Pharmacokinetics of Tobramycin in Adults with Cystic Fibrosis: Implications for Once-Daily Administration

Abstract

ABSTRACT Once-daily administration of aminoglycosides is routinely used in many institutions. However, comparative efficacy data for patients with cystic fibrosis (CF) are lacking. The purpose of the present study was to compare the predicted pharmacodynamic activity of tobramycin at 10 mg/kg of body weight/day administered every 24 h (q24h), q12h, and q8h. Pharmacokinetic (PK) data were derived from analysis of data on the drug concentration in sera from 60 adult CF patients. Individual maximum a posteriori probability Bayesian PK parameter values were used to construct serum concentration-versus-time curves and to determine various indices (peak concentration/MIC ratio [peak/MIC], area under the concentration-time curve/MIC ratio [AUC/MIC], and time that the concentration was less than the MIC [ T <MIC]) for the three regimens described above. MICs of 1, 2, and 4 μg/ml for Pseudomonas aeruginosa were assumed in the simulations. Irrespective of the MIC, significantly lower peak/MIC but shorter T <MIC were noted when regimens of q8h versus q12h ( P < 0.001), q8h versus q24h ( P < 0.001), and q12h versus q24h ( P < 0.001) were compared. This analysis suggests that the potential benefit of achieving a greater peak/MIC with once-daily aminoglycoside administration may be offset by the significantly greater T <MIC in CF patients compared with that achieved with multiple-daily-dosing regimens. Clinical trials are necessary to determine if once daily aminoglycoside administration is efficacious in the CF population before its routine use can be recommended.