Pharmacokinetic Evaluation of Imipenem Combined with Cilastatin in Cystic Fibrosis

Abstract

The pharmacokinetics of imipenem (MK-787) and cilastatin (MK-791) were studied in 30 patients with cystic fibrosis (CF) receiving the drug for therapeutic purposes at doses of 11 mg/kg given as a 30-min infusion. The serum concentrations and urine elimination were studied after the first dose and during steady state. The concentrations were assayed by high-pressure liquid chromatography. The total areas under the imipenem serum concentration curves (AUCs) to infinity were 30.4 ± 6.8 mg-h/1 after the first dose compared with 29.1 ± 7.1 mg-h/1 during steady state (NS). The cilastatin AUCs on the 2 days were 40.3 ± 9.3 and 38.3 ± 0.4 mg-h/1 (NS), respectively. The urinary recovery of imipenem was 47.8 ± 17.8% after the first dose and 57.8 ± 24.2% during steady state (NS). The amounts of cilastatin eliminated in the urine during 6 h were 6/ 7.3 ± 22.9% after the first dose and 60.5 ± 17.0% of the dose during steady state (NS). The mean half-life of imipenem in these CF patients was 1.2 ± 0.4 h on the first day of the examination and within the same range during steady state. The distribution volume (Vdβ) was in the range of 28 liters, the total body clearance was 16.3 liters/h (285 ml/min) on the first day. The t1/2 of cilastatin was 0.59 ± 0.14 h after the first dose and 0.61 ± 0.14 h during steady state. Thus patients with CF eliminated cilastatin more quickly than imipenem.

Pharmacokinetics of High-Dose Meropenem in Adult Cystic Fibrosis Patients

“…This is not surprising since studies with another carbapenem, imipenem, also resulted in similar pharmacokinetics when compared with a control group [5,8]. In a previous study, CF subjects had significantly greater clearance when compared to non-CF subjects, but this could have been the result of comparing children versus older adults [14].…”

“…The effect of CF on the pharmacokinetics of ß-lactam (semisynthetic penicillins, cephalosporin and carbapenem) antibiotics is Bui/Ambrose/Nicolau/Lapin/ Nightingale/Quintiliani variable [5][6][7][8][9][10][11], however, it most often results in more rapid elimination of these agents. These alterations may reduce the probability of clinical success by lowering the plasma concentrations and by shortening the duration of serum concentrations.…”

Optimization of anti‐pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: I. aztreonam and carbapenems

“…Four PK studies analyzing imipenem–cilastatin in 77 CF patients (age range 8–33 years) have been performed utilizing doses ranging from 45–100 mg/kg/day divided every 6 hr 45–48. The study by Reed et al45 concluded that imipenem–cilastatin administered at a dose of 90–100 mg/kg/day divided every 6 hr would be adequate to maintain serum imipenem concentrations above the MIC of the majority of P. aeruginosa isolates: S: ≤4 mg/L; R: >8 mg/L (EUCAST); S: ≤4 mg/L; R: >16 mg/L (CLSI; Tables 1 and 4).…”