Antimicrobial Dosing in Specific Populations and Novel Clinical Methodologies: Kidney Function

Abstract

Kidney function is a common parameter used to define antimicrobial drug dosage and frequency of administration. Several methods exist to measure kidney function but for pragmatic reasons rely on estimated kidney function equations based on the endogenous biomarker serum creatinine and common clinical variables. Current regulatory guidance on the design of studies in patients with abnormal kidney function in the United States also recommend consideration of estimated kidney function for this reason. Over the past few decades, alternate endogenous biomarkers, administration of exogenous biomarkers for noninvasive measurement, use of probe substrates to characterize individual kidney drug clearance pathways, modifications to conventional equations to account for time‐varying clearance, and improved clinical trial modeling and simulation to factor in these uncertainties have occurred. Furthermore, major changes to kidney replacement therapy delivery in the outpatient, inpatient, and at‐home setting are occurring. Antimicrobial drug dose adjustment in this diverse population is complex and in a state of flux due to technical innovations. Over‐reliance on kidney function estimates to guide drug dosing in patients with infectious diseases can bias underdosing especially among the acutely ill. A holistic approach to drug dose adjustment in patients with abnormal kidney function is necessary to optimize clinical outcomes.

Comparison of Race‐Based and Non–Race‐Based Equations for Kidney Function Estimation in Critically Ill Thai Patients for Vancomycin Dosing

“…This key limitation is also not addressed in drug development when building population PK models in patients with critical illness and is a major caveat that impacts interpretation of kidney function-based dose adjustment in this population. 30,31 Our simulations are also based on infusing vancomycin MD at 500 mg/h that is half the typical rate of that in the United States. We acknowledge these limitations with the rigor and detailed disclosure of our analysis.…”

Kidney function as a key driver of the pharmacokinetic response to high‐dose L‐carnitine in septic shock

“…The Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) has established equations to estimate glomerular filtration rate (eGFR) based on S cr and/or S cys , patient age, sex, and race. Given the increasing controversy about inclusion of patient race as a variable 20 and the drawbacks of S cr as a kidney biomarker, 21 we estimated eGFR using four iterations of the CKD‐EPI equation: the 2009 CKD‐EPI equation 22 (includes patient race and S cr ); the 2021 CKD‐EPI equation 23 (uses S cr but drops patient race); the 2012 CKD‐EPI equation 24 (uses S cys ); and the 2021 CKD‐EPI equation 23 (includes both S cr and S cys without an adjustment for race). All eGFR calculations were calculated according to standard body surface area and are in the units of mL/min per 1.73 m 2 .…”

Diversity in Clinical Pharmacology and Therapeutics

“…In our April themed issue on Therapeutic Innovations in Infectious Diseases , we published the first series of “Special Populations” reviews associated with a specific therapeutic area 21–24 and we are planning to continue this in the upcoming themed issue on Therapeutic Innovations in Neuroscience , scheduled for publication in April 2022.…”