Pharmacokinetic parameters of cefepime in 2 g plasma and lung tissue bid over 3 days to achieve the steady-state was studied in 16 patients (15 male, one female) subjected to lung surgery for bronchial epithelioma. The aims of this study were firstly to quantify cefepime lung diffusion with cefepime lung concentrations in comparison with cefepime serum concentrations, and secondly to estimate population pharmacokinetic parameters of cefepime in lung tissue using NONMEM. The mean characteristics of patients were: age, 60 years (range, 51-69 years), weight, 73 kg (range, 62-87 kg) and creatinine clearance, 77 ml/min (range, 62-92 ml/min). Both serum sample (two per patient) and lung sample (one per patient) cefepime concentrations were analysed by HPLC with UV detection. Five groups were made according to the time of sampling after the last cefepime intravenous infusion at the fifth infusion: 0.5 h (n=2), 2 h (n=5), 4 h (n=3), 8 h (n=3) and 12 h (n=3). The cefepime concentration ratio between lung and serum was calculated for each group and statistical analysis show no significant difference between groups. The mean concentration ratio between lung and serum was 101% (range, 70-130%). To explain this observation a two-compartment pharmacokinetic model with a population approach was used to describe pharmacokinetic parameters of cefepime both in lung and in serum. Serum was assimilated at the central compartment and lung was the peripheral compartment. NONMEM was used to estimate the mean and the variance of the pharmacokinetic parameters. Central volume of distribution (V(d)), steady-state volume of distribution (V(ss)), central clearance (CL) and transfer constants (K(cp)) from serum to lung and (K(pc)) from lung to serum were estimated. Central elimination half-life t(1/2Kbeta)was extrapolated from elimination constant beta. Results were: V(d)= 15.62 +/- 2.56 l, V(ss)= 17.58 +/- 2.58 l, CL = 3.65 +/- 1.25 l/h, beta = 0.234 h(-1), t(1/2beta)= 2.96 hours, K(cp)= 12.25 +/- 8.56 h(-1)and K(pc)= 0.242 +/- 0.085 h(-1). The results show that cefepime diffusion in lung occurs quickly without lagtime and in similar concentrations to that in serum.
Copyright Academic Press.