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


OBJECTIVE
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.
Pharmacy, Intermountain Primary Children's Medical Center, Salt Lake City, Utah, USA.
Jeffery T
JT
Zobell
Chris
C
Stockmann
David C
DC
Young
Jared
J
Cash
Brittany J
BJ
McDowell
Kent
K
Korgenski
Catherine M T
CM
Sherwin
Michael
M
Spigarelli
Barbara A
BA
Chatfield
Krow
K
Ampofo
D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D002969:Clavulanic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008826:Microbial Sensitivity Tests; D013982:Ticarcillin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D002969:Clavulanic Acids; D004338:Drug Combinations; C043215:ticarcillin-clavulanic acid; D013982:Ticarcillin