Laura Bem Olivo¹, Keli Jaqueline Staudt¹, Bibiana Verlindo de Araújo¹
(1) Federal University of Rio Grande do Sul, Brazil
Introduction/Objectives: PBPK are bottom-up models that integrate physiological information of the organism with the physicochemical characteristics of the drug, allowing a priori simulation of pharmacokinetic profiles¹. These models have gained greater application in recent decades due to the development of software that would enable PBPK modeling for the growth of this approach which facilitates the application of those in the most different scenarios and now, are currently applied in the routine of large pharmaceutical industries for studies of interspecies and intraspecies translations and definition of the first dose in humans². In the clinical setting, this strategy is used to study drug-drug interaction and to understand the influence of pathophysiology on pharmacokinetic and pharmacodynamic processes³. In this work, PBPK modeling was applied to evaluate the influence of infection on the antimicrobial distribution process. The drug chosen was piperacillin based on its importance in the treatment of nosocomial infections and sepsis (associated with tazobactam).
Methods: The base model was initially built for naïve rats at doses corresponding to doses used in humans (60 mg/kg and 120 mg/kg). Physicochemical information about the drug was collected, such as logP, molecular weight, water solubility and pKa, and previously published pharmacokinetic information such as free fraction and renal clearance. For the development of the model, the software PK-SIM (Bayer Company) was used. The model was validated for total plasma and free muscle concentrations through previously published data and the calculation of the Average Fold Error (AFE).
Results: The proposed model describes linear kinetics for the PIP, since the values ??of the PK parameters, such as renal clearance (16.57 mL/min/kg) and half-life (27.7 min) are equal between this two doses and that area under the curve (AUC) value increases in proportion to the dose increase, being 3621.18 ug*min/mL for the lower dose and 7242.36 ug*min/mL for the highest. The concentrations predicted by the model in the light of the data in the literature were adequate, with AFE values ??within the acceptance criterion of 0.5 – 2.0, being: 1.12, for plasma at a dose of 60 mg / kg; and 0.88, for plasma at a dose of 120 mg / kg; 1.23, for muscle at the dose of 60 mg / kg and 1.09, for muscle at the dose of 120 mg / kg. The method for assessing tissue penetration addressed in this work is the penetration coefficient tissue (Kp), calculated using the Rodgers and Rowland equation, which was estimated by the software for the muscle at 0.40.
Conclusions: Thus, it can be concluded that the developed PBPK model was able to predict the concentrations of PIP in plasma and tissue and the next step is the inclusion of pathophysiological characteristics such as variation in pH and blood flow, using data from rats infected with E. coli and then to translate these data to the clinical scenario, considering human populations with sepsis, seeking to evaluate the chances of successful therapy through simulations.
References:
[1] KUEPFER, L. et al. Applied Concepts in PBPK Modeling: How to Build a PBPK/PD Model. CPT: Pharmacometrics and Systems Pharmacology, v. 5, n. 10, p. 516–531, 2016.
[2] SAGER, J. E. et al. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: A systematic review of published models, applications, and model verification. Drug Metabolism and Disposition, v. 43, n. 11, p. 1823–1837, 2015.
[3] JONES, H. M.; ROWLAND-YEO, K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT: Pharmacometrics and Systems Pharmacology, v. 2, n. 8, p. 1–12, 2013.
Reference: PAGE 29 (2021) Abstr 9871 [www.page-meeting.org/?abstract=9871]
Poster: Drug/Disease Modelling - Absorption & PBPK