Defining the unbound target exposure of teicoplanin part 2: Dose individualization through population pharmacokinetic modelling

Abstract Objectives The pharmacokinetic index of teicoplanin is best described by the area of the unbound concentration under the concentration time curve (fAUC). In clinical practice the total trough concentration is used for the purpose of TDM. An fAUC24 of 75 mg·h/L has been proposed as a target. This study aimed to develop a population pharmacokinetic model based on unbound teicoplanin concentrations to evaluate and improve teicoplanin dosing. Methods In this observational clinical trial 30 patients admitted to the ICU or hematology department were included. Dosing was at the discretion of the treating physicians. Samples were taken on day 2 (T=0, 1, 2 and 4) and day 5 (T= 0, 4, 8, 16 and 24) of therapy. Teicoplanin pharmacokinetics were characterized by Non-Linear Mixed Effects Modeling. The final model was used to simulate the probability of achieving an fAUC24 of 75-150 mg*h/L under current dosing regimens, and to evaluate the potential improvement through model-informed precision dosing. Results In total 188 samples were collected from 30 patients. Median full body weight was 80 kg [IQR 71-90], median eGFR (CKD-EPI) was 88 mL/min [IQR 46-117] and median serum albumin was 19.5 g/L [IQR 16-24]. Median unbound fraction was 21% [IQR 16-23]. A two-compartment pharmacokinetic model with eGFR as covariate for unbound clearance and albumin as covariate for Bmax best fitted the data. Simulations showed that probability of target attainment (PTA) in ICU patients is 58%. Failure to achieve the target was predominantly observed in patients with elevated eGFR. Simulations showed PTA can be augmented to 71% with improved dosing schedules, and to 91% when the model is applied to model-informed precision dosing. Conclusion We developed a pharmacokinetic model capable of guiding teicoplanin dosing based on fAUC24. Current dosing schedules are suboptimal from a pharmacokinetic viewpoint. Model-informed precision dosing of unbound teicoplanin is advised to maximize target attainment.