Population pharmacokinetic modelling and Monte Carlo simulation of piperacillin administered as extended infusion in critically ill patients
Ana Alarcia Lacalle (1,2), Carlos Valdazo (1,3), Andrés Canut (2,4), Helena Barrasa (2,5), Alicia Rodríguez Gascón (1,2), Arantxa Isla (1,2)
(1) Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain., (2) Bioaraba, Microbiology, Infectious Diseases, Antimicrobials and Gene Therapy Research Group, Vitoria-Gasteiz, Spain, (3) Pharmacy Service. University Hospital Araba. Vitoria-Gasteiz, Spain., (4) Microbiology Service. University Hospital Araba. Vitoria-Gasteiz, Spain., (5) Intensive Care Unit. University Hospital Araba. Vitoria-Gasteiz, Spain.
Introduction/Objectives: Piperacillin/tazobactam is a beta-lactam/beta-lactamase inhibitor combination with activity against gram-positive and gram-negative aerobic and anaerobic bacteria [1]. Piperacillin exhibits time-dependent activity, so the time during which the free drug concentration is above the minimum inhibitory concentration (MIC) is directly associated with the efficacy of the treatment (%fT>MIC). Therefore, in order to improve the effectiveness against infections caused by multi-resistant bacteria and those for which the MIC is high, extended infusion of beta-lactams are increasingly being recommended to prevent from low antibiotic exposure [2]. This work aimed to develop a population pharmacokinetic model of piperacillin in critically ill patients after its administration as a 4-hour infusion and explore the pharmacokinetic/pharmacodynamic (PK/PD) target attainment.
Methods: The study is being carried out at the Araba University Hospital (Vitoria-Gasteiz). The protocol was approved by the Basque Clinical Research Ethics Committee (CEIm-E) (EOM2021078). The patients received a dose of 4/0,5 g of piperacillin/tazobactam q6h as a 4-hour infusion. Five plasma samples of each patient were collected at steady state at different times over a dosing interval and drug concentration was quantified using a validated HPLC-UV technique. A population PK model was developed in Monolix (version 2023R1). Parameters were estimated by the SAEM algorithm. The model selection was based on biological plausibility, the decrease in objective function value (OFV), the relative standard errors (RSE) of the parameters, and the goodness-of-fit plots (GOFs). Demographic and clinical variables were studied as potential covariates using a stepwise covariate model procedure (SCM). Furthermore, a Monte Carlo simulation with 10.000 subjects using Oracle® Crystal Ball Fusion Edition v.11.1.2.3.500 (Oracle USA Inc., Redwood City, CA) was carried out to estimate the probability of target attainment (PTA). As PK/PD targets, we considered 50%fT>MIC as well as 100%fT>MIC [3,4]. PTA values ≥ 80% but < 90% are associated with moderate probabilities of success, whereas values ≥ 90% are considered as optimal [5].
Results: Ten patients (50 samples) have been included in the population PK analysis for the time being. Piperacillin plasma concentration-time data were best described by a one-compartment model. The mean parameter estimates and RSE (%) were: clearance (CL) 15.36 L/h (17.1%) and volume of distribution (V) 13.25 L (9.13%). Interindividual variability estimates expressed as CV% (RSE%) were, for the CL, 50.14% (33.5%) and, for V, 26.31% (30.5%). The residual error was estimated using a combined error model. The model included correlation between CL and V. Different covariates were explored (age, creatinine clearance, albumin, glucose, gender, APACHE and body weight, among other) but they did not resulted in a relevant reduction in the OFV. The PTA was 85% or higher for MIC values up to 16 mg/L or 2 mg/L when considering 50%fT >MIC or 100%fT >MIC, respectively.
Conclusions: The pharmacokinetics of piperacillin has been best described by a one-compartment model and no covariates were included. Considering the results obtained until now, the administration of piperacillin/tazobactam every 6 h in 4-h infusion allows to achieve the PD target (free piperacillin concentrations for more than 50% or 100% of the dosing interval) for MIC values of 16 mg/L and 2 mg/L, respectively. In any case, this is an ongoing study and it is still necessary to recruit more patients in order to develop a final model and to evaluate the possible influence of covariates in the model.
Acknowledgments: This work has been supported by the Basque Government (2021111049, IT1587-22) and the University of the Basque Country (GIU20/048).
References:
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