Augmented renal clearance of aminoglycosides

population based pharmacokinetic modelling with Bayesian estimation in paediatric ICU

Significance 

Augmented renal clearance (ARC) is a phenomenon in critically ill patients characterized by increased creatinine clearance and elimination of renally eliminated medications. What was previously reported as a condition prevalent in adult populations, recent studies have shown its increasing prevalence as well in pediatric intensive care population. Patients with ARC under antibiotic administration are at risk of subtherapeutic antibiotic exposure and therefore need higher dosages to avoid life-threatening complications. In order to identify ARC, estimated glomerular filtration (eGFR) is the gold standard measurement for the assessment of renal function but method to obtain this value has been challenging and unreliable. Aminoglycoside drug clearance is an alternative measure to obtain eGFR because it is freely filtered with minimum non-renal clearance. By identifying ARC in paediatric patients, it will allow us to adjust dosage regimens with optimal pharmacokinetic profile.

Indeed, optimizing dosing strategies in critically ill patients with ARC remains a goal of continued research. In a recent publication in the Journal of Antimicrobial Chemotherapy, scientists at University of California San Diego:  Professor John Bradley, Joshua Valdez and Dr. Jennifer Le together with Dr. Sean Avedissian, Dr. Nathaniel Rhodes, and Yuna Kim at Midwestern university conducted a retrospective study to identify the prevalence of ARC from population data in two hospitals. The researchers used PK modelling and Bayesian posterior estimation to calculate aminoglycoside clearance. They selected one and two compartment clearance models as base models and aminoglycoside concentration was calculated from the ultimate best fit model. Additionally, to measure variables contributing as risk factors for ARC, multivariate logistic model was used.

The authors observed that there was a significant prevalence of ARC in the two paediatric populations. Two compartment model was used in the final PK analysis and multiple aminoglycoside concentration was fitted into the model to calculate overall clearance. The overall clearance model required value for creatine clearance, total body weight, serum creatinine and maturation term. They reported a prevalence of ARC of 19.5% in the paediatric patients with a median clearance of 157 ml/min/1.73m2.

Furthermore, the research team identified factors that contributed to the risk of ARC in paediatric population including increasing age, sepsis and low baseline serum creatinine. Additionally, increased clearance was correlated with decreased 24-hour AUC (body exposure to drug over the first 24 hour). This showed that with further studies aminoglycoside can be a reliable alternative to measure eGFR in paediatric population.

This is the first report that used population PK modelling and Bayesian estimation to determine ARC in a paediatric patient population. In a statement to Medicine Innovates, Professor Jennifer Le, the corresponding author, explained that their study showed paediatric patients experiencing ARC require higher doses to reach recommended PK/PD target exposures. ARC is often overlooked in this population due to unreliable screening methods and subsequently affects the optimal therapeutic dosage range. The study indeed will pave the way in understanding the importance of ARC in paediatric population and henceforth taking necessary actions to avoid complications. Recently, increasing antibiotic resistance is detrimental to the healthcare system especially in an ICU setting hospital. Using methods similar to the ones in the study as the basis for ARC detection along with further research will give insight into a suitable dosing regimen for ARC patients and therefore decrease the chances of antibiotic resistance in them. It will help us advance our understanding in possible pathophysiological mechanism for ARC and ultimately strategize in the management of ARC patients.

Augmented renal clearance of aminoglycosides using population based pharmacokinetic modelling with Bayesian estimation in paediatric ICU - Medicine Innovates

About the author

Dr. Jennifer Le is Professor of Clinical Pharmacy at the University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences. She received her Bachelors of Science in Biology from University of California, Los Angeles in 1995; PharmD from University of California, San Francisco in 2000; and Masters in Clinical Research from University of California, San Diego in 2012.  As a board-certified pharmacotherapy specialist with added qualification in infectious diseases since 2007, Dr. Le has been involved in clinical pharmacy services in pediatric infectious diseases and patient-oriented research over 19 years.

She is an invited member of the federal advisory board for the Food and Drug Administration’s (FDA) Antimicrobial Drugs Advisory Committee that makes official recommendations to FDA about safety and efficacy of antibiotics for use in the United States. She is also an advisory board member of the Asian Pacific Health Foundation; has also been a member of an NIH Special Emphasis Panel and participates in Scientific Review Groups; is an invited editorial board member for Pediatric Pharmacotherapy, Pharmacotherapy Journal, Pediatric Medicine and Infectious Diseases and Therapy Journal; and invited program reviewer for the national board certification programs through the American College of Clinical Pharmacy, including Self-Assessment Programs in Pediatrics (PedSAP), Ambulatory Care (ACSAP), and Pharmacotherapy (PSAP).

Dr. Le’s primary research encompasses three domains: (1) the appropriate and safe use of antibiotics and antifungal agents, (2) clinical pharmacology, and (3) outcomes associated with resistant infections in pediatrics across the wide age spectrum from infancy (including critically-ill premature neonates) to adolescence. She specializes in pharmacokinetics – the processes by which a drug is absorbed, distributed, metabolized and eliminated by the body – and pediatric clinical pharmacology research.

She has published over 135 articles in reputable medical and pharmacy journals and books, including Pediatrics, Journal of Pediatrics, and Merck Manuals and serves as the second author of the current vancomycin guidelines endorsed by the American Society of Health-System Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and Society of Infectious Diseases Pharmacists.  Dr. Le was a past recipient of the American College of Clinical Pharmacy’s Investigator Development Award and the K23 Career Development Award from the National Institutes of Health for her research in pharmacokinetic-pharmacodynamic modeling of antibiotics in children. She also serves as an investigator for pharmacokinetic studies through the RO1, U54 & T32/34 award mechanisms for developmental and translational pharmacology of pediatric antimicrobial therapy funded by the National Institutes of Health.

She was bestowed the honor of fellow of the Infectious Diseases Society of America, American College of Clinical Pharmacy and California Society of Health Systems Pharmacists; and received awards such as Sternfels Prize for Drug Safety Innovation and Outstanding Mentor at University of California, San Diego Faculty Mentor Program. Dr. Le is most proud of her passion and continued effort to improve pediatric health and wellness extending globally through her humanitarian work in Vietnam, Taiwan and for Jordan over the past 8 years.

Reference

Avedissian S., Rhodes N., Kim Y., Bradley J., Valdez J., Le J., Augmented renal clearance of aminoglycosides using population-based pharmacokinetic modelling with Bayesian estimation in paediatric ICU, Journal of Antimicrobial Chemotherapy,2020;75: 162-169

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