Measurement of Skeletal Muscle Area Improves Estimation of Aminoglycoside Clearance across Body Size

Abstract

A consistent approach to the dosing of aminoglycosides across the modern body size distribution has been elusive. We evaluated whether radiologically derived measures of body composition could explain more of the interpatient variability in aminoglycoside pharmacokinetics (PK) than standard body size metrics. This retrospective study included adult patients treated with gentamicin or tobramycin with at least three drug concentrations and computed tomography (CT) imaging available. Aminoglycoside volume and clearance (CL) estimates were computed using a two-compartment model by Bayesian analysis. Morphomic data were extracted from CT images using a custom algorithm. Bivariable and multivariable linear regression were used to assess relationships between PK parameters and covariates. A total of 335 patients were included with a median (minimum, maximum) of 4 (3, 16) aminoglycoside concentrations per patient. The median (minimum, maximum) age, height, and weight of included patients were 57 (21, 93) years, 170 (145, 203) centimeters, and 81 (42, 187) kilograms. Both standard and morphomic measures poorly explained variability in volume ( < 0.06). Skeletal muscle area and volume explained more of the interpatient variability in CL than weight or sex. Higher precision was observed using a modified Cockcroft-Gault equation with skeletal muscle area at L3 ( 0.38) or L4 ( 0.37) than the standard Cockcroft-Gault equation using lean ( 0.23), adjusted ( 0.23), or total ( 0.22) body weights. These results highlight that skeletal muscle measurements from CT images obtained in the course of care can improve the precision of aminoglycoside CL estimation over current body size scalars.

Comparison of Body Size, Morphomics, and Kidney Function as Covariates of High‐Dose Methotrexate Clearance in Obese Adults with Primary Central Nervous System Lymphoma

“…Patients with PCNSL undergo multiple radiologic assessments that can also be used to characterize individual body composition. Our group has developed analytical morphomic tools that use existing radiologic data to generate estimates of skeletal muscle, fat, and other relevant body phenotype measures that can serve as scalars of PK parameters 19,20 . Similar to body size, multiple equations exist to estimate kidney function that has traditionally included the Cockcroft‐Gault formula for creatinine clearance (eCrCL) and more recently the Chronic Kidney Disease Epidemiology (CKD‐EPI) equation for the glomerular filtration rate (eGFR) 21,22 .…”

“…Our group has developed analytical morphomic tools that use existing radiologic data to generate estimates of skeletal muscle, fat, and other relevant body phenotype measures that can serve as scalars of PK parameters. 19,20 Similar to body size, multiple equations exist to estimate kidney function that has traditionally included the Cockcroft-Gault formula for creatinine clearance (eCrCL) and more recently the Chronic Kidney Disease Epidemiology (CKD-EPI) equation for the glomerular filtration rate (eGFR). 21,22 The current investigation compared the PK of HD-MTX in obese and non-obese patients with PCNSL who had radiologic data for analytic morphomic assessment.…”

Evaluation of Current Amikacin Dosing Recommendations and Development of an Interactive Nomogram: The Role of Albumin

“…Similarly, antimicrobial guidelines also have no consensus on the weight measure best describing the variability of amikacin PK. Exceptions to the use of TBW for amikacin dosing are described in the guidelines evaluated (i.e., ABW above 30 mg/kg/m 2 ) in addition to new body size scalars proposed, such as skeletal muscle area, as better predictor of interpatient PK variability [ 56 ]. Amikacin dosing recommendations based on TBW seem to be valid for normal-weight patients (BMI < 25 kg/m 2 ) ( Figure S1 ) [ 9 , 57 ].…”

Antimicrobial Dosing in Specific Populations and Novel Clinical Methodologies: Obesity

“…98 Based on this initial proof-of-concept study, additional work has been performed with the aminoglycosides, gentamicin, and tobramycin that undergo routine therapeutic drug monitoring and dosed on body size. 97 This evaluation included 335 patients with a median (min, max) age, weight, BMI of 57 (21,93) years, 81 (42,187) kg, and 29 (14,73) kg/m 2 , respectively. Similar to vancomycin, the correlation of body size and morphomic parameters to Vc was weak.…”

“…These proof-of-concept studies suggest that use of repurposed information from radiologic data can improve upon the current body size standard. 97 Additional studies are needed to ensure reproducibility and rigor of these methods before broader implementation can be suggested. Extension of this approach to other antibiotics and other drug classes and disease conditions are also necessary to move this field forward.…”