Population pharmacokinetic modelling of gentamicin and vancomycin in patients with unstable renal function following cardiothoracic surgery

Aims To describe the population pharmacokinetics of gentamicin and vancomycin in cardiothoracic surgery patients with unstable renal function. Methods Data collected during routine care were analyzed using NONMEM. Linear relationships between creatinine clearance (CLCr) and drug clearance (CL) were identified, and two approaches to modelling changing CLCr were examined. The first included baseline (BCOV) and difference from baseline (DCOV) effects and the second allowed the influence of CLCr to vary between individuals. Final model predictive performance was evaluated using independent data. The data sets were then combined and parameters re-estimated. Results Model building was performed using data from 96 (gentamicin) and 102 (vancomycin) patients, aged 17-87 years. CLCr ranged from 9 to 172 ml min(-1) and changes varied from -76 to 58 ml min(-1) (gentamicin) and -86 to 93 ml min(-1) (vancomycin). Inclusion of BCOV and DCOV improved the fit of the gentamicin data but had little effect on that for vancomycin. Inclusion of interindividual variability (IIV) in the influence of CLcr resulted in a poorly characterized model for gentamicin and had no effect on vancomycin modelling. No bias was seen in population compared with individual CL estimates in independent data from 39 (gentamicin) and 37 (vancomycin) patients. Mean (95% CI) differences were 4% (-3, 11%) and 2% (-2, 6%), respectively. Final estimates were: CLGent (l h(-1)) = 2.81 x (1 + 0.015 x (BCOVCLCr-BCOVCLCr Median) + 0.0174 x DCOVCLCr); CLVanc (l h(-1)) = 2.97 x (1 + 0.0205 x (CLCr-CLCr Median)). IIV in CL was 27% for both drugs. Conclusions A parameter describing individual changes in CLcr with time improves population pharmacokinetic modelling of gentamicin but not vancomycin in clinically unstable patients.