Optimization of Vancomycin Initial Dosing Regimen in Neonates Using an Externally Evaluated Population Pharmacokinetic Model.

BACKGROUND: Vancomycin therapeutic monitoring guidelines were revised in March 2020, and a population pharmacokinetics-guided Bayesian approach to estimate the 24-hour area under the concentration-time curve to the minimum inhibitory concentration ratio has since been recommended instead of trough concentrations. To comply with these latest guidelines, we evaluated published population pharmacokinetic models of vancomycin using an external dataset of neonatal patients and selected the most predictive model to develop a new initial dosing regimen. METHODS: The models were identified from the literature and tested using a retrospective dataset of Canadian neonates. Their predictive performance was assessed using prediction- and simulation-based diagnostics. Monte Carlo simulations were performed to develop the initial dosing regimen with the highest probability of therapeutic target attainment. RESULTS: A total of 144 vancomycin concentrations were derived from 63 neonates in the external population. Five of the 28 models retained for evaluation were found predictive with a bias of 15% and an imprecision of 30%. Overall, the Grimsley and Thomson model performed best, with a bias of -0.8% and an imprecision of 20.9%; therefore, it was applied in the simulations. A novel initial dosing regimen of 15 mg/kg, followed by 11 mg/kg every 8 hours should favor therapeutic target attainment. CONCLUSIONS: A predictive population pharmacokinetic model of vancomycin was identified after an external evaluation and used to recommend a novel initial dosing regimen. The implementation of these model-based tools may guide physicians in selecting the most appropriate initial vancomycin dose, leading to improved clinical outcomes.

Potential benefits of therapeutic drug monitoring for beta-lactam antibiotics in augmented renal clearance patients: a case report.

Augmented renal clearance (ARC) is commonly described in critically ill patients, making drug pharmacokinetics even harder to predict in this population. This case report displays the value of therapeutic drug monitoring (TDM) of piperacillin/tazobactam (PTZ) in this population. We identified two patients with ARC and intermittent administration of PTZ who took part in a prospective, descriptive study conducted at Hôpital du Sacré-Cœur de Montréal. Both had plasma samples drawn at peak, middle, and end of their dosing intervals of PTZ. Minimal inhibitory concentrations (MICs) of 4 and 8 mg/L were chosen to evaluate therapeutic target attainment at middle and end of dosing interval. The first patient was a 52-year-old male with a renal clearance rate estimated at 147 mL/min who received 3.375 g PTZ every 6 h. The second patient, a 49-year-old male, had an estimated renal clearance rate of 163 mL/min and received the same regimen. Both patients had piperacillin concentrations above the target MICs at middle of the dosing interval, but they failed to reach a trough concentration above 8 mg/L. The present case report showcases two patients with subtherapeutic PTZ concentrations despite strict following of local administration protocols. This suboptimal administration could not only lead to treatment failure, but also to the selection and growth of resistant pathogens. Implementing TDM would offer the possibility to adjust drug regimens in real-time and prevent situations like these from occurring.

Exposure levels and target attainment of piperacillin/tazobactam in adult patients admitted to the intensive care unit: a prospective observational study.

PURPOSE: The objective of this study was to evaluate the exposure and the pharmacodynamic target attainment of piperacillin/tazobactam (PTZ) in adult critically ill patients. METHODS: We conducted a prospective observational study in the intensive care unit (ICU) of the Hôpital du Sacré-Cœur de Montréal (a Level I trauma centre in Montreal, QC, Canada) between January 2021 and June 2022. We included patients aged 18 yr or older admitted to the ICU who received PTZ by intravenous administration. Demographic and clinical characteristics were collected, and clinical scores were calculated. On study day 1 of antimicrobial therapy, three blood samples were collected at the following timepoints: one hour after PTZ dose administration and at the middle and at the end of the dosing interval. The sampling schedule was repeated on days 4 and 7 of therapy if possible. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector to determine the total piperacillin concentration. Middle- and end-of-interval concentrations were used for target attainment analyses, and were defined as a concentration above the minimal inhibitory concentration of 16 mg·L-1, corresponding to the breakpoint of Enterobacteriaceae and Pseudomonas aeruginosa. RESULTS: Forty-three patients were recruited and 202 blood samples were analyzed. The most prevalent dose was 3/0.375 g every six hours (n = 50/73 doses administered, 68%) with a 30-min infusion. We observed marked variability over the three sampling timepoints, and the median [interquartile range] piperacillin concentrations at peak, middle of interval, and end of interval were 109.4 [74.0-152.3], 59.3 [21.1-74.4], and 25.3 [6.8-44.6] mg·L-1, respectively. When assessing target attainment, 37% of patients did not reach the efficacy target of a trough concentration of 16 mg·L-1. The majority of patients who were underexposed were patients with normal to augmented renal clearance. CONCLUSION: In this prospective observational study of adult ICU patients receiving intravenous PTZ, a large proportion had subtherapeutic concentrations of piperacillin. This was most notable in patients with normal to augmented renal clearance. More aggressive dosage regimens may be required for this subpopulation to ensure attainment of efficacy targets.

RéSUMé: OBJECTIF: L'objectif de cette étude était d'évaluer l'exposition et l'atteinte des cibles pharmacodynamiques de la pipéracilline/tazobactam (PTZ) chez la patientèle adulte aux soins intensifs. MéTHODES: Nous avons réalisé une étude observationnelle prospective dans l'unité de soins intensifs (USI) de l'Hôpital du Sacré-Cœur de Montréal (un centre de traumatologie de niveau 1 à Montréal, QC, Canada) entre janvier 2021 et juin 2022. Nous avons inclus les patient·es adultes âgé·es de 18 ans ou plus admis·es à l'USI ayant reçu de la PTZ par administration intraveineuse. Les caractéristiques démographiques et cliniques ont été recueillies, et les scores cliniques ont été calculés. Au jour 1 de la thérapie antimicrobienne, trois échantillons sanguins ont été prélevés aux moments suivants : 1 h après l'administration de la dose de PTZ, au milieu et à la fin de l'intervalle d'administration. Le calendrier d'échantillonnage a été répété aux jours 4 et 7 de la thérapie si possible. Les échantillons ont été analysés par chromatographie liquide à ultra-haute performance avec détecteur à diodes pour déterminer la concentration totale de pipéracilline. Les concentrations du milieu et de fin d'intervalle ont été utilisées pour les analyses d'atteinte de cible, définie comme une concentration supérieure à la concentration minimale inhibitrice de 16 mg·L-1, associée aux Enterobacteriaceae et au Pseudomonas aeruginosa. RéSULTATS: Quarante-trois patient·es ont été recruté·es et 202 échantillons sanguins ont été analysés. La dose la plus prévalente était une dose de 3/0,375 g aux 6 h (n = 50/73 doses administrées, 68 %) avec une perfusion sur 30 min. Nous avons observé une variabilité marquée aux trois temps de prélèvement, et les concentrations médianes [intervalle interquartile] de pipéracilline au pic, au milieu et à la fin de l'intervalle étaient respectivement de 109,4 [74,0-152,3], 59,3 [21,1-74,4] et 25,3 [6,8-44,6] mg·L−1. Lors de l'évaluation de l'atteinte de la cible, 37 % des patient·es n'ont pas atteint la cible d'efficacité d'une concentration de 16 mg·L−1 à la fin de l'intervalle posologique. La majorité des patient·es sous-exposé·es étaient des personnes dont la clairance rénale était normale ou augmentée. CONCLUSION: Dans cette étude observationnelle prospective de patient·es adultes aux soins intensifs recevant de la PTZ par voie intraveineuse, une grande proportion de patient·es présentait des concentrations sous-thérapeutiques de pipéracilline. Ceci était plus marqué chez les patient·es ayant une clairance rénale normale ou augmentée. Des schémas posologiques plus agressifs pourraient être nécessaires pour cette sous-population afin de favoriser l'atteinte des cibles d'efficacité.

Impact of piperacillin unbound fraction variability on dosing recommendations in critically ill patients.

A common approach to assess the efficacy of piperacillin is to first measure the total concentration and afterwards apply a theoretical unbound fraction of 70% to obtain the unbound concentration. However, hypoalbuminemia is a common phenomenon in critically ill patients, resulting in variations in unbound fraction, therefore we aimed to simulate the impact of piperacillin unbound fraction fluctuations on the predictive performance of a population pharmacokinetic model and on the dosing recommendations of piperacillin. Unbound factors of 70%, 75%, 80% and 85% were applied to total concentrations of piperacillin administered by continuous infusion from an external dataset. A validated model was used for assessment of predictive performance and to estimate patient clearance. Dosing simulations were performed to evaluate target attainment. Variation in unbound fractions caused minimal impact on piperacillin clearance and target attainment but seemed to influence model validity.

Tobramycin a Priori Dosing Regimens Based on PopPK Model Simulations in Critically Ill Patients: Are They Transferable?

BACKGROUND: In recent years, multiple population pharmacokinetic models have been developed for drugs such as tobramycin that need therapeutic drug monitoring. Some of these models have been used to develop a priori dosing regimens for their respective populations. However, these dosing regimens may not apply to other populations. Therefore, this study aimed to evaluate tobramycin population pharmacokinetic models in critically ill patients and establish an adequate dosing regimen. METHODS: Evaluated models were identified from a literature review of aminoglycoside population pharmacokinetic models in critically ill patients. After retrospective data collection in 2 Quebec hospitals, external evaluation and model re-estimation were performed with NONMEM (v7.5) to assess imprecision and bias values. Dosing regimens were simulated and compared between the best-performing model and its re-estimated counterparts. RESULTS: None of the 3 evaluated models showed acceptable imprecision or bias values in the data sets of the 19 patients. Similar percentages of target attainment were obtained for the original and re-estimated models after the dosing regimen simulations. CONCLUSION: Although the predictive performance evaluation criteria were inadequate, the original and re-estimated models yielded similar results. This raises the question of what a priori bias and imprecision thresholds should be defined as acceptable for the external evaluation of models to be applied in clinical practice. Studies evaluating the impact of these thresholds are needed.

New Recommendations of a Height-Based Dosing Regimen of Tobramycin for Cystic Fibrosis in Adults: A Population Pharmacokinetic Analysis.

BACKGROUND: Acute pulmonary exacerbations (APEs) in patients with adult cystic fibrosis (CF) are treated with a beta-lactam and an aminoglycoside for activity against Pseudomonas aeruginosa (PA). Emerging drug resistance and changing pharmacokinetic profile in an aging population involve a reevaluation of tobramycin dosing recommendations. The objective of this study was to develop a population pharmacokinetic model and establish optimal dosing recommendations for tobramycin using Monte Carlo simulations. METHODS: This retrospective clinical study and data collection were performed at the CF center of the McGill University Health Center (MUHC), Canada. Model development and simulations were performed using a nonlinear mixed-effect modeling approach (NONMEM, version 7.4.2). The ratios of maximal concentration (C max ) to the minimal inhibitory concentration (MIC) (C max /MIC ≥8 and ≥10) and area under the curve (AUC) to the MIC (AUC/MIC ≥70 and ≥100) were evaluated. RESULTS: Adult patients with CF (n = 51) treated with tobramycin were included in the study. Plasma concentrations of tobramycin were obtained for 699 samples from the MUHC database. The two-compartmental model best described the pharmacokinetics of tobramycin. The association of patient height with the central volume of distribution significantly improved this model. Height, rather than weight, induced the best reduction in objective function. According to simulations, doses between 3.4 mg/cm and 4.4 mg/cm were necessary to achieve C max /MIC values of ≥8 and ≥10, respectively. However, higher doses were required to achieve the AUC/MIC targets. CONCLUSIONS: This study demonstrated that height of the patients seems to be more suitable than their weight for dosing adjustments in adult patients with CF. According to this model, initial doses of tobramycin between 3.4 and 4.4 mg/cm should be recommended for patients with a median height of 164 cm and weight of 55 kg to achieve the target plasma concentrations.

Development and Evaluation of a Height-Based Tobramycin Initial Dosing Nomogram for the Treatment of Adult Cystic Fibrosis Pulmonary Exacerbations.

ABSTRACT: Tobramycin is widely used to treat pulmonary exacerbations of cystic fibrosis. Height has been previously found to be significantly more predictive of tobramycin pharmacokinetics than body weight. This study aimed to develop a height-based initial dosing nomogram and evaluate its performance in peak concentration (Cmax) precision relative to standard and fixed dosing. Monte Carlo simulations were performed to develop a nomogram representing the doses required to reach Cmax targets at different heights. Cmax data observed at 2 clinical centers [McGill University Health Centre (MUHC) and Institut universitaire de cardiologie et pneumologie de Québec (IUCPQ-UL)] were compared with population-predicted Cmax using the doses derived from the nomogram alongside a fixed dose. Height-based dosing resulted in significantly less variable-predicted Cmax values [coefficient of variation (CV) MUHC = 15.7% and IUCPQ-UL = 10.8%] than the Cmax values observed in clinical practice (CV MUHC = 30.0% and CV IUCPQ-UL = 26.9%) and predicted Cmax values obtained from a fixed dose (CV MUHC = 21.2% and CV IUCPQ-UL = 16.3%). An initial dosing nomogram was developed to help reduce pharmacokinetic variability in the observed Cmax. More precise dosing would allow for better clinical outcomes in adult patients with cystic fibrosis.

Consideration of height-based tobramycin dosing regimens for the treatment of adult cystic fibrosis pulmonary exacerbations.

AIMS: Some population pharmacokinetic models have been developed using height to explain some of the interindividual variability in tobramycin pharmacokinetics in cystic fibrosis patients. However, their predictive performance when extrapolated to other clinical centres is unclear. Therefore, the aim of this study was to externally evaluate the predictability of tobramycin population pharmacokinetic models with an independent dataset and perform simulations using previously recommended height-based dosing regimens. METHODS: A literature search was conducted through the PubMed database to identify relevant population pharmacokinetic models. Tobramycin plasma concentration data from April 2014 to November 2019 were retrospectively collected from the Institut universitaire de cardiologie et de pneumologie de Québec, Canada. External evaluations were performed using NONMEM® v7.5 and RStudio® v1.3.1073. Monte Carlo simulations were performed to evaluate the probability of target attainment of Cmax /MIC ratios for several dosing regimens. RESULTS: The validation dataset included 27 patients and 143 concentration samples. Three models were evaluated. Only the ones by Crass et al. and Alghanem et al. performed satisfactorily in terms of prediction-based diagnostics with MDPE values of -3.4% and 29.3% and MDAPE values of 19.0 and 29.5%, respectively. In simulation-based evaluations, both pcVPC and NPDE showed no evidence of model misspecification. Our simulations suggest that patients treated with a once-daily dose of 3.4 mg/cm should produce peak and trough levels consistent with current guidelines. CONCLUSION: Our results show that the models by Crass et al. and Alghanem et al. are appropriate for simulation-based applications to aid individualized dosing in our population and that height-based dosing regimens could be considered in cystic fibrosis patients.

VANCOmycin dose adjustments comparing trough levels to the ratio of the area under de curve to the minimum inhibitory concentration method using a BAYESian approach: A feasibility study.

WHAT IS KNOWN AND OBJECTIVE?: The latest published guidelines advocate for the area under the concentration-time curve to minimal inhibitory concentration (AUC0-24h /MIC) estimated with bayesian calculations. This recommended pharmacokinetic monitoring transition is not based on randomized controlled prospective data. METHODS: In this open-label feasibility RCT, patients were assigned to have their vancomycin dosing adjusted based on bayesian-guided AUC0-24h /MIC or trough levels. Primary outcomes were consent rate, number of patients recruited per month, compliance with blood sampling schedule and compliance with bayesian software recommendations. Secondary outcomes focused on target attainment, safety and operational impacts. RESULTS AND DISCUSSION: Forty-five patients underwent randomization (23 bayesian, 22 trough). Consent rate was 37,5% for an average of 9.8 patients recruited per month meeting pre-specified objectives of 30% (p = 0.073) and 10 (p = 0.74) respectively. A 74.8% compliance with blood sampling schedule was below the pre-specified objective of 80% (p = 0.038). There was no statistically significant difference between the 83.7% compliance with bayesian software recommendations and the pre-specified objective of 90% (p = 0.21). Although exploratory, key clinical results were significant increases in the bayesian group for proportion of levels at target (RR 1.32; 95% CI 1.01-1.72; P = 0.038), number of blood samplings for patients (p = 0.036) and pharmacists' time spent on monitoring (p < 0.0001). A tendency towards a reduced incidence of nephrotoxicity in the Bayesian group was observed (RR 0.57; 95% CI 0.16-2.12; p = 0.46). WHAT IS NEW AND CONCLUSIONS?: This trial demonstrates that it would be feasible to conduct a properly sized RCT comparing vancomycin Bayesian-guided AUC0-24h /MIC to trough level monitoring. Although exploratory, this trial also showed a tendency towards reduced incidence of nephrotoxicity and an increased proportion of dosages at therapeutic targets with Bayesian monitoring.

Validation of the Augmented Renal Clearance in Trauma Intensive Care scoring system for augmented renal clearance prediction in a trauma subgroup of a mixed ICU population.

WHAT IS KNOWN AND OBJECTIVE: Augmented renal clearance is prevalent in trauma patients and leads to subtherapeutic levels of renally eliminated medications with potentially unfavourable clinical outcomes. The Augmented Renal Clearance of Trauma in Intensive Care (ARCTIC) score has been developed to predict augmented renal clearance in critically ill trauma patients. Our primary objective was to validate this score among the trauma subgroup of a mixed intensive care patient cohort. METHODS: This single-centre, retrospective, observational cohort study assessed augmented renal clearance using a timed 24-h urine collection performed weekly. ARC was defined as a measured creatinine clearance of ≥130 ml/min/1.73 m2 . ARCTIC score performance was evaluated through a receiver operator characteristic curves and analysis of sensitivities and specificities for the trauma subgroup, the medical/surgical subgroup and the pooled cohort. RESULTS AND DISCUSSION: Augmented renal clearance was observed in 33.9% (n = 58) of trauma patients (n = 171) and 15.7% (n = 24) of medical/surgical patients (n = 153). Examination of different cutoffs for the ARCTIC score in our trauma population confirmed that the optimal cutoff score was ≥6. Comparison between ROC curves for ARCTIC score and for regression model based upon our data in trauma patients indicated validation of the score in this subgroup. Comparison of sensitivities and specificities for ARCTIC score between trauma (93.1% and 41.6%, respectively) and medical/surgical subjects (87.5% and 49.6%, respectively) showed no clinical nor statistical difference, suggesting validation for the medical/surgical subgroup as well. WHAT IS NEW AND CONCLUSION: In our mixed ICU population, the ARCTIC score was validated in the trauma subgroup. We also found that the score performed well in the medical/surgical population. Future studies should assess the performance of the ARCTIC score prospectively.

Evaluation of current dosing guidance for oral rifampicin treatment in adult patients with osteoarticular infections.

For management of osteoarticular infections, rifampicin appears to be the key antibiotic. We aimed to evaluate the actual rifampicin dosing regimens using a population pharmacokinetic model of rifampicin in patients with osteoarticular infections. A Monte Carlo simulation study was performed to simulate steady-state plasma concentrations for 1000 randomly sampled subjects using a total daily dose between 600 and 1200 mg (600 and 900 mg once daily, 450 and 600 mg twice daily, or 300 mg 3 times daily). When rifampicin was administered with fusidic acid, the pharmacokinetic/pharmacodynamic (PK/PD) target (area under the curve/minimum inhibitory concentration ≥952) was achieved with all tested dosing regimen, except 600 mg once daily for Staphylococcus epidermidis infections. Without coadministration of fusidic acid, none of tested dosing regimens achieved this PK/PD target. Most recommended drug-dosing regimens allow attaining the fixed area under the curve/minimum inhibitory concentration target for Staphylococcus aureus and coagulase-negative staphylococcal osteoarticular infections. In future studies, PK/PD target for osteoarticular infections in human should also be confirmed.

External evaluation of population pharmacokinetic models for continuous administration of meropenem in critically ill adult patients.

PURPOSE: Beta-lactams (BL), the most commonly prescribed class of antibiotics, are recommended as the first-line therapy for multiple indications in infectious disease guidelines. Meropenem (MERO) is frequently used in intensive care units (ICU) to treat bacterial infections with or without sepsis. The pharmacokinetics of MERO display a large variability in patients admitted to ICUs due to altered pathophysiology. The aim of this study was to perform an external evaluation of published population pharmacokinetic models of MERO in order to test their predictive performance in a cohort of ICU adult patients. METHODS: A literature search in PubMed/Medline database was made following the PRISMA statement. External evaluation was performed using NONMEM software, and the bias and inaccuracy values were calculated. RESULTS: An external validation dataset from the Timone Hospital in Marseille, France, included 84 concentration samples from 27 patients. Four models of MERO were identified according to the inclusion criteria of the study. None of the models presented acceptable values of bias and inaccuracy. CONCLUSION: While performing external evaluations on some populations may confirm a model's suitability to diverse groups of patients, there is still some variability that cannot be explained nor solved by the procedure. This brings to light the difficulty to develop only one model for ICU patients and the need to develop one specific model to each population of critically ill patients.

Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

BACKGROUND: To perform a review describing the pharmacokinetic (PK) parameters and covariates of interest of the eight first choice ß-lactams (BL) antibiotics for treatment of severe infections in pediatric population. Pediatric sepsis and septic shock reportedly affect 30% of children admitted to pediatric intensive care units, with a 25% mortality rate. Eight BL are included as first choice antibiotic for severe infections in pediatric population in the World Health Organization model list of essential medicines for children. METHODS: The PubMed/Medline databases was searched and included studies if they described a population PK model of piperacillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cloxacillin, imipenem or meropenem in neonates or children. We compared the PK parameters for each drug. We analysed the used covariates to estimate PK parameters. We compared the pharmacokinetics/pharmacodynamics (PK/PD) targets and the drug dosing recommendations. RESULTS: Thirty-four studies met inclusion criteria with seven studies for piperacillin, five for amoxicillin, three for ampicillin, three for cefotaxime, two for ceftriaxone, two for imipenem and twelve for meropenem. None met inclusion criteria for cloxacillin. Ages ranged from 0-19.1 years with 12 studies including preterm. Body weight, age and renal function were the three major covariates in neonates and children. Different PK/PD targets were observed (between 40% to 100% of the dosing regimen interval of time over which the unbound (or free) drug concentration remains above the minimal inhibitory concentration (MIC) (fT>MIC) or four times the MIC (fT>4xMIC)). Several drug-dosing regimens were fond recommended according to the age and pathogens MIC using intermittent, timed or continuous infusions. CONCLUSIONS: Consensus is lacking on the optimal dosing regimens for these eight first choice antibiotics. A more personalized approach to antibiotic drugs dosing with individual characteristics of patient and pathogen susceptibility is required. According PK/PD targets and used dosing regimens, prospective clinical studies are required to investigate clinical cure, patient survival and emergence of antimicrobial resistance.

Population pharmacokinetic model for tumescent lidocaine in women undergoing breast cancer surgery.

PURPOSE: Tumescent lidocaine anesthesia (TLA) is an opportunity to perform mastectomy for breast cancer without general anesthesia in elderly women. Few reports are available on the pharmacokinetics of lidocaine in a context of TLA during a unilateral mastectomy. The aim of this study was to describe lidocaine pharmacokinetics in elderly women undergoing breast cancer surgery after TLA and to explore the risk of the toxicity of this technique. METHODS: A prospective study was conducted to examine the pharmacokinetics of lidocaine in women undergoing TLA. TLA consists of an intradermal lidocaine instillation (20 mL, 1% [200 mg]) followed by a tumescent lidocaine infiltration (100 mL of 1% lidocaine [1000 mg] and 0.5 mg epinephrine to 1 L Ringer's lactate) via an infusion pump. A population pharmacokinetic (popPK) analysis was performed using the nonlinear mixed effects model (NONMEM). RESULTS: The analysis included 116 observations from 17 women with a median (range) age of 83.4 (60.5-90.0). The median tumescent lidocaine dose was 800 mg (range 375-1000 mg) infused over 48.0 ± 11.0 min. A one-compartment disposition model with first order absorption, two input compartments, and a central elimination best described the pharmacokinetics of lidocaine. The estimates (between subject variability; relative standard error, %) of apparent volume, apparent clearance, tumescent absorption rate, and instillation absorption rate were 195.0 (46.3; 14.5%) L, 24.7 (48.9; 13.3%) L h-1, 0.28 (39.6; 13.8%) h-1, and 2.56 (135.3; 44.9%) h-1, respectively. CONCLUSIONS: This is the first popPK model developed to describe kinetic profiles of TLA. These findings confirm the slow diffusion of lidocaine from the tumescent deposit.

Pharmacokinetic Variability in Pediatrics and Intensive Care: Toward a Personalized Dosing Approach.

Providing a safe and efficacious drug therapy for large and often heterogeneous populations is a challenging objective in clinical drug development and routine clinical practice. It has been known for years that the optimum dose required for many therapeutic agents among individuals is quite variable. A wide interindividual pharmacokinetic variability was described in clinically relevant populations such as pediatrics and critically ill patients. The aim of this article was to present the main individual factors influencing variability in these two populations and their applications. Growth and development are two specific features of children that are not observed in adults. And critically ill patients have a much higher level of sickness severity that is associated with profound pathophysiological changes. These particular features could lead to difficulties to attain therapeutic targets. Nonlinear mixed effects modeling is a common approach to identify unexplained population variability. This approach is often applied to evaluate and optimize drug therapy in particular populations. Numerous studies have been conducted in these two specific populations to characterize pharmacokinetic parameters and to identify individual factors influencing variability. Size, age and organ function appeared to be the main factors influencing pharmacokinetics in pediatrics. Factors influencing pharmacokinetics in critically ill patients were mainly cardiovascular system, organ dysfunction and organ support. Dosage individualization seems to be a key issue to optimize drug treatment in these specific populations. Clinically utility and safety of a model-based personalized drug therapy has been demonstrated for vancomycin in pediatrics. Many programs were available to optimize drug regimens, especially for antibiotic drugs in critically ill patients. This innovative personalized dosing approach is a promising way to optimize drug therapy in clinically relevant populations, such as pediatrics and critically ill patients.

Population pharmacokinetics of rifampicin in adult patients with osteoarticular infections: interaction with fusidic acid.

AIMS: Rifampicin represents the key antibiotic for the management of osteoarticular infections. An important pharmacokinetic variability has already been described, particularly for absorption and metabolism. All previous pharmacokinetic studies have been focused only on patients treated for tuberculosis. The objective of the present study was to describe a population pharmacokinetic model of rifampicin in patients with staphylococcal osteoarticular infections, which has not been investigated to date. METHOD: Rifampicin concentrations were collected retrospectively from 62 patients treated with oral rifampicin 300 mg three times daily. Plasma concentration-time data were analysed using NONMEM to estimate population pharmacokinetic parameters. Demographic data, infection characteristics and antibiotics taken in addition to rifampicin antibiotics were investigated as covariates. RESULTS: A one-compartment model, coupled to a transit absorption model, best described the rifampicin data. Fusidic acid coadministration was identified as a covariate in rifampicin pharmacokinetic parameters. The apparent clearance and apparent central volume of distribution mean values [95% confidence interval (CI)] were 5.1 1 h-1 (1.2, 8.2 1 h-1 )/23.8 l (8.9, 38.7 l) and 13.7 1 h-1 (10.6, 18.0 1 h-1 )/61.1 1 (40.8, 129.0 1) for patients with and without administration of fusidic acid, respectively. Interindividual variability (95% CI) in the apparent clearance and apparent central volume of distribution were 72.9% (49.5, 86.0%) and 59.1% (5.5, 105.4%), respectively. Residual variability was 2.3 mg l-1 (1.6, 2.6 mg l-1 ). CONCLUSION: We developed the first population pharmacokinetic model of rifampicin in patients with osteoarticular infections. Our model demonstrated that fusidic acid affects rifampicin pharmacokinetics, leading to potential high drug exposure. This finding suggests that fusidic acid dosing regimens should be reconsidered.

Levodopa in Parkinson's Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis.

BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the management of Parkinson's disease, the accurate determination of this optimal dosage is complicated by marked between-subject and between-occasion variability in this population.  This review presents a synthesis of the population pharmacokinetic and pharmacodynamic models of levodopa described in Parkinson's disease. METHODS: A literature search was conducted from the PubMed database, from their inception through April 2016, using the following terms: levodopa, pharmacokinetic(s), pharmacodynamic(s) population, model(ling) and nonlinear mixed effect. Articles were excluded if they were not pertinent. References of all selected articles were also evaluated. RESULTS: A total of 12 articles were finally retained. The following covariates were selected as interindividual variability factors: body weight, age, sex, creatinine clearance and levodopa dose. The clinical response versus effect site concentration relationship was described with different sigmoidal Emax models. Different pharmacodynamic effects were described: UPDRS, Tapping, Dyskinesia, CURSΣ and treatment response scale. DISCUSSION: This review allows us to realize interpretation of a patient's clinical picture and confirmed the appropriateness of the pharmacokinetic-pharmacodynamic modeling for levodopa. External evaluation of previous published models should be also continued to evaluate these previous studies. New pharmacokinetic and/or pharmacodynamic population modelling studies could be consider to improve future models and decrease variability, to better understand the evolution of patients with Parkinson's disease treated by levodopa. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Analytical interference during cefepime therapeutic drug monitoring in intensive care patient: About a case report.

ß-lactams therapeutic drug monitoring (TDM) appears as an essential tool to ensure the achievement of pharmacokinetic-pharmacodynamic targets and prevent induced toxicity in intensive care unit patients. Indeed, those patients exhibit important pharmacokinetic variabilities that could lead to unpredictable plasma concentrations, potentially associated with poor clinical outcome, development of antibiotic resistance or increased side effects. Here, we report the case of a 48-year-old-patient admitted to intensive care unit and treated by cefepime using TDM. Due to inconsistency between observed cefepime plasma concentrations and patient clinical examination, investigations were started. After analytical tests, we highlighted an underlying analytical interference that overestimated cefepime plasma concentration with our in-house high performance liquid chromatography with ultraviolet detection (HPLC-UV) method. Only the inadequacy between plasmatic concentration and patient situation alerted pharmacologists and clinicians. As we found no previous case in literature, we believe this report must serve as an example of analytical limits that required pharmacologist awareness and expertise in TDM realization.

Population Pharmacokinetics of High-Dose Oxazepam in Alcohol-Dependent Patients: Is There a Risk of Accumulation?

BACKGROUND: According to the guidelines, benzodiazepines with a short half-life are the reference medication to treat alcohol withdrawal syndrome. The doses of oxazepam used in this population may reach up to 300 mg per day, significantly higher than usual doses. Its use in these patients deserves further information to confirm that the half-life remains constant and that no accumulation appears. The objective of this study was to investigate the pharmacokinetics of high doses of oxazepam in alcohol-dependent patients treated for alcohol withdrawal syndrome. METHODS: Overall, 63 outpatients [weight, 71.1 kg (45.0-118.0); age, 47.6 years (31-67)] followed in the addictology unit, were studied. Total mean dose of 96.0 mg per day (range, 20-300 mg/d) was administered by oral route. Therapeutic drug monitoring allowed the measurement of 96 plasma concentrations. The following covariates were evaluated: demographic data (age, body weight, height, gender) and biological data (creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase). Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model. RESULTS: Data were modeled with a 1-compartment pharmacokinetic model. The population typical mean 90% confidence interval values for clearance, apparent volume of distribution (V), and duration of absorption (D1) were 6.8 L/h (range, 3.9-8.0 L/h), 159 L (range, 98.0-282 L), and 2 hours (fixed), respectively. The interindividual variability of clearance and V, and residual variability (90% confidence interval) were 74% (44%-96%), 69% (40%-89%), and 32% (20%-41%), respectively. The elimination half-life was 16 hours (range, 3-42 hours). CONCLUSIONS: Oxazepam exhibited a linear pharmacokinetics with a proportional relationship from 20 to 300 mg per day, the dose range currently used in alcohol-dependent patients treated for alcohol withdrawal syndrome. We did not find any evidence of drug accumulation with these doses.