Vancomycin dosing nomograms targeting high serum trough levels in different populations: pros and cons.

PURPOSE: Utilization of higher doses of vancomycin to achieve the trough concentrations of 15-20 mg/L for complicated infections has been recommended by the Infectious Diseases Society of America clinical practice guideline in recent years. Concerning this recommendation, several nomograms have been constructed targeting this optimal trough level range in different populations of patients. In this review, we have collected available nomograms targeting high trough serum levels of vancomycin, particularly comparing their advantages and limitations. METHOD: The data were collected by searching Scopus, PubMed, Google scholar, Medline, and Cochrane database systematic reviews. The key words used as search terms were "vancomycin", "high trough level", "dosing nomogram", "dosing strategy", "neonates", "critically ill", "pediatrics", and "hemodialysis". We have included 17 related human studies published up to the date of this publication. RESULTS & CONCLUSION: Most of the available nomograms have determined the doses according to body weight and renal function. Their initial predicting success rate were 44-76 % for non-critically ill patients, 42-84 % for critically ill patients, 54 % for one nomogram specially designed for hemodialysis patients, and 71 % for the only nomogram developed for neonates. Based on validation studies, in most of cases, using a vancomycin dosing nomogram significantly improved and accelerated achievement of target trough concentrations. However, it should be noted that there are limited data about patients' clinical and microbiological outcomes and they are only validated in narrow groups of patients. Thus, their widespread application could not be encouraged for all patients before performing adequately powered, prospective randomized studies.

Predictive performance of population pharmacokinetic models of imatinib in chronic myeloid leukemia patients.

BACKGROUND AND AIM: Chronic myeloid leukemia is a myeloproliferative neoplasm associated with the specific chromosomal translocation known as the Philadelphia chromosome. Imatinib is a potent BCR-ABL tyrosine kinase inhibitor, which is approved as the first line therapy for CML patients. There are various population pharmacokinetic studies available in the literature for this population. However, their use in other populations outside of their cohort for the model development has not been evaluated. This study was aimed to perform the predictive performance of the published population pharmacokinetic models for imatinib in CML population and propose a dosing nomogram. METHODS: A systematic review was conducted through PubMed, and WoS databases to identify PopPK models. Clinical data collected in adult CML patients treated with imatinib was used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions. RESULTS: Eight imatinib PopPK model were selected for evaluating the model performance. A total of 145 plasma imatinib samples were collected from 43 adult patients diagnosed with CML and treated with imatinib. The PopPK model reported by Menon et al. had better performance than all other PopPK models. CONCLUSION: Menon et al. model was able to predict well for our clinical data where it had the relative mean prediction error percentage ≤ 20%, relative median absolute prediction error ≤ 30% and relative root mean square error close to zero. Based on this final model, we proposed a dosing nomogram for various weight groups, which could potentially help to maintain the trough concentrations in the therapeutic range.

Model Re-Estimation: An Alternative for Poor Predictive Performance during External Evaluations? Example of Gentamicin in Critically Ill Patients.

BACKGROUND: An external evaluation is crucial before clinical applications; however, only a few gentamicin population pharmacokinetic (PopPK) models for critically ill patients included it in the model development. In this study, we aimed to evaluate gentamicin PopPK models developed for critically ill patients. METHODS: The evaluated models were selected following a literature review on aminoglycoside PopPK models for critically ill patients. The data of patients were retrospectively collected from two Quebec hospitals, the external evaluation and model re-estimation were performed with NONMEM® (v7.5) and the population bias and imprecisions were estimated. Dosing regimens were simulated using the best performing model. RESULTS: From the datasets of 39 and 48 patients from the two Quebec hospitals, none of the evaluated models presented acceptable values for bias and imprecision. Following model re-estimations, all models showed an acceptable predictive performance. An a priori dosing nomogram was developed with the best performing re-estimated model and was consistent based on recommended dosing regimens. CONCLUSION: Due to the poor predictive performance during the external evaluations, the latter must be prioritized during model development. Model re-estimation may be an alternative to developing a new model, especially when most known models display similar covariates.

Initial dosing of intermittent vancomycin in adults: estimation of dosing interval in relation to dose and renal function.

OBJECTIVES: Due to the high interindividual variability in vancomycin pharmacokinetics, optimisation of its dosing is still challenging. This study aimed to explore vancomycin pharmacokinetics in adult patients and to propose an easy applicable dosing nomogram for initial treatment. METHODS: Vancomycin pharmacokinetics was calculated in a two-compartmental model based on therapeutic drug monitoring data. A linear regression model was used to explore the relationship between vancomycin elimination half-life and glomerular filtration rate estimated according the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. RESULTS: In the whole study population (n=66), vancomycin volume of distribution, clearance and half-life median (IQR) values were 0.69 (0.58-0.87) L/kg, 0.031 (0.022-0.050) L/h/kg and 14.4 (9.5-25.2) hours, respectively. Vancomycin half-life was associated with glomerular filtration rate (r2=0.4126, p<0.0001) according to the formula: t1/2 (h) = -0.247×eGFRCKD-EPI (mL/min/1.73 m2)+32.89. This relationship was used to construct a dosing nomogram. CONCLUSIONS: We propose an easy-to-use dosing nomogram for vancomycin therapy initiation that allows individualisation of the dosing interval with respect to the administered dose size and functional renal status.

Actual body weight-based vancomycin dosing in neonates.

This study aimed to explore vancomycin pharmacokinetics and its covariates in critically ill neonates and to propose an easy applicable dosing nomogram for initial treatment. Individual vancomycin pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a one-compartmental model. A linear regression model was used for examination of covariates. The mean (SD) volume of distribution (Vd) and clearance (CL) for vancomycin were 0.73 (0.31) L/kg and 0.052 (0.020) L/h/kg, respectively. Vd was related to actual body weight (ABW), gestational and postmenstrual age. CL was also associated with ABW, gestational, postmenstrual age and also creatinine clearance. ABW was the strongest predictor for vancomycin pharmacokinetics and consequently dosing. Loading dose (mg) of 11.81 × ABW (kg) + 7.86 and maintenance dose (mg/day) of 40.92 × ABW (kg) -22.18 most closely approximated pharmacokinetic target. Vancomycin pharmacokinetics was mainly influenced by ABW in neonates and a practical ABW-based dosing algorithm was developed.

Genotype-guided dosing of warfarin through modeling and simulation.

Current genotype-guided algorithms for warfarin dosing fail to deliver optimal performance in two aspects: 1) these algorithms are not able to achieve the same level of benefits in non-white populations, since they were developed based on multivariate regression analysis with mostly European/White data and did not include genetic variants found frequently in non-white populations; 2) these algorithms do not account for the dynamic dose/response relationship and were limited in their usefulness to guide dosing during the initiation phase, as the possession of variant VKORC1 and/or CYP2C9 polymorphisms has been associated with a more rapid attainment of target international normalized ratio (INR) and higher risk of over-anticoagulation even in genotype-guided patients. To address these shortcomings, we report on the novel use of a previously published kinetic/pharmacodynamic (K/PD) model to develop a warfarin dosing nomogram to be used across genotypes and ethnicities. Our approach leverages data from both ethnically diverse and European patients, while accounting for the differential dose/response behaviors due to VKORC1 and CYP2C9 genotypes. According to simulations, the utilization of our dosing nomogram could enable effective attainment of therapeutic INR within one week in both ethnically diverse and European populations, while maintaining uniform INR response profiles across genotypes. Furthermore, in silico clinical trial simulations using the K/PD model could be a feasible approach to help to further refine our dosing nomogram to be more applicable in the clinical setting and explore possible outcomes even before prospective clinical trials are initiated.

Use of a simplified nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure.

STUDY OBJECTIVES: To compare the frequency of achieving a therapeutic serum digoxin concentration (SDC), defined as 0.5-0.9 ng/ml, by using a simplified nomogram to individualize digoxin dosing with standard dosing practices in patients with heart failure, and to characterize the relationship between genetic polymorphisms of the ABCB1 gene and SDC. DESIGN: Prospective study with a historical control group. SETTING: Outpatient care center of an urban academic medical center. PATIENTS: A total of 131 adults with heart failure due to left ventricular dysfunction who were treated with digoxin. INTERVENTION: Digoxin doses were determined either by the dosing nomogram (65 patients) or standard care (SC; 66 patients) by using historical controls who were randomly selected from a list of SDCs obtained from laboratory records and who had their digoxin doses determined by standard dosing practices. MEASUREMENTS AND MAIN RESULTS: The primary end point was the proportion of patients achieving a steady-state SDC of 0.5-0.9 ng/ml; secondary end points were mean SDC and proportion of patients achieving a steady-state SDC lower than 1.0 ng/ml. Postdistributive steady-state SDCs were measured 2-4 weeks after digoxin dosage adjustment or initiation. Therapeutic SDCs were achieved with similar frequency in both groups (38.7% in the nomogram group vs 34.5% in the SC group, p=0.65); however, more patients in the nomogram group had SDCs lower than 1.0 ng/ml than in the SC group (85.0% vs 44.9%, p<0.001). Mean daily digoxin doses were lower in the nomogram group (149 ± 67 µg vs 177 ± 74 µg, p=0.02), resulting in lower mean SDCs compared with those in the SC group (0.52 ± 0.30 ng/ml vs 1.12 ± 0.58 ng/ml, p<0.001). Patients in the pharmacogenetic substudy provided blood samples for genotyping of three common ABCB1 single nucleotide polymorphisms: C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642). SDCs were not significantly associated with ABCB1 genotypes. CONCLUSION: Our simplified digoxin dosing nomogram resulted in lower SDCs compared with standard dosing practices but achieved therapeutic SDCs with similar frequency. A greater proportion of patients dosed according to our nomogram had SDCs lower than 1.0 ng/ml, consistent with consensus guidelines. Genetic polymorphisms of the ABCB1 gene were not associated with SDC.

Evaluation of a vancomycin dosing nomogram based on the Modification of Diet in Renal Disease equation in intensive care unit patients.

PURPOSE: The purpose of the study is to evaluate the effectiveness of a vancomycin nomogram using actual body weight and the Modification of Diet in Renal Disease equation to estimate renal function in intensive care unit patients. METHODS: Retrospective evaluation (preimplementation group, n=57) was conducted from March 2011 to April 2011. Prospective evaluation was conducted after nomogram implementation (postimplementation group, n=60) from December 2011 to February 2012. RESULTS: The percentage of patients with an initial vancomycin trough concentration 15 µg/mL or higher increased in the postimplementation group as compared with the preimplementation group (72% vs 39%, P=.0004). The postimplementation group also demonstrated an increase in the percentage of patients with initial trough concentration between 15 and 20 µg/mL (42% vs 19%, P=.0099), and no statistical difference in the percentage of patients with an initial trough greater than 20 µg/mL (30% vs 19%, P=.2041). There was no difference in nephrotoxicity in the postimplementation group compared with the preimplementation group (18% vs 17.5%, P=1.0). CONCLUSION: Use of a vancomycin nomogram increased the percentage of initial vancomycin trough concentrations 15 µg/mL or higher in intensive care unit patients and was not associated with an increased occurrence of nephrotoxicity.