(M-133) Utilizing Opportunistic Clinical Study and Population-Based Pharmacometric Models to Identify Rational Empiric Dosing Regimens for Piperacillin-Tazobactam in Critically Ill Patients

Joshua A Reeder, BS – Graduate Student, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa; C. Buddy Creech, MD, MPH – Professor, Division of infectious Diseases, Vanderbilt University Medical Center; Roger Nation, PhD – Emeritus Professor, Monash Institute of Pharmaceutical Sciences, Monash University; Kenan Gu, PhD – Pharmacologist, National Institute of Allergy and Infectious Diseases; Demet Nalbant, PhD – Researcher, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa; Nan Wu, PhD – Graduate Student, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa; Natalia Jimenez-Truque, PhD – Research Assistant Professor, Division of infectious Diseases, Vanderbilt University Medical Center; William Fissell, MD – Associate Professor, Division of Nephrology and Hypertension, Vanderbilt University Medical Center; Stephanie Rolsma, MD, PhD – Assistant Professor, Division of infectious Diseases, Vanderbilt University Medical Center; Nicholas Fishbane, MS – Biostatistician, The Emmes Company; Carl Kirkpatrick, PhD – Professor, Monash Institute of Pharmaceutical Sciences, Monash University; Pratish Patel, PharmD, FIDSA, BCIDP, AAHIVP – Program Director, The Department of Pharmaceutical Services, Vanderbilt University Medical Center; Amy Watanabe, MS – Biostatistician Associate, The Emmes Company; Cornelia Landersdorfer, PhD – Associate Professor, Monash Institute of Pharmaceutical Sciences, Monash University; Patricia Winokur, MD – Professor, Department of Infectious Diseases, University of Iowa Carver College of Medicine; Guohua An, MD, PhD – Associate Professor, College of Pharmacy, University of Iowa

Objectives: Piperacillin, a β-lactam antibiotic, and tazobactam, a β-lactamase inhibitor, combine to offer broad antibacterial coverage with low toxicity. This combination is a first-line treatment for severe infections in critically ill patients. Given the significant pharmacokinetic (PK) variability caused by complex pathophysiological changes in critically ill patients, identifying effective dosing regimens of piperacillin-tazobactam for this special population is imperative [1]. To address this clinical need, this study aims to utilize a prospective, opportunistic clinical study and population-PK (popPK) models to characterize piperacillin-tazobactam disposition, predict the probability of target attainment (PTA) of piperacillin, and identify optimal dosing strategies.

Methods: In the clinical study, 112 critically ill patients received primary doses of piperacillin-tazobactam at 3000 mg/375 mg and 4000 mg/500 mg (dose intervals: 6, 8, or 12 h), with a consistent infusion duration of 4 h. A total of 239 piperacillin plasma concentrations from 111 subjects and 229 tazobactam plasma concentrations from 108 subjects were included in the population PK analysis. NONMEM 7.4.3 was used to perform popPK model estimation and Monte Carlo simulations. R 4.2.1 and SigmaPlot 14.0 were used for data processing and graphics.

Results: The final popPK models for both piperacillin and tazobactam were 1-compartment models with zero-order input and first-order elimination. Significant covariates includes lean body weight for piperacillin, and creatinine clearance, along with continuous renal replacement therapy, for both piperacillin and tazobactam. Monte Carlo simulations for piperacillin indicated that continuous infusion led to the highest PTA compared to 0.5 h and 4 h infusions. The optimal empirical dose for piperacillin was determined to be 16 g/day via continuous infusion when stratifying by renal function. However, if the maximum pharmacokinetic/pharmacodynamic (PK/PD) breakpoint for all patients is considered, a dose of 12 g/day via continuous infusion was found to be comparable to the 16 g/day continuous infusion.

Tazobactam PK profiles were simulated with three dosing regimens against the minimal critical concentrations (MCC) value, 4 mg/L [2]. Free plasma concentrations of tazobactam were well above the MCC threshold in >50% of the population with 0.5 g every 8 h (0.5 h infusion and 4 h infusion). With 1.5 g/day (continuous infusion), tazobactam showed the highest free plasma concentrations well above the MCC threshold in > 95% of the population. These results suggest that dosing regimens with more frequent dosing or extended infusion duration can effectively achieve the desired synergistic effects needed for optimal clinical effect.

Conclusion: The modeling and simulation work have provided crucial PTA results that can aid in the dose regimen selection of piperacillin-tazobactam in critically ill patients.

Citations: [1] J.A. Roberts, J. Lipman, Pharmacokinetic issues for antibiotics in the critically ill patient, Crit Care Med 37(3) (2009) 840-51; quiz 859.
[2] J. Zander, G. Döbbeler, D. Nagel, C. Scharf, M. Huseyn-Zada, J. Jung, L. Frey, M. Vogeser, M. Zoller, Variability of piperacillin concentrations in relation to tazobactam concentrations in critically ill patients, Int J Antimicrob Agents 48(4) (2016) 435-9.