Tobramycin In Plasma Research Articles

Using seconds-resolved pharmacokinetic datasets to assess pharmacokinetic models encompassing time-varying physiology.

Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench-top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours-scale, time-varying physiological processes. Given the recent advent of in vivo electrochemical aptamer-based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time-dense datasets to describe time-varying pharmacokinetic models with good statistical significance. We used seconds-resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one- and two-compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function. We found that a modified one-compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two-compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one-compartment, time-varying model was statistically preferred over the standard one-compartment model for 80% of our datasets. Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high-time resolution EAB sensor measurements to identify such impacts.

Application of a LC–MS/MS method for evaluating lung penetration of tobramycin in rats by microdialysis

A bioanalytical LC–MS/MS method was developed and validated to determine tobramycin in plasma and lung microdialysate samples. Tobramycin was separated using a C18 column and a mobile phase consisting of water and acetonitrile, both with 10mM of heptafluorobutyric acid, eluted as gradient. Apramycin was used as internal standard (IS) for plasma samples. Drugs were monitored using electrospray ionization operating on positive mode (ESI+) monitoring the transitions 468.2>163.3 m/z for tobramycin and 540.3>217.2 m/z for IS. The method showed linearity in the concentration range of 0.1–50μgmL−1 for microdialysate and 0.5–100μgmL−1 for plasma with coefficients of determination ≥0.991. The inter- and intra-day precision, the accuracy and the stability of the drug in different conditions were in accordance with the limits established by US Food and Drug Administration guideline. The concentrations of tobramycin in plasma and lung microdialysate, determined using CMA/20 probes and a Ringer solution at a flow rate of 1μLmin−1, were evaluated in healthy Wistar rats after a 10mgkg−1 i.v. bolus dose. Samples were harvested up to 12h post-dose. Before animal’s experiments, probe recovery was determined by dialysis and retrodialysis in vitro and by retrodialysis in vivo. Probes recovery was independent of drug concentration and method of determination. In vivo recovery was 27.74±7.70%. Pharmacokinetic parameters were estimated by non-compartmental analysis using the software Phoenix®. The estimated area under the curve (AUC0-∞) was 128±19μghmL−1 and 105±12μghmL−1 for plasma and lung, respectively. Tobramycin plasma clearance was 0.07±0.01L/h/kg and the volume of distribution was 0.49±0.09L/kg. Elimination half-life in plasma was 4.4±0.7h and in lung, 4.2±0.56h. The free tissue/free plasma AUC0-∞ ratio was 0.94. This is the first study showing a validated method to quantify tobramycin in microdialysate samples and to evaluate the lung interstitial concentration of the drug.

A Pharmacokinetics and Safety Comparison of a Highly Concentrated Tobramycin Solution with TOBI

Improved inhalation device/drug combinations are necessary to advance inhaled antibiotic therapy in cystic fibrosis (CF). Previously, for a novel drug/inhaler combination, equivalent lung deposition was demonstrated; here, we investigated its safety and pharmacokinetics. In a randomized, open-labeled, multicenter, active controlled, parallel 28-day study, we compared a new tobramycin formulation (T100 PARI, 150 mg/1.5 mL) nebulized with a drug-specific PARI eFlow(®) nebulizer and TOBI(®) (300 mg/5 mL) nebulized with a PARI LC PLUS(®) nebulizer in 78 CF patients. Noninferiority of the primary endpoint peak plasma tobramycin concentrations and the secondary endpoint area under the concentration time curves in plasma were observed. Sputum concentrations exceeded expected minimum inhibitory concentrations of Pseudomonas aeruginosa and were the same across both treatment groups, as were tolerability and safety. The nebulization time (4.6 vs. 16.1 min) was much shorter for the new drug/device combination. Inhaled therapy with T100 PARI delivered by an investigational eFlow offers a patient treatment time benefit and comparable safety and pharmacokinetics.

Pharmacokinetic studies on tobramycin in horses

The objective of the study was to evaluate the pharmacokinetics of tobramycin in plasma and urine in the horse (n = 7) after intravenous administration of a dose of 4 mg/kg b.w. Plasma tobramycin concentrations were assayed microbiologically and by means of HPLC analyses. Pharmacokinetic parameters, calculated on the basis of concentrations determined with the microbiological assay were not statistically different from those obtained when data from HPLC analysis were used, but the microbiological assay was more sensitive in the detection of low plasma and urine values. The values of the total body clearance (Cl(B)) were 101.4 +/- 30.1 and 130.0 +/- 49.9 mL/kg/h, respectively. The overall extraction ratio was 2.9%. The determined capacity of elimination of tobramycin in horses was similar to those for other aminoglycosides. Within 24 h after treatment, 57.6 +/- 12.2% of injected antibiotic was excreted in the urine.

Determination of tobramycin in saliva is not suitable for therapeutic drug monitoring of patients with cystic fibrosis

Background Tobramycin, used in the treatment of infections caused by Gram-negative bacteria, requires therapeutic drug monitoring (TDM) due to its narrow therapeutic index. The collection of blood for these assays may cause pain and trauma to the child and/or be difficult because of limited access to appropriate blood vessels. We undertook an evaluation of the role of saliva concentrations in the TDM of once-daily tobramycin therapy in patients with cystic fibrosis. Methods Fourteen patients (mean age 15 years) with cystic fibrosis were enrolled at Women's and Children's Hospital, Adelaide (WCH). All patients received once-daily dose of intravenous tobramycin for 2–3 weeks and had plasma levels measured once a week. At the same time of blood sampling at 1 and 6 h after initiation of tobramycin infusion, the patients also provided saliva samples. For collection of saliva, the Salivette® (Sarstedt Laboratories) system was used which was developed specifically for saliva sampling. Concentrations in blood and saliva were measured by the Beckman Synchron CX® system, which is utilized for routine assays of plasma tobramycin. Results and conclusion Tobramycin could not be detected in saliva within the first 6 h after a once-daily dosing. Therefore, plasma cannot be substituted with saliva for the TDM of tobramycin using the clinical routines at WCH.

Application of Neural Networks to Population Pharmacokinetic Data Analysis

This research examined the applicability of using a neural network approach to analyze population pharmacokinetic data. Such data were collected retrospectively from pediatric patients who had received tobramycin for the treatment of bacterial infection. The information collected included patient-related demographic variables (age, weight, gender, and other underlying illness), the individual’s dosing regimens (dose and dosing interval), time of blood drawn, and the resulting tobramycin concentration. Neural networks were trained with this information to capture the relationships between the plasma tobramycin levels and the following factors: patient-related demographic factors, dosing regimens, and time of blood drawn. The data were also analyzed using a standard population pharmacokinetic modeling program, NONMEM. The observed vs predicted concentration relationships obtained from the neural network approach were similar to those from NONMEM. The residuals of the predictions from neural network analyses showed a positive correlation with that from NONMEM. Average absolute errors were 33.9 and 37.3% for neural networks and 39.9% for NONMEM. Average prediction errors were found to be 2.59 and -5.01% for neural networks and 17.7% for NONMEM. We concluded that neural networks were capable of capturing the relationships between plasma drug levels and patient-related prognostic factors from routinely collected sparse within- patient pharmacokinetic data. Neural networks can therefore be considered to have potential to become a useful analytical tool for population pharmacokinetic data analysis.

Tobramycin concentrations in fallopian tube and ovary after a single intramuscular injection

SummaryTo FIND out if adequate levels are produced, tobramycin concentrations in the fallopian tube and ovary were measured in 12 patients undergoing salpingo-oophorectomy. The verbal consent of all the patients was obtained. Three of the patients studied (10, 11 and 12) were postmenopausal. The mean age of the patients was 44·21±11·6 years (range 21-60). No other medication was given and the renal function of all patients was normal. Tobramycin 1 mg/kg was given intramuscularly. One hour later a 2 cm section from the middle of the tube and one-half of the ovary on the same side were removed. Simultaneously with the tissue specimens, blood samples were taken from the antecubital vein for determination of plasma tobramycin concentrations.