Comparison of the pharmacokinetics and pharmacodynamic profile of carumonam in cystic fibrosis patients and healthy volunteers

Abstract

Our objectives were to compare the pharmacokinetics (PK) of carumonam, a monobactam, between cystic fibrosis (CF) patients and healthy volunteers and assess its pharmacodynamic profile. We studied 10 adult CF patients and 18 healthy volunteers of similar body size (dose: 2.166 g of carumonam as 15-min intravenous infusion). High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used for drug analysis and NONMEM® (ICON, Ellicot City, MD) for population PK and Monte Carlo simulation with targets between ≥20% and 100% free time above MIC ( fT > MIC). Unscaled renal clearance was 24% higher in CF patients. Lean body mass and creatinine clearance explained the difference in average clearance and volume of distribution between both subject groups. For a daily dose of 6 g per 70 kg of total body weight, 15-min infusions q8h achieved robust (>90%) probabilities of target attainment (PTAs) (target, 60% fT > MIC) for MICs ≤3 mg/L in CF patients and ≤6 mg/L in healthy volunteers. At the same dose, 4-h infusions q8h achieved robust PTAs up to markedly higher MICs ≤8 to 12 mg/L in CF patients and ≤16 mg/L in healthy volunteers.