Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients
Femke de Velde,
Brenda C. M. de Winter,
Michael N. Neely,
Jan Strojil,
Walter M. Yamada,
Stephan Harbarth,
Angela Huttner,
Teun van Gelder,
Birgit C. P. Koch,
Anouk E. Muller,
on behalf of the COMBACTE-NET Consortium
Affiliations
Femke de Velde
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
Brenda C. M. de Winter
Department of Hospital Pharmacy, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
Michael N. Neely
Laboratory of Applied Pharmacokinetics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
Jan Strojil
Department of Pharmacology, Palacky University, CZ-779 00 Olomouc, Czech Republic
Walter M. Yamada
Laboratory of Applied Pharmacokinetics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
Stephan Harbarth
Division of Infectious Diseases, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland
Angela Huttner
Division of Infectious Diseases, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland
Teun van Gelder
Department of Hospital Pharmacy, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
Birgit C. P. Koch
Department of Hospital Pharmacy, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
Anouk E. Muller
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90–120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated.
