Pharmacokinetics of ticarcillin and clavulanic acid (timentin) in relation to renal function

Abstract

The disposition of coadm,inistered tic,ircillin (3 g/1.73 m2) and clavulanic acid (100 mg/1.73 m2) was examined after a 30-min infusion in 24 noninfected subjects with various degrees of renal function. Noncompartmental pharmacokinetic parameters for the individual compounds were determined from plasma concentrations and urinary excretion rates. All clearances (total, renal, and nonrenal) and urinary recoveries of unchanged drug were found to be linearly related to creatinine clearance (CLcR). The steady-state volume of distribution (9.9 and 12.9 liters for ticarcillin and clavulanic acid) approximated the extracellular fluid space and was not related to CLCR. The half-lives increased with redqced renal function and ranged from 56 to 392 min for ticarcillin and 26 to 266 min for clavulanic acid. The clearances of both drugs decreased proportionately with reduction in renal function, facilitating dosing adjustments based on CLCR. Calculations of expected steady-state maximum and minimu,, concentrations in pla,sma using constant doses and an extended dosing interval related to CLCR further rationalized use of the 30:1 drug combination ratio for all patients.Ticarcillin is a wide-spectrum penicillin which can be hydrolyzed by a number of beta-lactamases. Clavulanic acid is a potent inhibitor of these enzymes, and a synergistic effect is exhibited when the two agents are coadministered (5,18,20). A ticarcillin:clavulanic acid combination of 30:1 is used clinically, partly on the basis of pharmacokinetic matching in subjects with normal renal function (1).Previous studies evaluated the pharmacokinetics of ticarcillin and clavulanic acid when administered separately (3,4) or in combination (1, 2, 6) in subjects with normal renal function, but the disposition of the combination has not been assessed in relation to renal impairment. The purpose of this study was to evaluate the pharmacokinetics of ticarcillinclavulanic acid in subjects with various degrees of renal impairment to evolve dosage guidelines and to determine whether the dosing ratio of 30:1 remains suitable in the presence of severe renal dysfunction.MATERIALS AND METHODS Subjects. A total of 24 adult subjects, aged 18 to 61 years, who gave informed written consent for the study were divided into four groups based on renal function (creatinine clearances [CLCRI, 10 to 30, 30 to 60, 60 to 80, and >100 ml min-'). By chance, there were no subjects available with CLCR between 80 and 100 ml min-'. Individuals with a history of hypersensitivity to penicillins-or cephalosporins, females with known or suspected pregnancy, and individuals on hemodialysis or peritoneal dialysis, with an infection, or with major cardiovascular or hepatobiliary dysfunction were excluded frpm the study. CLCR for each subject was determined over 24 h within 7 days before the study. Complete blood counts and blood chemistries were also performed within 7 days before the start of the study and 10 days after the study. Th1 subjects were also monitored for possible adverse effects througho...

Differences in Antimicrobial Drug Exposure in Patients with Various Degrees of Renal Function Based on Recommendations from Dosing References

“…When more than one published study was available for an agent, one was selected for this analysis based on the total number of patients, number of patients at each Cl cr , range of Cl cr , and coefficient of determination (R 2 ) of the regression equation. [1][2][3][4][5][6][7][8][9][10][11][12][13] Then, the Cl T of each at the five levels of Cl cr was calculated from the regression equation describing the relationship between Cl cr and Cl T .…”

“…Drugs that are eliminated primarily by glomerular filtration have prolonged serum halflives as a result of decreased clearance in patients with renal impairment. [1][2][3][4][5][6][7][8][9][10][11][12][13] Depending on the extent of renal impairment, drug regimens may be altered by adjusting the dose and/or dosing interval to avoid accumulation and potential toxicity while maintaining clinically effective drug concentrations. Fortunately, references are available to help clinicians determine appropriate dosages of antimicrobials in patients with altered renal function.…”

Pilot study of side effects and serum and urine concentrations of amoxicillin–clavulanic acid in azotemic and non-azotemic cats

“…3 In human patients with decreased renal function, potentiated penicillins have decreased renal clearance, resulting in higher serum concentrations in comparison with patients with normal renal function. 4,5 Furthermore, drug exposure increases in relation to the severity of renal impairment. The mean clearance for amoxicillin can be reduced by as much as 90% and clavulanic acid up to 70% in patients with varying degrees of renal impairment.…”

“…With decreasing creatinine clearance, a subsequent decrease in urinary excretion of the drug is observed. 5 It has thus been recommended in human patients with reduced kidney function that the dose of potentiated penicillins be altered (ie, decreased dose or decreased frequency) based on creatinine clearance to avoid excessive drug accumulation.…”