens considered meropenem susceptible (≤ 4 μg/mL) and intermediately resistant (8 μg/mL), respectively.

• Publisher: EM Inc USA,Excerpta Medica,Elsevier Limited
• Subject: Adult / Anti-Bacterial Agents - administration & dosage / Anti-Bacterial Agents - adverse effects / Anti-Bacterial Agents - pharmacokinetics / Antibiotics / Antimicrobial agents / Biological and medical sciences / Chemotherapy / continuous infusion / Cross-Over Studies / Cystic fibrosis / Cystic Fibrosis - drug therapy / Dose-Response Relationship, Drug / Drug dosages / Drug Stability / Female / Hospitals / Humans / Infusions, Intravenous / Male / Medical sciences / meropenem / Middle Aged / Outpatients / Pharmacodynamics / Pharmacokinetics / Pharmacology. Drug treatments / Thienamycins - administration & dosage / Thienamycins - adverse effects / Thienamycins - pharmacokinetics / Time Factors