Population Pharmacokinetic and Pharmacodynamic Modeling of High-Dose Intermittent Ticarcillin-Clavulanate Administration in Pediatric Cystic Fibrosis Patients

作者：Zobell Jeffery T^*; Stockmann Chris; Young David C; Cash Jared; McDowell Brittany J; Korgenski Kent; Sherwin Catherine M T; Spigarelli Michael; Chatfield Barbara A; Ampofo Krow

来源：Clinical Therapeutics, 2011, 33(11): 1844-1850.

DOI：10.1016/j.clinthera.2011.09.010

• antibiotics
• cystic fibrosis
• pediatrics
• pharmacodynamics
• ticarcillin-clavulanate

Background: The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)-approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen.
Objectives: The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF).
Methods: This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included >= 30% for bacteriostasis and >= 50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses.
Results: A total of 127 patients (age, 0-19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 mu g/mL and a bacteriostasis PK-PD MIC breakpoint of 32 mu g/mL.
Conclusions: The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs <16 mu g/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs >32 mu g/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen. (Clin Ther.

• 出版日期2011-11