PBPK Modeling and Simulation of Antibiotics Amikacin, Gentamicin, Tobramycin, and Vancomycin Used in Hospital Practice

Abigail Ferreira,Rui Lapa,Helena Martins,Nuno Vale,José Carlos Oliveira

doi:10.3390/life11111130

Abstract

The importance of closely observing patients receiving antibiotic therapy, performing therapeutic drug monitoring (TDM), and regularly adjusting dosing regimens has been extensively demonstrated. Additionally, antibiotic resistance is a contemporary concerningly dangerous issue. Optimizing the use of antibiotics is crucial to ensure treatment efficacy and prevent toxicity caused by overdosing, as well as to combat the prevalence and wide spread of resistant strains. Some antibiotics have been selected and reserved for the treatment of severe infections, including amikacin, gentamicin, tobramycin, and vancomycin. Critically ill patients often require long treatments, hospitalization, and require particular attention regarding TDM and dosing adjustments. As these antibiotics are eliminated by the kidneys, critical deterioration of renal function and toxic effects must be prevented. In this work, clinical data from a Portuguese cohort of 82 inpatients was analyzed and physiologically based pharmacokinetic (PBPK) modeling and simulation was used to study the influence of different therapeutic regimens and parameters as biological sex, body weight, and renal function on the biodistribution and pharmacokinetic (PK) profile of these four antibiotics. Renal function demonstrated the greatest impact on plasma concentration of these antibiotics, and vancomycin had the most considerable accumulation in plasma over time, particularly in patients with impaired renal function. Thus, through a PBPK study, it is possible to understand which pharmacokinetic parameters will have the greatest variation in a given population receiving antibiotic administrations in hospital context.

Highlights

The four antibiotics studied here, amikacin, gentamicin, tobramycin, and vancomycin, are the most frequently monitored in inpatients, which can be explained by their narrow therapeutic indexes and potential to cause adverse effects, namely nephrotoxicity, in prolonged treatments [15,16,17]
As expected for IV infusions, the predicted fraction absorbed (Fa) and bioavailability (F) of all antibiotics were >99%, and a peak in antibiotic concentration was always predicted to be reached at the end of infusions
The imstrated, of bytherapeutic highlightingdrug the influence of parameters such as a patient’s body weight portance monitoring and regimen adjustment was total further demonand the significant impact of renal function on antibiotic plasma concentrations

Summary

Introduction

TDM is indicated and recommended for critically ill patients undergoing sufficiently long treatment to justify dosage adjustment [3], whether with anticancer drugs [4], anti-infectives [5], antiretrovirals [6], biologic therapeutic agents [7] or psychotropic agents [8], etc. For this work, therapeutic drug monitoring and dosage adjustments are crucial for antibiotics, and have confirmed beneficial results [9,10,11,12,13,14,15]. The four antibiotics studied here, amikacin, gentamicin, tobramycin, and vancomycin, are the most frequently monitored in inpatients, which can be explained by their narrow therapeutic indexes and potential to cause adverse effects, namely nephrotoxicity, in prolonged treatments [15,16,17]. The value of TDM of these antibiotics has been extensively demonstrated [13,14,18,19,20,21,22,23,24,25,26,27]

Methods

Results

Conclusion