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Clin Ther. 2011 Nov;33(11):1844-50. doi: 10.1016/j.clinthera.2011.09.010. Epub 2011 Oct 21.

Population pharmacokinetic and pharmacodynamic modeling of high-dose intermittent ticarcillin-clavulanate administration in pediatric cystic fibrosis patients.

Author information

1
Pharmacy, Intermountain Primary Children's Medical Center, Salt Lake City, Utah, USA.

Abstract

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 μg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 μg/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 μg/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs >32 μg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen.

PMID:
22018680
DOI:
10.1016/j.clinthera.2011.09.010
[Indexed for MEDLINE]

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