Assessment of aminoglycoside dosing and estimated glomerular filtration rate in determining gentamicin and tobramycin area under the curve and clearance

Lim, Andy; Mathanasenarajah, Gayathiri; Larmour, Ian

doi:10.1111/imj.12684

Cited by 10 publications

(12 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to tobramycin, renal function estimates (eGFR or GFR based on 24-h urine collection) were inferior to TBW in predicting gentamicin clearance, despite the fact that in both studies individuals with a similar distribution in body weights and renal function (all >60 ml/min) were included. Interestingly, this finding has been reported before by other studies, describing stronger correlations between eGFR and drug clearance for tobramycin than gentamicin ( 15 , 29 ). To explain this difference between tobramycin and gentamicin, it could be hypothesized that transporters play a role.…”

Section: Discussionsupporting

confidence: 88%

“…The influence of obesity on aminoglycoside clearance has been reported in some studies over the years ( 11 – 13 , 15 , 16 , 29 ). Although in general these studies found an increase in clearance with increasing body weight, their results have to be interpreted with caution since individuals in most of these studies were only moderate obese compared to present-day standards with average body weights around 85–105 kg with standard deviations of ±12–18 kg ( 12 , 13 , 16 ).…”

Section: Discussionmentioning

confidence: 95%

“…Lim et al . found in a retrospective study with 342 patients with ~30% being obese, that de-indexed eGFR outperformed their unadjusted counterparts in predicting aminoglycoside clearance ( 29 ). Leader et al .…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study

Smit

Wasmann²,

Wiezer

et al. 2019

Pharm Res

View full text Add to dashboard Cite

Purpose Tobramycin is an aminoglycoside antibiotic of which the 24 h exposure correlates with efficacy. Recently, we found that clearance of the aminoglycoside gentamicin correlates with total body weight (TBW). In this study, we investigate the full pharmacokinetic profile of tobramycin in obese and non-obese individuals with normal renal function. Methods Morbidly obese individuals ( n = 20) undergoing bariatric surgery and non-obese healthy volunteers ( n = 8), with TBW ranging 57–194 kg, received an IV dose of tobramycin with plasma concentrations measured over 24 h ( n = 10 per individual). Statistical analysis, modelling and simulations were performed using NONMEM. Results In a two-compartment model, TBW was the best predictor for central volume of distribution ( p < 0.001). For clearance, MDRD (de-indexed for body surface area) was identified as best covariate ( p < 0.001), and was superior over TBW (( p < 0.05). Other renal function estimates (24 h urine GFR and de-indexed CKD-EPI) led to similar results as MDRD (all p < 0.001)). Conclusions In obese and non-obese individuals with normal renal function, renal function estimates such as MDRD were identified as best predictors for tobramycin clearance, which may imply that other processes are involved in clearance of tobramycin versus gentamicin. To ensure similar exposure across body weights, we propose a MDRD-based dosing nomogram for obese patients. Electronic supplementary material The online version of this article (10.1007/s11095-019-2651-2) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study

Smit

Wasmann²,

Wiezer

et al. 2019

Pharm Res

View full text Add to dashboard Cite

show abstract

“…Studies with aminoglycosides, compounds that serve as excellent probes of glomerular filtration, have verified that the CKD-EPI equation is likely to be more precise than either the C-G or MDRD equations. 35,36 The CKD-EPI equation has also been shown to be relevant for stratification of risk when dosing edoxaban in patients with good renal function. 37 Also, the CKD-EPI estimate of renal function led to concordant dosing recommendations of antiretroviral dosing in a French cohort of patients with HIV.…”

Section: The Fork In the Roadmentioning

confidence: 99%

“…The CKD‐EPI equation has demonstrated utility in predicting drug pharmacokinetics and informing dosing. Studies with aminoglycosides, compounds that serve as excellent probes of glomerular filtration, have verified that the CKD‐EPI equation is likely to be more precise than either the C‐G or MDRD equations . The CKD‐EPI equation has also been shown to be relevant for stratification of risk when dosing edoxaban in patients with good renal function .…”

Section: The Fork In the Roadmentioning

confidence: 99%

Estimating Renal Function in Drug Development: Time to Take the Fork in the Road

Crass

Pai

2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Renal function is the most commonly applied patient-specific quantitative variable used to determine drug doses. Measurement of renal function is not practical in most clinical settings; therefore, clinicians often rely on estimates when making dosing decisions. Similarly, renal function estimates are used to assign subjects in phase 1 pharmacokinetic studies, which inform dosing in late-phase clinical trials and ultimately the product label. The Cockcroft-Gault estimate of creatinine clearance has been the standard renal function metric; however, this paradigm is shifting toward the Modification of Diet in Renal Diseases (MDRD) estimate of the glomerular filtration rate (GFR). The proportion of approved new drug labels with dosing recommendations based on the MDRD equation was 16.7% in 2015, 70.0% in 2016, and 46.7% in 2017. Disharmonious recommendations from the United States Food and Drug Administration and the European Medicines Agency will continue to increase this heterogeneity in the assessment of renal function in drug development and negatively impact industry, health systems, and clinicians. In this review, we discuss the current regulatory guidance for the conduct of renal impairment pharmacokinetic studies and review the implications of this guidance across the medication use system with 3 recently approved antibiotics: ceftazidime/avibactam, delafloxacin, and meropenem/vaborbactam. Finally, we suggest measuring GFR in phase 1 studies and employing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to integrate data across clinical trials. This will help to harmonize CKD staging, population pharmacokinetic analyses, and dosing by estimated renal function.

show abstract

Network pharmacodynamic models for customized cancer therapy

Gallo

Birtwistle

2015

WIREs Mechanisms of Disease

View full text Add to dashboard Cite

Pharmacokinetics [PKs] and pharmacodynamics [PDs] have always been integral to the design of rational drug dosing regimens. Early on PK-driven approaches came under the auspices of therapeutic drug monitoring that progressed into population-based PK and PK/PD modeling analyses. Since the availability of tissue samples for measurement of drug concentrations is limited in patients, the bulk of such model-based methods relied on plasma drug concentrations to both build models and monitor therapy. The continued advances of systems biology and the spawning of systems pharmacology propelled the creation of enhanced PD (ePD) models. A main characteristic of ePD models is that they are derived from mechanistically grounded biochemical reaction networks. These models are commonly represented as systems of coupled ordinary differential equations with the ability to tailor each reaction and protein concentration to an individual’s genomic/proteomic profile. As patient genomic analyses become more common, many genetic and protein abnormalities can be represented in the ePD models, and thus offer a path towards personalized anticancer therapies. By linking PK models to ePD models, a full spectrum of pharmacological simulation tools is available to design sophisticated multidrug regimens. However, ePD models are not a panacea and face challenges in model identifiability, scaling and parameter estimation. Nonetheless, as new technologies evolve and are coupled with fresh ideas on model implementation, it is likely that ePD and PK/ePD models will be considered a viable enterprise to customize anticancer drug therapy.

show abstract

Assessment of aminoglycoside dosing and estimated glomerular filtration rate in determining gentamicin and tobramycin area under the curve and clearance

Abstract: Current guideline dosing may be suboptimal for achieving target area-under-the-curve. The CKD-EPI equation adjusted for patient body surface area best predicts aminoglycoside clearance, and could be evaluated as a covariate in determining initial aminoglycoside dosing.

Cited by 10 publications

References 24 publications

Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study

Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study

Estimating Renal Function in Drug Development: Time to Take the Fork in the Road

Network pharmacodynamic models for customized cancer therapy

Contact Info

Product

Resources

About