Practical, Individualized Dosing: 21st Century Therapeutics and the Clinical Pharmacometrician

Neely, Michael; Jelliffe, Roger W.

doi:10.1177/0091270009356572

Cited by 53 publications

(64 citation statements)

References 25 publications

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“…For 21st century vancomycin management, optimally sampled, AUC-guided dosing with computerized decision support should be more widely used and evaluated, as has been recommended by others (37). While there are barriers to the implementation of such a strategy in hospitals and clinics (24), these are largely logistic and educational, not technological, and can be overcome (38).…”

Section: Discussionmentioning

confidence: 99%

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Neely

Youn

Jones

et al. 2014

Antimicrob Agents Chemother

334

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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Section: Discussionmentioning

confidence: 99%

Are Vancomycin Trough Concentrations Adequate for Optimal Dosing?

Neely

Youn

Jones

et al. 2014

Antimicrob Agents Chemother

334

351

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“…This could include using PK model-based dosing with milrinone concentration measurements as feedback. 19 This would allow for evidencebased and meaningful interpretation of sparse PK data to individualize care in the complex critical care setting. One practical limitation to this strategy is that currently few clinical laboratories offer a rapid turnaround assay for measuring milrinone concentrations to allow meaningful clinical use.…”

Section: Discussionmentioning

confidence: 99%

Retrospective Evaluation of Milrinone Pharmacokinetics in Children With Kidney Injury

Gist

Mizuno

Goldstein

et al. 2015

Therapeutic Drug Monitoring

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Pediatric patients with AKI have significantly lower milrinone clearance compared with published data in patients without AKI. Large variability was noted in milrinone concentrations, and they were frequently outside the target range. The large between-patient variability in milrinone concentrations suggests that dosing regimens should be individualized in this population of critically ill patients. Evaluation of PK model-based milrinone dose optimization and the use of biomarkers as predictors of changes in clearance warrant further study.

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“…Optimised dosing using an estimation of an individual's PK to identify the optimal dosage has not been undertaken with anti-bacterial agent. Pilot studies, within other infectious diseases areas, have demonstrated with HIV drugs in paediatric patients and in the management of invasive pulmonary aspergillosis with voriconazole (Neely and Jelliffe 2010;Hope et al 2013). The impact of dosage adaptation on patient outcome requires further study.…”

Section: Accepted Manuscriptmentioning

confidence: 99%