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PHARMACOKINETICS |
From the School of Pharmacy, University of Queensland, Brisbane, Australia (Ms Teigen, Dr Duffull, Ms Dang); Diakonhjemmet Hospital Pharmacy, Oslo, Norway (Ms Teigen); the Department of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia (Dr Johnson); and the School of Pharmacy, University of Otago, Dunedin, New Zealand (Dr Duffull).
Address for reprints: Stephen Duffull, MPharm, PhD, School of Pharmacy, University of Otago, Dunedin, New Zealand; e-mail: stephen.duffull{at}stonebow.otago.ac.nz.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Aminoglycosides • hemodialysis • end-stage renal disease • pharmacokinetics
Surprisingly, after more than 50 years of clinical experience with aminoglycosides, many aspects with regard to their use remain unresolved. When prescribing aminoglycoside antibiotics to patients with ESRD, it appears to be common practice to administer the drug after the patient has received hemodialysis. Emerging data and theoretical considerations suggest this may not be the most beneficial manner of administration.4 Over recent years, a more complete understanding of the pharmacokinetic-pharmacodynamic relationships of aminoglycosides has led to a global change in clinical practice from multiple to once-daily dosing. Relevant pharmacokinetic-pharmacodynamic aspects of aminoglycosides include bactericidal activity that is linked to Cmax (efficacy improves with higher peak concentrations),5-8 adaptive resistance that is reversed by an adequate interval of low drug concentration between doses,9-12 and exposure-dependent toxicity.13-16
Most once-daily dosing regimens are based on achieving an equivalent exposure (area under the concentration-time curve [AUC]) to that which would have been achieved with divided doses; thus, it is suggested that the risk of toxicity should be no higher when the dose is administered once daily.17,18 The pharmacokinetic-pharmacodynamic behavior of aminoglycosides that led to longer dose intervals with higher Cmax values also strongly supports administration of these agents before hemodialysis. The overall pharmacokinetic-pharmacodynamic goal when prescribing aminoglycosides in hemodialysis patients is to achieve a concentration-time profile that approaches the profile seen after once-daily dosing in patients with normal renal function. In doing this, it is believed that the benefits of aminoglycosides when used in patients with normal renal function can be conferred to those receiving hemodialysis. It is hypothesized that dosing of aminoglycosides prior to, rather than after, hemodialysis will allow for a higher dose to be administered for any given level of exposure and hence provide higher peak concentrations.4 Predialysis dosing has been supported based on simulations from a semimechanistic model describing the influence of ESRD and hemodialysis on the pharmacokinetics of aminoglycosides.19 The subsequent dialysis session provides clearance of the drug that approaches that of patients with normal renal function and leads to lower concentrations prior to administering the next dose so that exposure (AUC) is reduced. It also remains possible that the aminoglycoside could be administered during the initial stage of dialysis to decrease waiting time. This concept has been tried previously with vancomycin.20
Only one published article that described the profile of aminoglycosides when administered predialysis was found. In this study of arbekacin in 10 patients,4 dosing prior to dialysis appeared to produce an AUC of approximately 40% that of the AUC when the same dose was given postdialysis. The aim of the current study was to evaluate dosing schedules of gentamicin in patients with ESRD and receiving hemodialysis.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Population
The study patients were enrolled prospectively from the Princess Alexandra Hospital, a tertiary referral hospital in Brisbane, Australia. Patients were eligible if they were enrolled in the hemodialysis program and were receiving gentamicin to treat a suspected or proven infection. Because of recruitment difficulties, some patients were also enrolled retrospectively. Patients were studied on the dosing they happened to be receiving at the time they presented (regardless of time of dosing in relation to dialysis), and they were eligible for inclusion both on first and subsequent doses of gentamicin. Patients were excluded if they had been on the dialysis care program for less than 1 month.
Data Collection
Collected data included dose, dose interval, the timing of all doses, the infusion time, the time of blood samples, and the subsequent concentrations of gentamicin, start and stop times for hemodialysis sessions, blood flow to the dialyzer, dialyzer filter thickness, surface area, dialysate rate, and amount of fluid to be removed. Demographic data collected included age, sex, weight (immediately after dialysis when possible), height, and a predialysis creatinine concentration. Creatinine clearance (CLCR) was approximated with the Cockcroft and Gault formula21 using a predialysis plasma concentration of creatinine and ideal body weight,22 as determined by height.23 This is an easily available approximation, which has numerous limitations that are especially relevant in this patient group.24-27 Thus, the CLCR descriptor is not intended to reflect true residual renal function but rather to provide an overall descriptor of the patients' functional status. It is likely that CLCR is a marker of lean mass and nonrenal mechanisms for clearance of creatinine in this setting.
Ethics
The study was reviewed and approved by the Princess Alexandra Hospital Research Ethics Committee before patient involvement commenced. Prospective patients provided written informed consent before joining the study.
Pharmacokinetic Sampling
Four blood samples were taken from most prospectively enrolled patients. The first blood sample for the study was taken by venipuncture at approximately 30 minutes after the end of the infusion of the study dose of gentamicin. This blood sample represents an approximation to Cmax. Three further blood samples were collected from each patient to establish plasma concentrations of the aminoglycoside antibiotic and clearance within and between dialysis sessions. Typically, this involved a blood sample at the beginning of dialysis, a blood sample at the end of dialysis (both taken from the dialysis machine), and an interdialytic blood sample taken prior to the next dialysis session. Any additional blood samples that were taken as a part of routine clinical care were also used for data analysis. For the retrospective component of the study, blood samples were available from the computerized patient records as a part of usual clinical care.
Gentamicin plasma concentrations were determined using the Bayer Advia Centaur assays. The between-run coefficient of variation has been estimated as 7.4% at 2.2 mg/L and 5.9% at 6.5 mg/L. The lowest level of detection was 0.3 mg/L.
Population Analysis
A model was developed using the first-order conditional estimation method (FOCE) with the interaction option in NONMEM (version 5). The model fit was evaluated by considering the value of the objective function, parameter estimates, their between-subject variability (BSV), and visual inspection of diagnostic plots. Pharmacokinetic parameters for the patient population were estimated, such as interdialytic clearance (termed nonhemodialysis CL [CLNHD]), clearance during hemodialysis (CLHD), apparent volume of distribution (Vd), BSV of the estimates, and variance of the residual uncertainty. It was assumed that the elimination of gentamicin during dialysis was mediated by a first-order process. The NONMEM covariance command was used to obtain standard errors of the estimates. Model fit was assessed by the likelihood ratio test, where it is assumed that the difference of 2 NONMEM objective function values for nested models is asymptotically and approximately 
2 distributed. Under this assumption, the likelihood ratio test at 
= .05 significance level was used as a guide to statistical significance for model discrimination and a reduction of more than 3.84 units in the objective function is considered significant for models with 1-parameter difference (2, P < .05). Hemodialysis was considered an essential covariate, and therefore a base hemodialysis model was established before other covariates were considered.
Inclusion of covariates into the model was based on 4 criteria: (1) the parameter values produced by the covariate model had to be biologically plausible; (2) inclusion of the covariate into the model led to a significant drop in the objective function of 3.84 points or more; (3) the inclusion of the covariate produced a drop in the unexplained between-subject variance; and (4) the observed change in the parameter values as a result of the covariate inclusion were clinically significant (eg, >20% change in the parameter value given the range of covariate values). The model was specified as an ordinary differential equation, with a time-related switch that adjusted clearance due to start and stop times for hemodialysis. Volume of distribution was also allowed to increment during the interdialytic interval associated with an accumulation in extracellular fluid. The statistical model for the data was given by additive, proportional, or combined errors (combined error shown):
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where yij is the jth observed concentration for the ith individual and f(
i, xij) is the model-predicted concentration, 
1ij is the proportional residual error, and 2ij is the additive residual error. It is assumed that 1ij and 2ij are independent and identically distributed of the form 
N(0, 
2). The statistical model for BSV was
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where 
i represents a vector of differences between the ith individual parameter estimates from the population parameter values. It is assumed that are independent and identically distributed with mean zero and variance-covariance (
).
Evaluation of Dosing Schedules
The desirable targets when administering gentamicin to adult patients with normal renal function are Cmax greater than 10 mg/L and a 24-hour AUC between 70 and 120 mg·h/L.17 For the purpose of this patient population, a lower Cmax target of 8 mg/L was considered a success, thus accounting for a necessary dose reduction in patients with ESRD when administering aminoglycoside antibiotics. The value of 8 mg/L is also the concentration target for conventional multiple daily dosing.17 A maximum 24-hour AUC value of 120 mg·h/L was chosen, as this represents the upper limit proposed by Begg et al,17 rather than the more usual 100 mg·h/L for patients who have normal to moderately impaired renal function.
Therefore, treatment success was based on achieving a success in each of the following 3 criteria, assuming a 48-hour dialysis schedule:
8 mg/L 140 mg·h/L/48 h 
240 mg·h/L/48 h The final covariate model was used to simulate various dosing schedules. MATLAB (version 6.0.0.88 [EC] , release 12) was used to perform simulations for 1000 virtual patients for each proposed dosing schedule. Three doses administered over a treatment period of 6 days were simulated for each virtual patient, where hemodialysis was administered every 48 hours. We did not include a 72-hour interdialytic period once per week, as would commonly be the case in clinical practice. An extended break would not affect the interpretation of the simulations because it would serve only to increase the success rate across all dosing regimens for 1 dose interval. The primary outcome measures were peak concentration of aminoglycoside (Cmax) and AUC. Treatment success in 1 of the criteria was denoted by an indicator variable set to 1, and treatment failure was set to 0. With 3 administered doses and 3 indicator variables, an overall success for a virtual patient was provided by the product of the 9 indicator variables. Success rates for the separate criteria for individual doses were also considered. The best dosing schedule was one that provided the highest likelihood of overall success (in all categories on all doses). Execution variability was incorporated into the simulation model to account for variable times of starting hemodialysis in relation to the dose (up to 4 hours delayed) and also variability regarding the duration of the infusion (15-60 minutes).
A postdialysis dosing schedule was simulated, giving 3 commonly used postdialysis doses (160 mg as the first dose and 120 mg as the second and third dose) within 4 hours after the termination of each dialysis session every 48 hours. Consequently, success rates were compared between the proposed best dosing regimen and the empirical (postdialysis) dosing schedule.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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30 L/h).
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Population Analysis
A zero-order input 1-compartment model with log normal BSV of CL and Vd and a combined proportional and additive error provided the best fit to the data and was chosen as the best base model. Hemodialysis was the most appropriate first step to improve model fit, and the incorporation of hemodialysis resulted in a drop in the objective function value of 69 points (see Table II for parameter values). Between-subject variability was only included for CLNHD and Vd, because the data set did not support its inclusion for CLHD. A more mechanistic model, which included a factor for dialysis clearance taking into account differences in dialyzer filter thickness, surface area of the membrane, intrinsic clearance, and blood flow was not explored, because no random effect could be estimated for CLHD and hence no improvement in model fit could occur. We did however assess the influence of adding the filter type (high- or low-flux) into the model that had a BSV term for CLHD. This resulted in a 9% increase in CLHD for the high-flux filters compared to low-flux. However, this was not statistically significant, and filter type was not retained in the model. The indicator covariate CLCR was the only influential covariate (for CLNHD) and resulted in a drop in the objective function value by a further 24.1 points. The CLCR indicator variable explained 35% of the between-subject variance in CLNHD and also reduced the between-subject variance in Vd by 53% (see Table II for parameter values with different models).
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Including weight or ideal body weight into the model alone or combined as influential factors on Vd or CLNHD did not improve model fit. An attempt was made to include fluctuations in extracellular fluid volume as a function of the changing wet weight as a covariate for the Vd, but the data did not support this.
The final model contained HD as a covariate for CLHD and centered CLCR as a covariate for CLNHD. The mean value of interdialytic gentamicin clearance was 0.453 L/h, and the mean value for gentamicin clearance during dialysis was 4.69 L/h. The observed versus predicted concentrations for the base and final model are shown in Figure 1.
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Of the study patients, 38 had postdialysis dosing and an evaluable peak concentration taken. The remaining patients who had postdialysis dosing did not have a blood sample taken near (within 30 minutes of) the actual time of the Cmax (see Figure 2 for the distribution of observed "Cmax" values). Four patients (11% of these patients) attained a peak concentration 8 mg/L, and 2 of these patients had an AUC above the maximum target of 240 mg·h/L/48 h. Both patients had estimated values of CLNHD and CLCR lower than the average values for the population, and the administered doses were 120 mg and 180 mg postdialysis. Only one patient received predialysis dosing (specifically 240 mg gentamicin immediately before dialysis), and this patient achieved an observed peak concentration of 8.5 mg/L, and an AUC of 89.6 mg·h/L. Only 4 patients in the study had AUC values above the maximum target. Thirty-four patients had low values of the observed "Cmax" values of between 2 and 7 mg/L.
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None of the simulated patients receiving the postdialysis dosing schedule (160 mg, 120 mg, and 120 mg as first, second, and third dose, respectively) achieved overall success, and the main reason for this was the low peak concentrations achieved with this dosing regimen (see Table III). This regimen was better at meeting the AUC criteria than the peak concentration criterion; thus, unacceptable aminoglycoside exposure appears to be relatively infrequent with this dosing schedule.
It is worth noting that although we provide dosing suggestions for up to 3 days postdose that these doses would need to be adjusted to meet the patient's pharmacokinetic and clinical needs. We include the doses to highlight 2 points, to show that (1) doses when given predialysis are larger (almost twice the dose) and that (2) minimal accumulation occurs when dosing is given predialysis. This latter point is shown as the second and subsequent doses are not greatly reduced from that of the first dose when the doses are administered predialysis.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Although it appears to be common practice to dose aminoglycosides after patients have received hemodialysis, simulations from the model indicate that attainment of suitable peak concentrations is very poor in this circumstance. However, it appears that these regimens may provide a suitable exposure level. Simulations of a postdialysis dose of gentamicin of 160 mg yielded no patients who attained a Cmax greater than 8 mg/L on the first dose. This dose however provided a reasonable distribution of AUC values, which suggests that doses that will provide appropriate Cmax values are likely to result in overexposure. The only dose from which a small fraction of patients actually met the peak concentration treatment criterion was for the third dose and essentially arose because of significant accumulation that occurred over the 3 dose periods. Whenever doses lower than the 160 mg/120 mg/120 mg scenario are administered, even poorer results may be anticipated in terms of efficacy than with the simulated postdialysis regimen.
The estimated value of gentamicin clearance during dialysis (4.7 L/h) is similar to values of clearance observed in patients with normal renal function.28 In addition, in our study we found a 51% BSV in gentamicin clearance, which is comparable to 45% for patients with normal renal function.28 In 2 other studies evaluating dialyzer membranes with increased permeability (high-flux membranes), only moderately higher values than this (5.5 L/h and 7 L/h) are reported, corresponding to a half-life of 2.2 hours or more during dialysis.29,30 In a typical patient with normal renal function and weighing 72.4 kg (the mean value in this study population), an elimination half-life of 2.5 hours would be expected, which relates to a clearance in such a patient to be approximately 5 L/h. Xuan et al recently found a gentamicin clearance of 4.32 L/h in a pharmacokinetic evaluation of 939 adult hospitalized patients on aminoglycoside therapy.31 Thus, hemodialysis appears to offer almost normal clearance conditions in patients with ESRD during the dialysis period. In essence therefore, the dialysis period will provide the most close to "normal" pharmacokinetic-pharmacodynamic profile for gentamicin in patients with ESRD. From this study, for a typical 4-hour hemodialysis session, the clearance of gentamicin during dialysis (18.8 L/4 h) is approximately equivalent to the average total clearance during the interdialytic interval (19.9 L/44 h).
Based on predialysis dosing simulations from this study, it was found that an appropriate dosing strategy of gentamicin for patients who dialyze 3 times a week to be 300 mg predialysis as the first dose and then subsequent predialysis doses of 240 mg and 220 mg as second and third dose, respectively. This regimen produced a desirable peak concentration (above 8 mg/L) in 97% of patients for the first and second dose and a 91% success for patients for the third dose without unacceptably high exposure (see Table III). This illustrates how higher doses (300 mg, 240 mg, 220 mg) can be administered predialysis, because of the subsequent clearance provided by dialysis (similar to gentamicin clearance in patients with normal renal function), resulting in a lower total exposure than when administering lower doses (160 mg, 120 mg, 120 mg) postdialysis. The doses discussed here are only starting conditions, and it is recommended to monitor gentamicin concentrations from the first dose and adjust the dose accordingly using Bayesian dose individualization methodology in conjunction with knowledge of the patient's current clinical picture. It should also be noted that the optimal exposure levels have yet to be determined for this patient population, and it has been assumed in this study that exposure levels for patients with some level of intact renal function are a reasonable surrogate for those with ESRD.
The final model included the indicator for residual renal function, provided by CLCR, as a covariate, and this was the only covariate that improved model fit. Creatinine clearance as a measure for residual renal function is expected to be less accurate in hemodialysis patients compared to patients with normal renal function or less advanced renal impairment.25 In hemodialysis patients, plasma creatinine is a reflection of dialysis adequacy and the amount of body muscle, as well as residual renal function. In addition, tubular secretion of creatinine may contribute to an overestimation of glomerular filtration, which may be more significant as renal dysfunction progresses.25-27 The observed range for the estimated CLCR in this study is high (range, 0.27-1.24 L/h; mean, 0.53 L/h). It is likely that estimation of CLCR by urine collection would have resulted in lower values, as urine production in a considerable proportion of patients is often minimal. Nevertheless, the covariate CLCR was a clinically and statistically significant predictor of interdialytic gentamicin clearance. The variation in CLCR explained a substantial amount of the observed variability in clearance between dialysis sessions. Whether CLCR in this setting is predominantly a characterization of creatine producing body mass or some level of residual renal function is unknown. Caution should be taken if this relationship is extrapolated to other types of dialysis settings.
The developed model in this study was empirically based (although has reasonable biological grounds) and included a switch that turned clearance due to dialysis on and off according to onset and offset times of hemodialysis. A semimechanistic model that was developed previously,19 which accounts for hemodialysis factors that vary between patients, such as blood flow rates, filter thickness, and surface area of the membrane, was not implemented in this model. The application of this model depended on the ability to estimate the random variability between patients in their value of CLHD. Unfortunately, this was not supported by the data, and hence the more complex semimechanistic model could not be assessed for its ability to explain the random variability associated with CLHD. This more complex model remains a candidate to achieve better predictions of the within-dialytic clearance of gentamicin.
In summary, this study provides strong support for predialysis dosing of aminoglycosides in patients on hemodialysis. Hemodialysis provides a replacement for normal renal function in terms of gentamicin clearance so that the concentration-time curve approaches that of patients without ESRD for at least a portion of the dose interval. In patients with ESRD and hemodialysis who are at high risk of death from infection, predialysis dosing of gentamicin in the setting of suspected or confirmed sepsis would seem to represent a rational, efficacious, and safe strategy. Target concentration intervention strategies that employ Bayesian methodology are warranted to dose individual patients receiving gentamicin who have ESRD and are receiving hemodialysis.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: We also wish to acknowledge the University of Queensland for financial support through an ECR Grant (2003).
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REFERENCES |
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