(T-067) A quantitative systems pharmacology-physiologically based pharmacokinetic model-guided antibiotics regimen design for the treatment of sepsis and septic shock patients

Eun Kyoung Chung, Pharm.D., Ph.D. – Professor, Kyung Hee University

Objectives: Successful clinical trials of sepsis and guidance regarding the optimal antibiotic regimen for sepsis are extremely limited. Here, we harness Quantitative Systems Pharmacology—Physiologically-Based Pharmacokinetics (QSP-PBPK) hybrid modeling to overcome the inadequate animal models that reproduce human pathophysiology and the heterogeneity of patients with sepsis and suggest a model-guided optimal antibiotic regimen.

Methods: We develop a QSP-PBPK hybrid model of antibiotic treatment for sepsis based on a dynamic network that includes bacterial infection, host immune response, cardio-renal physiology, and antibiotic (vancomycin) drug action. The model is built by integrating previously published models and represented by a system of ordinary differential equations. We explore and compare hypothetical treatment scenarios: immediate (1 hour after infection) vs. delayed (12 hours after infection), with or without the initial loading dose, and 7 days, 14 days, and 21 days of treatment.

Results: The simulation results of the model with no antibiotic treatment showed rapidly deteriorated organ function, which did not recover to the normal range. Compared to a sterile state, sustained bacterial infection decreased the mean arterial pressure (MAP) below 60mmHg, which was sustained at around 65mmHg. Glomerular filtration rate (GFR) fluctuated and rapidly decreased around 40mL/min. For the early antibiotic treatment (one hour after infection) case, augmented renal clearance (GFR >130mL/min) was predicted to occur 46 hours after the infection, which resolved after 282 hours. Earlier antibiotic initiation was predicted to show GFR and MAP improvement 200~300 hours earlier and delay recurrent infection 100 hours in seven days of treatment. Our simulation results showed suppression of the recurrent infection for 14 and 21 days of antibiotic treatment with early initiation. The initial loading dose was also predicted to delay about 30 hours or suppress the recurrent infection depending on the treatment duration (7 days or 14 and 21 days, respectively). When the initiation of the antibiotic was delayed (12 hours after infection), only 21-day treatment was predicted to inhibit recurrent infection.

Conclusions: The QSP-PBPK hybrid model of antibiotic treatment for sepsis suggests the necessity of prolonged antibiotic treatment, particularly for patients at risk of transitioning to shock. Our study presents that mathematical model have a potential as a viable alternative to animal model. The model could be a starting point for assisting in the translation to clinical trials and the personalized treatment of sepsis.

Citations: [1] R. Rao, C. J. Musante, R. Allen, A quantitative systems pharmacology model of the pathophysiology and treatment of COVID-19 predicts optimal timing of pharmacological interventions. NPJ Syst Biol Appl 9, 13 (2023)
[2] K. M. Hallow, Y. Gebremichael, A Quantitative Systems Physiology Model of Renal Function and Blood Pressure Regulation: Application in Salt-Sensitive Hypertension. CPT Pharmacometrics Syst Pharmacol 6, 393-400 (2017)
[3] J. K. Diep, T. A. Russo, G. G. Rao, Mechanism-Based Disease Progression Model Describing Host-Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia. CPT Pharmacometrics Syst Pharmacol 7, 507-516 (2018).