Comparison of Four Renal Function Estimation Equations for Pharmacokinetic Modeling of Gentamicin in Geriatric Patients

Charhon, Nicolas; Neely, Michael; Bourguignon, Laurent; Maire, Pascal; Jelliffe, Roger W.; Goutelle, Sylvain

doi:10.1128/aac.05634-11

Cited by 30 publications

(21 citation statements)

References 34 publications

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“…In particular, in this population of nonobese elderly patients with normal mean body weight, estimates provided by the CG equation were generally lower than those provided by the original MDRD and CKD-EPI equations, which is consistent with previous works from our group and many others (26)(27)(28)(29)(30)(31)(32). Because of this systematic difference, the use of the newer MDRD or CKD-EPI equation in place of the CG equation for drug dosing may have serious implications and cause overdosing in elderly patients for many drugs that are not monitored with concentration measurement (29,32,33).…”

Section: Discussionsupporting

confidence: 91%

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Influence of Renal Function Estimation on Pharmacokinetic Modeling of Vancomycin in Elderly Patients

Glatard

Bourguignon

Jelliffe³

et al. 2015

Antimicrob Agents Chemother

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Vancomycin is a renally excreted drug, and its body clearance correlates with creatinine clearance. However, the renal function estimation equation that best predicts vancomycin clearance has not been established yet. The objective of this study was to compare the abilities of different renal function estimation equations to describe vancomycin pharmacokinetics in elderly patients. The NPAG algorithm was used to perform population pharmacokinetic analysis of vancomycin concentrations in 78 elderly patients. Six pharmacokinetic models of vancomycin clearance were built, based on the following equations: CockcroftGault (CG), Jelliffe (JEL), Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (both in milliliters per minute per 1.73 m 2 ), and modified MDRD and CKD-EPI equations (both in milliliters per minute). Goodness-of-fit and predictive performances of the six PK models were compared in a learning set (58 subjects) and a validation set (20 patients). Final analysis was performed to estimate population parameters in the entire population. In the learning step, the MDRD-based model best described the data, but the CG-and JEL-based models were the least biased. The mean weighted errors of prediction were significantly different between the six models (P ‫؍‬ 0.0071). In the validation group, predictive performances were not significantly different. However, the use of a renal function estimation equation different from that used in the model building could significantly alter predictive performance. The final analysis showed important differences in parameter distributions and AUC estimation across the six models. This study shows that methods used to estimate renal function should not be considered interchangeable for pharmacokinetic modeling and model-based estimation of vancomycin concentrations in elderly patients.

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Section: Discussionsupporting

confidence: 91%

“…In a previous study conducted by our group with elderly patients who were administered gentamicin, the CG-and the JEL-based models provided better predictive performance than the MDRD-based models (26). These findings do not support a general switch from older to new renal function estimation equations for drug dosing.…”

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confidence: 58%

Influence of Renal Function Estimation on Pharmacokinetic Modeling of Vancomycin in Elderly Patients

Glatard

Bourguignon

Jelliffe³

et al. 2015

Antimicrob Agents Chemother

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“…The first data set was from a study originally published in 1990 (9). The data consisted of vancomycin dosing history, concentrations prospectively determined at frequent intervals, and patient covariates such as weight and CL CR estimated by the Jelliffe formula (17), which is comparable, from a modeling perspective, to the Cockroft-Gault formula, at least for gentamicin (18). The data were obtained from adults with prosthetic cardiac valves who each received a single dose of vancomycin prior to an outpatient dental procedure and from acutely ill adults in the cardiac intensive care unit with suspected or proven staphylococcal infections.…”

Section: Methodsmentioning

confidence: 99%

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Neely

Youn

Jones

et al. 2014

Antimicrob Agents Chemother

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333

351

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eThe current vancomycin therapeutic guidelines recommend the use of only trough concentrations to manage the dosing of adults with Staphylococcus aureus infections. Both vancomycin efficacy and toxicity are likely to be related to the area under the plasma concentration-time curve (AUC). We assembled richly sampled vancomycin pharmacokinetic data from three studies comprising 47 adults with various levels of renal function. With Pmetrics, the nonparametric population modeling package for R, we compared AUCs estimated from models derived from trough-only and peak-trough depleted versions of the full data set and characterized the relationship between the vancomycin trough concentration and AUC. The trough-only and peak-trough depleted data sets underestimated the true AUCs compared to the full model by a mean (95% confidence interval) of 23% (11 to 33%; P ‫؍‬ 0.0001) and 14% (7 to 19%; P < 0.0001), respectively. In contrast, using the full model as a Bayesian prior with troughonly data allowed 97% (93 to 102%; P ‫؍‬ 0.23) accurate AUC estimation. On the basis of 5,000 profiles simulated from the full model, among adults with normal renal function and a therapeutic AUC of >400 mg · h/liter for an organism for which the vancomycin MIC is 1 mg/liter, approximately 60% are expected to have a trough concentration below the suggested minimum target of 15 mg/liter for serious infections, which could result in needlessly increased doses and a risk of toxicity. Our data indicate that adjustment of vancomycin doses on the basis of trough concentrations without a Bayesian tool results in poor achievement of maximally safe and effective drug exposures in plasma and that many adults can have an adequate vancomycin AUC with a trough concentration of <15 mg/liter.

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“…Therefore, it is essential to use an appropriate initial dose and dosing interval for gentamicin to minimize its toxicity, while maintaining its efficacy. When determining the appropriate gentamicin dose, many factors need to be considered, eg, infection site, patient age, sex, body weight, serum creatinine, and creatinine clearance 2–4…”

Section: Introductionmentioning

confidence: 99%

Predictive performance of gentamicin dosing nomograms

Lee¹,

Yoon²,

Shin³

et al. 2014

DDDT

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BackgroundSeveral nomograms have been proposed to facilitate the determination of initial gentamicin dosing regimens in clinical settings. This study aimed to assess the predictive performance of these nomograms in Korean patients.MethodsGentamicin concentrations were determined in 84 patients with infective endocarditis (IE) and in 95 patients with other infections. All patients underwent therapeutic drug monitoring in Seoul National University Hospital from 2006 to 2012. Individual pharmacokinetic parameters were estimated using a Bayesian method, which predicted steady state peak and trough serum concentrations. Six nomograms were evaluated in patients with “other” infections: the Thomson guidelines, Hull-Sarubbi table, and Rule of Eights, for multiple daily dosing; and the Hartford nomogram, Barnes-Jewish Hospital nomogram, and Sanford Guide, for extended-interval dosing. In IE patients, synergistic combination dosing nomograms, based on the American Heart Association dosing interval guidelines, were evaluated.ResultsGentamicin dosing nomograms performed poorly in attaining the target peak serum concentrations. Multiple-daily dosing nomograms predicted peak serum gentamicin concentrations better than did the extended-interval dosing nomograms (31.9%–72.3% vs 4.3%–45.7%, respectively). Similarly, in patients with IE, the once-daily dosing nomogram resulted in a significantly lower percentage of patients achieving target peak gentamicin concentrations than that associated with the thrice-daily dosing nomogram (P=0.0015). All of the multiple-daily dosing, extended-interval dosing, and synergistic combination dosing nomograms predicted the nontoxic target trough concentrations in >80% of patients.ConclusionGentamicin dosing nomograms performed poorly in achieving the target peak serum concentrations. New gentamicin nomograms may be required in patients with IE, particularly for once-daily dosing. Therapeutic drug monitoring is highly recommended for gentamicin to ensure that the target concentrations are achieved.

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Comparison of Four Renal Function Estimation Equations for Pharmacokinetic Modeling of Gentamicin in Geriatric Patients

Cited by 30 publications

References 34 publications

Influence of Renal Function Estimation on Pharmacokinetic Modeling of Vancomycin in Elderly Patients

Influence of Renal Function Estimation on Pharmacokinetic Modeling of Vancomycin in Elderly Patients

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Predictive performance of gentamicin dosing nomograms

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