Pharmacokinetics and pharmacodynamics of cefepime in patients with various degrees of renal function

Abstract

This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL(CR)) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (C(min)). C(min) in this group was found to be 3.3 +/- 3.6 mg/liter (mean and standard deviation), compared to 19.5 +/- 21.5 mg/liter in patients with a CL(CR) of between 60 and 100 ml/min (P = 0.025) and 14.0 +/- 11.5 mg/liter in patients with a CL(CR) of <60 ml/min (P = 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL(CR) were highly correlated (P = 0.00033) according to the equation CL= 0.324 liters/h + (0.0551 x CL(CR)). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h(-1), respectively. The time-concentration profiles for 1,000 patients (CL(CR)s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a C(min) that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs < or = 2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are > or = 4 mg/liter), particularly when CL(CR) exceeds 120 ml/min.

Figures

FIG. 1.

Correlation between cefepime CL and CLCR.

FIG.2.

MIC distribution for 120 clinical isolates of P. aeruginosa. The MIC50 was 2 mg/liter; the MIC90 was >32 mg/liter.

FIG. 3.

Observed versus MAP Bayesian-predicted cefepime concentrations from a population pharmacokinetic model with covariates.

FIG. 4.

Probability of target attainment in patients with a CLCR of 120 ml/min. Doses were given over 30 min every 4 h (q4), every 6 h (q6), every 8 h (q8), and q12. The current recommended dose is 2 g q12; the maximal recommended dose is 2 g q8. 4xMIC, four times the MIC.

FIG. 5.

Probability of target attainment in patients with a CLCR of 60 ml/min. Doses were given over 30 min every 6 h (q6), q12, and q24. The current recommended dose is 2 g q24; the maximal recommended dose is 2 g q12. 4xMIC, four times the MIC.

FIG. 6.

Probability of target attainment in patients with a CLCR of 30 ml/min. Doses were given over 30 min q12 and q24. The current recommended dose is 1 g q24; the maximal recommended dose is 2 g q24. 4xMIC, four times the MIC.