Pharmacokinetics Of Tobramycin Research Articles

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

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. 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. 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. 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.

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.

Review of Tobramycin Dosing in Pediatric Patients With Cystic Fibrosis.

An institution's tobramycin pharmacokinetics (PK) database was reviewed to evaluate the efficacy and safety of empiric tobramycin dosing and monitoring strategies used in pediatric patients with cystic fibrosis (CF). The relationship between patient age and tobramycin dosing needed to achieve the area under the curve (AUC) goal was investigated. Retrospective chart review was performed for patients who received tobramycin during a CF exacerbation from 2009 to 2019 who received PK monitoring by pediatric pharmacists. Tobramycin dosing needed to achieve an AUC of 100 mg·hr/L was calculated for each patient. Serum creatinine and concomitant nephrotoxin use were collected as surrogate nephrotoxicity endpoints to evaluate safety. Goal AUC (100 ± 15 mg·hr/L) was achieved based on initial or repeat PK calculations in 43.5% (95% CI, 37.7-49.3) of 85 unique patients across 326 encounters. Patients with calculated recommended doses of 9.5 to 11.9 mg/kg every 24 hours empirically achieved goal AUC in 77% (78/101) of encounters. The odds of achieving goal AUC were 56% higher for children aged 10 vs 5 years (OR = 1.56; 95% CI, 1.04-2.34; p = 0.033) and 32% higher for children aged 15 vs 10 years (OR = 1.32; 95% CI, 1.07-1.61; p = 0.008). Overall rates of acute kidney injury and concomitant nephrotoxin use were 10.8% (95% CI, 6.2-15.5) and 80.7% (95% CI, 74.3-87.1), respectively. Desired AUC was achieved by 43.5% of pediatric patients with CF using tobramycin 10 mg/kg every 24 hours. Older patient age was associated with higher initial AUC attainment and fewer dose modifications. Younger children may require higher weight-based dosing to meet AUC goals.

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

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. 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. 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 3.4mg/cm should produce peak and trough levels consistent with current guidelines. 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.

Pharmacokinetic/pharmacodynamic evaluation of tobramycin dosing in critically ill patients: the Hartford nomogram does not fit.

Extended-interval dosing of tobramycin is widely applied in patients with the Hartford nomogram as a representative, while this dosing approach has not been extensively evaluated in critically ill patients. The goal of this study was to characterize the pharmacokinetics of tobramycin and to evaluate the appropriateness of the Hartford nomogram in critically ill patients. A retrospective analysis was performed based on a medical critical care database. The extracted concentration data of tobramycin were used for the construction of the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Real-world data-based simulations were conducted to evaluate the pharmacodynamic target attainment (Cmax/MIC ≥10) and safety (concentration <0.5 mg/L for at least 4 h) of the Hartford nomogram. A population pharmacokinetic model was built based on 307 measurements in 140 unique patients and externally validated by an independent study dataset. A two-compartment model was optimal for the structure model and creatinine clearance remained as the only covariate in the final model correlating to the clearance of tobramycin. Simulations indicated that the Hartford nomogram is effective for infections due to pathogens with an MIC of ≤1 mg/L, but not with an MIC of 2 mg/L. The percentage of patients who reached the non-toxicity target was quite low under the Hartford nomogram and a further extension of the dosing interval was necessary to minimize the toxicity. The Hartford nomogram was not suitable for critically ill patients with pathogen MICs of 2 mg/L and drug monitoring is required to manage efficacy and toxicity.

Evaluating the Impact of Education on Pharmacist Tobramycin Dose Recommendations for Cystic Fibrosis and a Review of Perceptions on Pharmacist-Led Charting

Background: Pharmacists routinely interpret and optimize tobramycin dosing for people with cystic fibrosis (PwCF). Objectives: To determine the impact of tobramycin therapeutic drug monitoring (TDM) education on pharmacist dose recommendations, and to explore nurses’ and medical doctors’ perceptions toward pharmacist-led TDM charting. Methods: This study involved 3 phases: a 12-month retrospective audit of PwCF prescribed tobramycin to identify the appropriateness of pharmacists’ dose recommendations, a pharmacist tobramycin educational intervention utilizing a voiceover presentation with pre- and post-online tobramycin TDM assessment (involving multiple choice pharmacokinetics and case-based scenario questions), and a cross-sectional survey of respiratory nurses’ and doctors’ perceptions toward pharmacist-led TDM charting. The pharmacists’ dose recommendations, in the audit and case-based questions, were considered appropriate if subsequent levels achieved the targeted area under the curve (AUC). Results: Audit results revealed that 44.4% of the 277 pharmacist dose recommendations identified were appropriate. The pre- and post-interventional assessments were completed by 51 and 52 pharmacists, respectively. Post intervention, correct scores were significantly higher than pre-intervention, evident in both the pharmacokinetics (median score 75% vs 100%; P = 0.048) and case-based scenario (median score 60% vs 90%; P < 0.0001) questions. Of the 54 nurses and medical doctors surveyed, 92.6% supported the implementation of pharmacist-led tobramycin charting. Conclusion: The study demonstrated an increased accuracy and appropriateness of pharmacists’ tobramycin pharmacokinetics knowledge and TDM dose recommendations post-educational intervention and highlighted nurses’ and medical doctors’ support of pharmacist-led tobramycin TDM charting.

Aminoglycosides in the Intensive Care Unit: What Is New in Population PK Modeling?

Background: Although aminoglycosides are often used as treatment for Gram-negative infections, optimal dosing regimens remain unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycoside pharmacokinetics in this population. Objective: This review provides comprehensive data on the pharmacokinetics of aminoglycosides in patients hospitalized in the ICU by summarizing all published PopPK models in ICU patients for amikacin, gentamicin, and tobramycin. The objective was to determine the presence of a consensus on the structural model used, significant covariates included, and therapeutic targets considered during dosing regimen simulations. Method: A literature search was conducted in the Medline/PubMed database, using the terms: ‘amikacin’, ‘gentamicin’, ‘tobramycin’, ‘pharmacokinetic(s)’, ‘nonlinear mixed effect’, ‘population’, ‘intensive care’, and ‘critically ill’. Results: Nineteen articles were retained where amikacin, gentamicin, and tobramycin pharmacokinetics were described in six, 11, and five models, respectively. A two-compartment model was used to describe amikacin and tobramycin pharmacokinetics, whereas a one-compartment model majorly described gentamicin pharmacokinetics. The most recurrent significant covariates were renal clearance and bodyweight. Across all aminoglycosides, mean interindividual variability in clearance and volume of distribution were 41.6% and 22.0%, respectively. A common consensus for an optimal dosing regimen for each aminoglycoside was not reached. Conclusions: This review showed models developed for amikacin, from 2015 until now, and for gentamicin and tobramycin from the past decades. Despite the growing challenges of external evaluation, the latter should be more considered during model development. Further research including new covariates, additional simulated dosing regimens, and external validation should be considered to better understand aminoglycoside pharmacokinetics in ICU patients.

Pharmacokinetics of Tobramycin Administered at the Beginning of Intermittent Hemodialysis Session (ESRD Study).

Background and Objectives:There is a renewed interest in the successful use of aminoglycosides due to increasing resistance in gram-negative infections. Few studies to date have examined the pharmacokinetics (PK) of intradialytic infusions of tobramycin. This study sought to characterize the pharmacokinetic profile of intradialytically administered tobramycin in infected patients receiving chronic intermittent hemodialysis and to determine whether it is possible to achieve favorable PK targets.Design, Setting, Participants, and Measurements:In this prospective pharmacokinetic study, a single dose (5 mg/kg) of tobramycin was administered intradialytically to 11 noncritically ill patients undergoing chronic intermittent hemodialysis. Blood samples were collected at selected time to determine tobramycin serum concentrations. The PK analysis was performed using Phoenix™ NLME. The efficacy exposure outcome for nonsevere gram-negative infections sensitive to tobramycin with a minimum inhibitory concentration ≤1 were maximum concentration (Cmax ≥ 10 mg/L) and area under the curve (AUC24 h > 30 mg⋅h/L). For toxicity, the goal was to identify plasma trough concentrations <2 mg/L.Results:Tobramycin disposition was best described by a one-compartment model using a total clearance composed of the systemic clearance and a transitory hemodialysis clearance. Tobramycin mean (SD) Cmax, trough levels, and AUC24h were 13.1 (1.3) mg/L, 1.32 (0.47) mg/L, and 61 (23) mg⋅h/L, respectively. Monte Carlo simulation run with 1000 virtual patients showed that a 5 mg/kg dose of tobramycin administered intradialytically can outperformed the usual low-dose postdialysis dosing (80% meeting all targets versus <1%, respectively).Conclusions:A single high dose of tobramycin can achieve favorable PK outcome when administered using intradialytic infusions in hemodialysis patients. This practical dosing regimen may represent an effective and safer alternative to the usual dosing in the treatment of nonsevere gram-negative infections.

Does Circadian Rhythm Affect the Pharmacokinetics of Once-Daily Tobramycin in Adults With Cystic Fibrosis?

In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of the time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated. In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 hours. Pharmacokinetic and kidney function parameters were compared between the 2 groups. Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 versus 1.43 mL/h*kg (P = 0.50) and mean volumes of distribution were 0.25 versus 0.27 L/kg (P = 0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group, indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 versus 0.2 mmol/L, P = 0.015). The time of administration (8:00 versus 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

Effects of CFTR modulators on pharmacokinetics of tobramycin during acute pulmonary exacerbations in the pediatric cystic fibrosis population.

Individuals with cystic fibrosis (CF) require higher dosages of aminoglycosides due to an increased volume of distribution (Vd ) and clearance. Optimal dosing of aminoglycosides in the CF population is essential as repeated exposure to aminoglycosides during acute pulmonary exacerbations increases risk of nephrotoxicity and ototoxicity. To date, no studies have evaluated whether chronic cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy affects pharmacokinetics of aminoglycoside antibiotics in patients with CF. The objective of this study was to determine if the addition of a CFTR modulator affects elimination rate (Ke ) for intravenously administered tobramycin in the pediatric CF population. This retrospective study included patients aged 2 to 18 years with CF receiving chronic therapy with a CFTR modulator. Patients included had an admission both pre- and post-chronic CFTR modulator therapy during which they received therapy with IV tobramycin. Thirty-four patients were included in the study. The median time between pre- and post-modulator admissions was 16.5 (13.8) months. Duration of CFTR modulator therapy before post-modulator admission was a median of 8 (10.3) months. There was no significant difference in Ke (hr-1 ) between pre- and post-modulator therapy, 0.41 (0.21) pre and 0.39 (0.09) post (P = .5). Vd and peak concentration were similar between both groups. There was no difference in nephrotoxicity as defined by the pRIFLE criteria (P = .25). The pharmacokinetic parameters of intravenously administered tobramycin during admission for acute pulmonary exacerbation do not appear to change significantly after initiating chronic therapy with a CFTR modulator. Empiric dose adjustments for patients on CFTR modulators are not recommended.

Comparison of Vancomycin Pharmacokinetics in Cystic Fibrosis Patients Pre and Post-lung Transplant

Background:Vancomycin is commonly used to treat acute cystic fibrosis (CF) exacerbations associated with methicillin-resistant Staphylococcus aureus (MRSA). Multiple studies have demonstrated pharmacokinetic differences of antimicrobials in the CF population. Very little data exist regarding pharmacokinetics postlung transplant, but 2 studies have noted changes in tobramycin pharmacokinetics. No such studies exist evaluating vancomycin in CF patients postlung transplant.Methods:A retrospective cohort review of CF patients who underwent lung transplantation and received vancomycin pre- and posttransplant was conducted. CF patients who underwent transplant between 2007 and 2016 at 4 medical centers throughout the United States were included. The primary endpoint was the change in elimination rate constant. The secondary endpoints were subgroup analyses of patients grouped by age, time posttransplant, and number of nephrotoxic medications.Results:A total of 25 patients were included, of which just under half were pediatric. Patients were significantly older and heavier posttransplant and had higher serum creatinine and number of nephrotoxic medications. The change in elimination rate constant from pre- to posttransplant was −0.50 hr−1 which was statistically significant (P < .001). This significant decrease was consistent among all subgroups of patients evaluated with the exception of pediatric patients.Conclusion:Vancomycin pharmacokinetics are significantly altered in CF patients in the posttransplant setting as evidenced by a decrease in elimination rate constant. This decrease may be related to a decrease in renal clearance and higher numbers of nephrotoxic medications posttransplant. Regardless, pretransplant vancomycin regimens may not predict appropriate posttransplant regimens.

Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model.

Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P < 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P < 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P < 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P < 0.001). Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.

Population Pharmacokinetics of Tobramycin Inhalation Solution in Pediatric Patients With Cystic Fibrosis

Tobramycin inhalation solution given as a twice daily inhalation of nebulized aerosols of 300 mg is approved for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis patients over 6 years of age. To investigate tobramycin pharmacokinetics (PK) after inhalation of tobramycin in pediatric cystic fibrosis patients below 7 years, a population PK approach was used to evaluate tobramycin PK data in patients 6 months to 44 years of age from 4 clinical studies. The final model used a 2-compartmental, first-order absorption model with effect of body mass index on the apparent central volume of distribution. Relative bioavailability in patients between 6 months and 7 years increased with age by a linear relationship, and was modeled as a ratio to that of patients over 7 years. Simulation showed that steady-state concentrations of tobramycin are lower in pediatric patients 6 months to 6 years than those in patients over 6 years. However, systemic exposure is not predictive of clinical efficacy due to direct dosing at the infection site. P aeruginosa eradication rate and safety profile in patients less than 7 years of age were similar to patients older than 6 years; therefore, no dose adjustment is warranted in the younger pediatric patients.

Assessing Predictive Performance of Published Population Pharmacokinetic Models of Intravenous Tobramycin in Pediatric Patients.

Several population pharmacokinetic models describe the dose-exposure relationship of tobramycin in pediatric patients. Before the implementation of these models in clinical practice for dosage adjustment, their predictive performance should be externally evaluated. This study tested the predictive performance of all published population pharmacokinetic models of tobramycin developed for pediatric patients with an independent patient cohort. A literature search was conducted to identify suitable models for testing. Demographic and pharmacokinetic data were collected retrospectively from the medical records of pediatric patients who had received intravenous tobramycin. Tobramycin exposure was predicted from each model. Predictive performance was assessed by visual comparison of predictions to observations, by calculation of bias and imprecision, and through the use of simulation-based diagnostics. Eight population pharmacokinetic models were identified. A total of 269 concentration-time points from 41 pediatric patients with cystic fibrosis were collected for external evaluation. Three models consistently performed best in all evaluations and had mean errors ranging from -0.4 to 1.8 mg/liter, relative mean errors ranging from 4.9 to 29.4%, and root mean square errors ranging from 47.8 to 66.9%. Simulation-based diagnostics supported these findings. Models that allowed a two-compartment disposition generally had better predictive performance than those that used a one-compartment disposition model. Several published models of the pharmacokinetics of tobramycin showed reasonable low levels of bias, although all models seemed to have some problems with imprecision. This suggests that knowledge of typical pharmacokinetic behavior and patient covariate values alone without feedback concentration measurements from individual patients is not sufficient to make precise predictions.

Antibiotic penetration and bacterial killing in a Pseudomonas aeruginosa biofilm model.

Treating biofilm infections successfully is a challenge. We hypothesized that biofilms may be considered as independent compartments with particular pharmacokinetics. We therefore studied the pharmacokinetics and pharmacodynamics of tobramycin in a seaweed alginate-embedded biofilm model. Seaweed alginate beads containing Pseudomonas aeruginosa were cultured in LB medium, sampled at day 1, 3, 5 or 7 and examined for the effect of treatment with tobramycin for 30 min. Treated beads were homogenized and the number of cfu was determined. The antibiotic concentration in the solution of homogenized beads was measured. Finally, beads were examined for live cells by Syto9 staining and for dead cells by propidium iodide staining using a confocal laser scanning microscope. The antibiotic level in each bead was relatively stable (range 30-42 mg/L; MIC = 1.5 mg/L). There were fewer cfu in the tobramycin-treated beads than the non-treated beads (P < 0.016) and bacterial killing was reduced as the culture period increased from 1 to 7 days. Throughout the study period, increasing size and more superficial positioning of the microcolonies within the beads were demonstrated by confocal laser scanning microscopy. More dead cells (measured by propidium iodide staining) were observed in the treated group of beads, which supports the results obtained by culture. The present study, simulating the clinical pharmacokinetics of tobramycin, demonstrates fast absorption of tobramycin in an in vitro biofilm model. In addition, this model system enables parallel investigation of pharmacokinetics and pharmacodynamics, providing a model for testing new treatment strategies.

The influence of breathing mode on tobramycin serum levels using the I-neb AAD system in adults with cystic fibrosis

BackgroundThe clinical effectiveness of inhaled tobramycin depends on the dose reaching the desired regions of the lungs. This study evaluates the influence of breathing mode on tobramycin lung deposition using its pharmacokinetics as surrogate for deposition. MethodsIn a randomized, open-label, crossover study lung deposition in 18 adult CF patients is evaluated following inhalation of tobramycin aerosol using the I-neb nebulizer with TBM (Tidal Breathing Mode) and TIM (Target Inhalation Mode) breathing patterns. Breathing in TIM forced the patient to inhale in a slow and deep manner. Patients were categorized in three subgroups according to their lung function: ≤59%, 60–79% or ≥80% of FEV1 predicted. Blood samples were collected in order to model tobramycin pharmacokinetics. Nebulization time was recorded. ResultsInhalation with TIM resulted in significantly higher maximum serum levels and area under the concentration–time curves (0–24h). Mean bioavailability of TIM relative to TBM was 1.53±0.41. Mean nebulization time was reduced by half with TIM. Subgroup category did not affect the results. ConclusionsSlow and deep inhalation of aerosolized tobramycin resulted in higher lung deposition and shorter nebulization time compared to tidal breathing, regardless of the disease severity of the CF patient.Dutch trial register number NTR3109.

Hydrophilic interaction chromatography combined with tandem mass spectrometry method for the quantification of tobramycin in human plasma and its application in a pharmacokinetic study.

A fast, sensitive and specific hydrophilic interaction chromatography combined with tandem mass spectrometry (HILIC-MS/MS) method was developed for the determination of tobramycin in human plasma. With sisomycin as internal standard, the analysis was carried out on a hilic column (150mm×2.1mm, 3.5μm) using a mobile phase consisting of acetonitrile: 5mM ammonium acetate and 0.1% formic acid (60:40, v/v). The detection was performed by tandem spectrometry via electrospray ionization (ESI). Linear calibration curves were obtained in the concentration range of 10.51-1051ng/mL for tobramycin, with a lower limit of quantification of 10.51ng/mL. The intra- and inter-day precision (RSD) values were below 15% and accuracy (RE) was 1.3-5.7% at all QC levels. The method was applicable to the clinical study of the pharmacokinetics of tobramycin in healthy volunteers.

WS14.5 Influence of breathing pattern on pulmonary aerosol deposition in patients with cystic fibrosis (CF): a pharmacokinetic approach

The therapeutic effect of inhaled antibiotics on lung infection in CF patients is dependent on the aerosol deposition achieved in the lungs. Objectives: To evaluate the influence of two breathing patterns on pulmonary aerosol deposition using pharmacokinetic parameters as surrogate for deposition. Methods: In a randomized, open-label, crossover study pulmonary deposition in 18 adult CF patients is evaluated following inhalation of tobramycin aerosol using the I-neb nebulizer with TBM (Tidal Breathing Mode) and TIM (Target Inhalation Mode) breathing patterns. Breathing in TIM forced the patient to inhale in a slow and deep manner. According to their lung function, patients were categorized in subgroup 1, 2 or 3 corresponding to FEV1 predicted ≤59%, 60-79% or ≥80%. Blood samples were collected in order to model tobramycin pharmacokinetics. Results: Mean Cmax and AUC0-24hr were significantly increased for TIM compared to TBM. Inhalation in TIM also resulted in higher mean Cmax and AUC0-24hr for each subgroup. Mean bioavailability of TIM relative to TBM breathing pattern (Frel) was 1.53±0.41 and mean Frel in each subgroup was also significantly higher than 1. Subgroup category did not affect the results. Conclusion: Slow and deep inhalation of aerosolized tobramycin with the I-neb nebulizer resulted in an estimated 53% higher lung deposition compared to tidal breathing. This result was independent from lung function category, which suggests that regardless the disease state, slow and deep inhalation always results in higher pulmonary aerosol deposition compared to tidal breathing.

Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis

This study aimed to characterize the pharmacokinetics of tobramycin administered one, two, or three times daily and to develop an optimal dosing scheme for children with cystic fibrosis. Therapeutic drug monitoring data were obtained from children hospitalized at three academic medical centres from 2006 to 2012. Population pharmacokinetic models were constructed using NONMEM 7.2. Model-based simulations were performed in Matlab R2012b to identify optimal dosing regimens using pharmacodynamic targets. The pharmacokinetic analysis involved 257 patients with a median age of 8.1years (range 0.1-18.8). Clearance was estimated as 5.59L/h and the volume of distribution was 18.90L. Mean (±SD) maximum serum concentrations were highest among patients dosed once per day (24.1±8.9μg/mL) and were lower among patients dosed two and three times per day (11.2±1.4 and 8.1±2.4μg/mL, respectively). Simulations revealed that once daily dosing was the only effective regimen for a Pseudomonas aeruginosa MIC of 1.5μg/mL and none of the tested regimens reliably achieved the pharmacodynamic target for MICs ≥2μg/mL. Once daily dosing resulted in higher maximum serum concentrations when compared to multiple-daily dosing. In simulations, once daily dosing was the only regimen to achieve the pharmacodynamic target for all subjects with MICs <2μg/mL.

Determination of Tobramycin Pharmacokinetics in Burn Patients to Evaluate the Potential Utility of Once-Daily Dosing in this Population

The objective was to determine the pharmacokinetics of tobramycin in critically ill adult burn patients and evaluate a variety of milligram per kilogram (mg/kg) total body weight (TBW) regimens to determine whether practical initial once-daily administration recommendations to attain desired plasma levels could be identified. A retrospective study was conducted in 58 eligible patients who received tobramycin and had at least one set of steady-state levels from which pharmacokinetic parameters could be determined using standard first-order pharmacokinetic equations. Classification and Regression Tree analysis was used to identify whether tobramycin clearance changed with time postburn. Monte Carlo Simulation was used to evaluate initial mg/kg TBW dosing regimens to determine whether a clinically useful once-daily tobramycin recommendation could be made. Tobramycin clearance was significantly greater for patients ≤45 days postburn vs patients >45 days postburn. Once-daily tobramycin dosing for patients ≤45 days postburn of 10 to 13 mg/kg TBW and for patients >45 days postburn of 8 to 10 mg/kg TBW provided levels similar to those known to be effective in nonburn injury patients. Once-daily tobramycin dosing recommendations for burn patients were determined. Variability in pharmacokinetics in this population and change in pharmacokinetics with time postburn injury necessitate monitoring of tobramycin levels to ensure targets are met and maintained.