Population pharmacokinetics of tobramycin.

1. Population pharmacokinetic parameters of tobramycin were determined in a heterogenous group of 97 patients using serum samples drawn for the routine monitoring of tobramycin concentrations, following multiple dosing regimens. 2. To describe the accumulation kinetics of tobramycin a two-compartment pharmacokinetic model was required. The best fit to the data was obtained when drug clearance (1 h-1) was related linearly to creatinine clearance (proportionality constant: 0.059 +/- 0.002 x CLcr (ml min-1)) and initial volume of distribution (1) was related linearly to body weight (proportionality constant: 0.327 +/- 0.014 x body weight (kg)). The intersubject variability in these two parameters was 32% and 3%, respectively, whilst the residual or intrasubject variability amounted to 21% of the tobramycin concentration. The terminal half-life of tobramycin, 26.6 +/- 9.4 h, was appreciably shorter than previously reported. 3. The population pharmacokinetic model was validated against data obtained from 34 independent patients and the predicted and observed concentrations were found to be in good agreement. The population pharmacokinetic model was used to design a priori dosing recommendations for tobramycin.     

Individualizing vancomycin dosage regimens: one- versus two-compartment Bayesian models

The absolute and relative predictive performances of one- and two-compartment Bayesian forecasting models were evaluated and compared. Initial population parameters were derived from 25 adult patients with stable renal function and who were being treated for presumed or documented gram-positive infections. The performance of each model was compared using these population parameters with and without steady-state or non-steady-state feedback concentrations to predict future peak and trough concentrations in an additional 20 patients. Both models tended to underpredict vancomycin peak and trough concentrations obtained at steady state. The use of a two-compartment model resulted in statistically less bias and more precise predictions of vancomycin peak concentrations when either population parameters or non-steady-state concentrations were used for future predictions. No difference in model performance was observed when steady-state concentrations were used to predict future steady-state concentrations. The results of this evaluation demonstrate that the two-compartment Bayesian model is less biased and more precise in determining future vancomycin serum concentrations given only population parameters or non-steady-state feedback information. No difference in model performance could be discerned when steady-state concentrations were used as feedback information.     

Comparison of aminoglycoside concentrations measured in plasma versus serum

The terms "serum concentration" and "plasma concentration" are often used interchangeably in therapeutic drug monitoring, but few studies have addressed the comparability of serum and plasma drug concentrations. Before implementing a change in the procedure for measuring aminoglycoside concentrations in our institution, we prospectively compared values for tobramycin and gentamicin concentrations measured in serum and plasma. For the 208 samples that were tested, plasma aminoglycoside concentrations were significantly lower than those in serum. This relationship was similar for tobramycin and gentamicin, and was unaffected by the presence of concurrent therapy with ticarcillin. This difference, while statistically significant, was not, in our estimation, of sufficient magnitude to be of clinical importance. Plasma aminoglycoside concentrations may be considered equivalent to serum concentrations and, owing to the shorter processing time involved, appear to be the preferred medium for measuring these values.     

Comparison of MS-DOS and Macintosh pharmacokinetic analysis programs using a two-compartment, two-infusion dosing scheme

Pharmacokinetic values derived by three nonlinear least-squares regression computer programs for sets of serum drug concentration data were compared. The three programs selected for comparison were the MS-DOS-based programs PCNONLIN and ADAPT and the Macintosh program BOOMER. Data on serum recainam hydrochloride concentration in 10 patients given an i.v. loading dose followed by a maintenance infusion were fitted by the appropriate models in each program. Samples had been subjected to reverse-phase isocratic high-performance liquid chromatography with ultraviolet light detection; intraday and interday coefficients of variation were less than 8% over the range of concentrations measured. A two-compartment model was used for all regressions. Each program was given identical initial estimates, and the simplex minimization algorithm of each program was used to fit the model to the data. An identical weighting scheme was used for all three programs. The mean pharmacokinetic values estimated by each program for the 10 data sets were essentially identical. Slightly larger rate constants and smaller volume terms were derived by BOOMER. BOOMER yielded the lowest weighted sum of squares and the highest correlation coefficient. A mean concentration-time plot showed that the programs all produced values that described the data very well. The three computer programs used in this analysis derived essentially the same pharmacokinetic values to describe sets of serum drug concentration data. The BOOMER program provides an acceptable alternative to MS-DOS-based programs for pharmacokinetic analysis.     

Evaluation of a Bayesian regression-analysis computer program using non-steady-state phenytoin concentrations

The predictive performance of a Bayesian regression-analysis computer program that uses non-steady-state phenytoin data was evaluated. Forty patients receiving phenytoin or phenytoin sodium who had two or more non-steady-state serum concentrations were selected for study. Additional serum concentrations and dosing data were collected as they became available, but no effort was made to control the number or timing of serum concentration determinations. Patients were categorized into four groups for evaluation of the effect of potential bioavailability problems and length of dosing history (time over which serum concentration-time data were collected) on the ability to predict subsequent phenytoin concentrations. Population parameters for phenytoin maximum rate of elimination (Vmax), apparent Michaelis-Menten constant (Km), volume of distribution (V), and bioavailability (F) were obtained from the literature. Predictions based on serum phenytoin concentrations and dosing histories (information intervals) of 5 or 10 days were compared with predictions based on naive (population-based) estimates using prediction-error analysis. In each patient group, the use of either 5-day or 10-day information intervals resulted in a significant increase in precision and a significant reduction in bias compared with naive estimates. For the group of patients who initially had two or more serum concentrations within the first five days of monitoring, predictions showed a marked increase in bias and a decrease in precision as the time interval from the last measured concentration to the time of prediction increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vancomycin pharmacokinetics and Bayesian estimation in pediatric patients

The vancomycin pharmacokinetic profile was characterized in six pediatric patients and the potential of nonlinear mixed effects modeling and Bayesian forecasting for vancomycin monitoring was explored using NONMEM V (1.1). Based on steady state serial vancomycin concentrations, the estimates of mean t1/2, Vd, and Cl derived by the Sawchuk and Zaske method (1) were 3.52 hours, 0.57 L/kg, and 0.12 L/h per kg, respectively. NONMEM analysis demonstrated that a weight-adjusted two-compartment model described individual patients' data better than a comparable one-compartment model. The two-compartment estimates of mean t1/2alpha, t1/2beta, Vss, and Cl were 0.80 hour, 5.63 hours, 0.63 L/kg, and 0.11 L/h per kg, respectively. The relatively long mean t1/2alpha suggests that peak vancomycin concentrations measured earlier than 4 hours postdose do not reflect postdistributional serum concentrations. NONMEM population modeling revealed that a weight-adjusted two-compartment model provided a better fit than a comparable one-compartment model. The resulting population parameters and variances were fixed in NONMEM to obtain Bayesian predictions of individual vancomycin serum concentrations. Bayesian estimation with either a single midinterval or trough sample has the potential to provide accurate and precise predictions of vancomycin concentrations. This should be evaluated using a vancomycin population pharmacokinetic model based on a larger sample of pediatric patients.     

Tobramycin serum level monitoring in young patients with normal renal function

Five clinical strategies for monitoring serum tobramycin concentrations were compared in a population of children and young adults with normal renal function receiving tobramycin for suspected sepsis. The drug monitoring strategies were evaluated on the basis of the ability of each to predict subsequent drug levels. The strategies included 3 methods requiring assessment of individual drug disposition: (a) measurement of peak drug concentrations after 2 separate doses; (b) a 3-point kinetic study to define distribution volume and elimination rate; (c) a 3-point kinetic study with adjustment of the value for elimination rate to account for deep compartment drug accumulation; and 2 strategies using a fixed-dose approach in which prediction of individual levels was made on the basis of mean population kinetic parameters. Although all methods were of similar accuracy, the fixed-dose strategy was the most precise in predicting subsequent serum tobramycin levels (95% tolerance limits = 84-135% of predicted). Poor performance of the other strategies was accounted for by interpatient variability of tobramycin disposition that was small relative to the intrapatient variability in these measurements. We conclude that these strategies for aminoglycoside serum level monitoring, which have proven beneficial in patients with impaired renal function, afford little benefit to children and young adults with normal renal function. Administration of these drugs on a fixed-dose schedule without serum concentration monitoring appears to be warranted in this select population. Alternatively, specific strategies for this population must be developed that consider the small interindividual differences in drug disposition and low incidence of toxicity.     

Midazolam therapeutic drug monitoring in intensive care sedation: a 5-year survey

During a 5-year period, 1997 to 2002, therapeutic drug monitoring of midazolam plasma concentrations in combination with the level of sedation as assessed by the Ramsay sedation scale was performed in 648 critically ill patients requiring artificial ventilation. In a subgroup of 189 patients sepsis-related organ failure assessment procedure was additionally performed. A total number of 3354 samples were analyzed. Significantly reduced clearance of midazolam was observed within the first 4 days of midazolam treatment of critically ill patients. As a result, accumulation of midazolam and its metabolites occurred within the first week of treatment. In contrast, parameters such as serum bilirubin or creatinine, which are commonly used to adapt drug therapy to organ dysfunction, showed significant changes with a delay of more than 10 days as compared with the findings of midazolam monitoring. Midazolam plasma concentrations showed a good correlation with the sedative capacity of the drug (r2 = 0.906). However, a great variability of the drug effect between patients could be demonstrated, which, as a consequence, may complicate the development of dosing strategies based on midazolam plasma concentrations to better control sedation in critically ill patients. Furthermore, patient age seems to be an important factor for the considerable variability of the sedative effect of midazolam. To achieve a certain levels of sedation, significantly lower midazolam infusion rates as well as plasma concentrations were required as the patients age increased. No significant sex-related differences could be observed for any pharmacologic parameter obtained in this study. Our findings suggest that midazolam therapeutic drug monitoring might be a useful tool to individualize midazolam therapy, especially in critically ill patients developing organ dysfunction and requiring long-term sedation to minimize the risk of drug accumulation and excessive sedation.     

Influence of infusion methods on therapeutic drug monitoring in pediatric patients

The purpose of this article is to emphasize the importance of infusion method on therapeutic drug monitoring in pediatric patients. Although effective serum concentrations are anticipated after intravenous infusion of drugs, studies with chloramphenicol and tobramycin have shown that the infusion method can have a profound influence on peak serum concentration and time to achieve peak concentration during therapy. Factors including infusion rate, injection site, volume of drug and fluid to be infused in the tubing, and type of infusion system should be considered for accurate drug delivery. Specific guidelines for drug infusions should be available at each institution. Since serum concentration predictions are based on the dose infused and infusion time, meaningful therapeutic monitoring data can be generated only with the understanding of the influence of infusion method on serum concentration-time profile of drugs.     

基于伏立康唑血药浓度监测的药物相互作用研究

目的 临床药师通过治疗药物监测(TDM)手段，研究利福平和伏立康唑之间的药物相互作用。方法 基于利福平和伏立康唑联用，及停用利福平后使用伏立康唑这两类患者的伏立康唑血药浓度监测情况，揭示利福平和伏立康唑间的药物相互作用强度与持续时间。结果 18例利福平和伏立康唑联用患者，94.44%患者的伏立康唑血药浓度低于有效治疗浓度范围下限(1.0mg/L)，其中72.22%患者低于定量下限0.16mg/L；19例停用利福平后再使用伏立康唑的标本中，停药6d内伏立康唑血药浓度小于1.0mg/L共12例，占总例数的63.16%，占停药6d内例数的91.67%；停药7d及以上伏立康唑血药浓度大于1mg/L的5例，占总例数的26.32%，占停药7d及以上例数的83.33%。结论 利福平会严重降低伏立康唑血药浓度，在停用利福平第7d起伏立康唑血药浓度很可能才上升有效浓度范围，因此临床上应避免伏立康唑与利福平联用。临床药师借助TDM成功干预了有临床意义的药物相互作用，TDM是临床药师参与药物治疗的有效技术手段。     

Comparison of EMIT versus bioassay to evaluate inactivation of tobramycin by piperacillin

We evaluated and compared the sensitivity of enzyme multiplied immunoassay (EMIT) and bioassay techniques in detecting the degree of inactivation of tobramycin by piperacillin in serum specimens. Specimens were prepared to contain initial tobramycin concentrations of 10 micrograms/ml and piperacillin concentrations of 62.5, 125.0, 250.0, and 500 micrograms/ml. The samples were stored at room temperature (25 degrees C), in the refrigerator (4 degrees C), and in the freezer (-10 degrees C) for up to 7 days. Tobramycin concentrations were determined by the two assay methods at the conclusion of 1, 3, and 6 h and 1, 3, 5, and 7 days of storage. The percentage of tobramycin activity as measured by EMIT and bioassay differed throughout the study period. Statistical analysis revealed that the assay method was the only significant variable to contribute to the variability observed in the differences of tobramycin concentration. Our results suggest that the bioassay technique is more sensitive than the EMIT assay for detecting the degree of inactivation of tobramycin by piperacillin. The EMIT assay overestimates tobramycin concentrations, which may be due to measurement of active and inactive tobramycin.     

Controlled release infusion kinetics of tobramycin

Ten healthy male volunteers received two doses of tobramycin (2 mg/kg) in a crossover fashion, first by intravenous piggyback (IVPB), then by the CRIS infusion system after a washout period. Serum samples were drawn both during and after the infusions. Twenty-four-hour urine collections were assayed for tobramycin. Residual fluid from the lines of both delivery systems was measured and assayed for tobramycin concentration. All samples were run in duplicate, using an enzyme-multiplied immunoassay technique assay. The results indicate that there was a statistically higher amount of drug delivered via the CRIS system (98.3 +/- 0.3% versus 90.4 +/- 2.3%). No significant difference was found in urinary recovery between the two groups. Peak serum levels were significantly higher with the CRIS system, with 8/10 subjects having at least one serum level greater than 10 micrograms/ml, as compared to 0/10 when given by IVPB. Peak serum levels occurred at 30 min in all subjects given tobramycin through the CRIS system, compared to 50-60 min when delivered by IVPB. This difference in peak serum levels is primarily related to the rate of drug delivery and to the difference in the dose delivered to each subject. The significance of the serum concentration profiles is discussed.     

Interlot variability in gentamicin and tobramycin concentration and its possible significance

Aminoglycoside therapy is routinely monitored at many institutions. It is widely known that serum concentrations of gentamicin and tobramycin may differ markedly among patients receiving the same doses of these drugs. One possible source of this variability may be interlot variation in the concentration of these drugs in commercial preparations. A study was designed to evaluate inter- and intralot variation in gentamicin and tobramycin concentrations at the labeled concentrations of 10 and 40 mg/ml. Multiple samples from six to 10 lots of commercially available gentamicin sulfate injection (Elkins-Sinn, Inc.) and tobramycin sulfate injection (Eli Lilly & Co.) were studied at each concentration. The actual percentage concentration of gentamicin in various lots ranged from 101 to 134% of the labeled concentrations; the actual percentage range was 101-109% at 10 mg/ml and 102-134% at 40 mg/ml labeled concentration. The actual percentage concentration of tobramycin in various lots ranged from 103 to 122% of labeled concentration; the actual percentage range was 107-117% at 10 mg/ml and 103-122% at 40 mg/ml labeled concentration. The intralot variation was less than 4% for both drugs at two concentrations. Based on these results, an 80-mg dose may in fact contain 107 mg of gentamicin or 98 mg of tobramycin. This may be clinically important in the care of patients and may at least in part explain the large variation in serum concentrations and difficulty in prediction of dosage requirements from routine monitoring. Furthermore, the available literature on pharmacokinetics, efficacy, and toxicity has not considered this interlot variation in aminoglycoside concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Can tobramycin inhalation be improved with a jet nebulizer?

Data on the pharmacokinetics of antibiotics after inhalation are limited. The aim of this pilot study was to assess the pharmacokinetics of tobramycin under optimalized and standardized aerosol circumstances and, furthermore, to be able to consider possible treatment of exacerbations with inhalation therapy. Six patients were studied after inhalation of 600 mg tobramycin. A jet nebulizer loaded with a 10% solution of tobramycin in water was used. The percentage of the dose that was systemically absorbed ranged from 1.0% to 16.6%. The maximum serum levels of tobramycin ranged from 0.77 mg/L to 3.63 mg/L (mean 1.70 +/- 1.01). The pharmacokinetic data were best described by a two-compartment model. Compared to intravenous administration, the long terminal half-life (mean 9.47 h +/- 3.28 h) could be explained by the slow absorption of tobramycin from the site of administration (flip-flop model). Despite standardized aerosol conditions, considerable interpatient variability was observed. However, the relatively low serum levels allow a further increase of the dose.     

The aminoglycoside panel: a new approach to monitoring aminoglycoside therapy

The aminoglycoside antibiotics gentamicin and tobramycin have been monitored traditionally by measuring peak and trough drug levels in serum. We found interpretation of these data to be hazardous, due to variations in the drug administration-specimen collection process and routine medical events and practices. We describe an aminoglycoside panel consisting of three serum levels drawn across one dosage interval. Gentamicin and tobramycin were measured by an enzyme immunoassay. 430 panels (1,290 samples) were evaluated by determining each panel's conformity to a classical monoexponential decay curve. Panels were then categorized by pattern of fit to this model. Sixty-two percent of the panels fell within acceptable limits of the model, while 13% displayed obvious errors. The percentage of acceptable panels on nursing units given an intensive educational program on the proper protocol for drug administration-specimen collection procedures was increased compared with the rest of the hospital. We propose the adoption of the aminoglycoside panel for the routine monitoring of these antibiotics as a means of gauging specimen and data quality.     

Comparative toxicity of netilmicin and tobramycin in dogs

Beagle dogs (four/group) were dosed intramuscularly with netilmicin or tobramycin once daily at doses of 20, 40, or 80 mg/kg. The dogs were dosed for 30 days or until death or sacrifice because of poor condition. Weekly otological examinations (response to Galton whistle) were conducted to evaluate effects on hearing. Hematologic, serum chemical and urinalysis data were collected weekly. Kidneys and cochleas were examined histologically. Dogs given 40 and 80 mg/kg of tobramycin became azotemic and died or were sacrificed in a moribund condition 9 to 22 days after dosing was initiated. Serum urea nitrogen and creatinine levels increased in $\text{2}\text{4}$ dogs given tobramycin at 20 mg/kg. No clinical signs of toxicity or unusual serum chemical changes occurred in the dogs dosed with netilmicin. Hearing did not appear to be affected by either compound. Microscopic examination of kidneys revealed tubular epithelial necrosis ranging from mild (netilmicin) to severe (tobramycin). Steady-state serum drug concentrations were established at all dose levels for netilmicin. In contrast, serum concentrations of tobramycin increased at all dose levels apparently as a result of nephropathy. Under the conditions of this study, netilmicin was clearly less toxic than tobramycin.     

Effect of various storage conditions on a fluorescence polarization immunoassay for tobramycin

The effects of various storage conditions on the results of a fluorescence polarization immunoassay for tobramycin were studied. Two venous blood samples (150 mL each) were drawn one hour and six hours after a single intramuscular dose of tobramycin. From each of these samples, which represented peak (6 micrograms/mL) and trough (1 microgram/mL) concentrations, aliquots of whole blood and of serum were prepared and stored in both glass and polypropylene containers. Serum samples were stored at -20 degrees C and assayed for tobramycin at intervals of 1-372 days. Samples of serum and whole blood were stored at 4 and 25 degrees C and assayed on days 1, 3, and 7. Mean tobramycin concentrations over time and between-run coefficients of variation were calculated for each set of samples. There was no substantial variation in tobramycin concentrations over time. Significant differences between tobramycin concentrations were noted only for peak serum samples in glass versus plastic containers at -20 degrees C and for trough serum samples stored in glass at -20 degrees C versus 25 degrees C. However, these differences were small and are unlikely to be clinically important. Under the conditions tested, the results of a fluorescence polarization immunoassay for tobramycin do not appear to be affected by storage time, storage temperature, container material, or storage medium (whole blood versus serum).     

Heparin interferes with tobramycin serum concentration determinations by Emit

Enzyme multiplied immunoassay (Emit) commonly is used to determine aminoglycoside concentrations. Its accuracy generally is comparable to that of radioimmunoassay (RIA). Poor reproducibility and questionable quantitation by the Emit assay have been reported when heparinized, severely lipemic, or icteric samples have been used. However, the significance of these interferences is documented poorly. We observed a ESRD patient in whom the underestimation by Emit of the tobramycin concentration in a plasma sample (heparin concentration of 41 U/ml) could have resulted in excessive drug administration and potential toxicity. Tobramycin therapy was initiated with a loading dose of 1.6 mg/kg and three tobramycin concentrations were obtained (2, 12, and 36 hours post-infusion) to define the patient's pharmacokinetic parameters. The first and third samples were collected in serum specimen tubes while the second sample was collected in a plasma tube. The tobramycin concentration in the plasma sample measured by Emit was 82 percent lower than the RIA value. Analyses of other samples by both procedures revealed no clinically significant differences. This case demonstrates that the presence of heparin may interfere with the Emit tobramycin assay in the clinical setting. The degree of reduction in tobramycin concentrations may be dramatic and potentially can alter a patients apparent tobramycin dosing requirements. Further investigation is warranted.     

Drug usage evaluation of aminoglycoside-induced nephrotoxicity in a community hospital

A DUE was conducted at this institution to determine the incidence of aminoglycoside-induced nephrotoxicity. The charts of all patients (113) who received an aminoglycoside during the first quarter of 1989 were reviewed. Information gathered included patient age, aminoglycoside used, loading and maintenance doses, serum peak and trough concentrations, changes in serum creatinine during aminoglycoside administration, and culture and sensitivity results. Physicians were inconsistent in prescribing loading doses, while all patients dosed by the pharmacy received an initial dose of 1.5 to 1.75 mg/kg of ideal body weight for gentamicin and tobramycin. Ninety percent of maintenance doses were calculated by the pharmacy. All patients had serum peak concentrations between 3 and 10 micrograms/ml, and only three patients had serum trough concentrations greater than 2 micrograms/ml. No patient demonstrated changes in serum creatinine suggestive of clinically apparent nephrotoxicity. This study suggests that with routine pharmacist intervention (via a pharmacist-managed dosing service), aminoglycosides can be prescribed with a low incidence of nephrotoxicity.     

Population kinetics of tobramycin in neonates

The population kinetics of tobramycin were studied in 140 neonates (100/40 patients for the index/validation groups, respectively) of 30 to 42 weeks' gestational age and 0.8 to 4.25 kg current body weight in their first 2 weeks of life, undergoing routine therapeutic drug monitoring of their tobramycin serum levels. The 365 tobramycin concentration measurements obtained were analyzed by use of NONMEM according to a one-compartment open model with zero-order absorption and first-order elimination. The effect of a variety of demographic, developmental, and clinical factors (gender, height, birth weight, current weight, gestational age, postnatal age, postconceptional age, and serum creatinine concentration) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. The final pharmacostatistical model with influential covariates was as follows (full population): clearance (L/h) = 0.0508 x current weight (kg), multiplied by 0.843 if birth weight was 2.5 kg or less (low-birthweight infants), and volume of distribution (L) = 0.533 x current weight (kg). Using the proportional error model for the random-effects parameters, interindividual variability for clearance and for volume of distribution was determined to be 25.8% and 21.9%, respectively, and the residual variability was 19.2%. In this study, the use of the NONMEM gave significant and consistent information on the pharmacokinetics and the determinants of the pharmacokinetic variability of tobramycin in neonates when compared with available bibliographic information. Moreover, the final population pharmacokinetic model may be used to design a priori recommendations for tobramycin and to improve the dosing readjustments through Bayesian estimation.