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Dosing of Gentamicin in Patients With End-Stage Renal Disease Receiving Hemodialysis Mette Maja B. Teigen, Stephen Duffull, Lily Dang and David W. Johnson J. Clin. Pharmacol. 2006; 46; 1259 DOI: 10.1177/0091270006292987 The online version of this article can be found at: http://www.jclinpharm.org/cgi/content/abstract/46/11/1259

Published by: http://www.sagepublications.com

On behalf of: American College of Clinical Pharmacology

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Dosing of Gentamicin in Patients With End-Stage Renal Disease Receiving Hemodialysis Mette Maja B. Teigen, BPharm, MClinPharm, Stephen Duffull, MPharm, PhD, Lily Dang, BPharm(Hons), and David W. Johnson, MBBS, FRACP, PhD

The aim of this study was to evaluate dosing schedules of gentamicin in patients with end-stage renal disease and receiving hemodialysis. Forty-six patients were recruited who received gentamicin while on hemodialysis. Each patient provided approximately 4 blood samples at various times before and after dialysis for analysis of plasma gentamicin concentrations. A population pharmacokinetic model was constructed using NONMEM (version 5). The clearance of gentamicin during dialysis was 4.69 L/h and between dialysis was 0.453L/h. The clearance between dialysis was best described by residual creatinine clearance (as calculated using the Cockcroft and Gault equation),

which probably reflects both lean mass and residual clearance mechanisms. Simulation from the final population model showed that predialysis dosing has a higher probability of achieving target maximum concentration (Cmax) concentrations (>8 mg/L) within acceptable exposure limits (area under the concentration-time curve [AUC] values >70 and 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): yij = f(θi, xij)e ε1ij + ε2ij

where yij is the jth observed concentration for the ith individual and f(θi, xij) is the model-predicted concentration, ε1ij is the proportional residual error, and ε2ij is the additive residual error. It is assumed that ε1ij and ε2ij are independent and identically distributed of the form ε ~ N(0, σ 2). The statistical model for BSV was θi = θe ηi

where ηi represents a vector of differences between the ith individual parameter estimates from the population parameter values. It is assumed that η are independent and identically distributed with mean zero and variance-covariance (Ω). 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: 1. Cmax ≥8 mg/L 2. AUC ≥140 mg·h/L/48 h 3. AUC ≤240 mg·h/L/48 h

The final covariate model was used to simulate various dosing schedules. MATLAB (version 6.0.0.88, 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 1261

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TEIGEN ET AL

Table I

Patient Characteristics Mean ± SD (range) or %

Patient Characteristic (n = 46)

Male Age, y Height, cm Weight, kga CLCR, L/hb No. of blood samples

50 57.3 ± 164.7 ± 72.4 ± 0.53 ± 4.6 ±

Dialysis details Blood flow rate, L/h Duration of dialysis, h Interdialytic period, h Time since starting dialysis, mo

14.6 4.1 47 22.4

± ± ± ±

17.3 (18-83) 11.6 (135-195) 17.2 (42.1-100.5) 0.2 (0.26-1.24) 2.2 (1-10)

years; there were 23 women and 23 men. Characteristics of the study subjects are shown in Table I. High-flux polysulfone membranes were the most commonly used dialyzer (used in approximately 59% of patients), followed by low-flux polysulfone membranes (used in 41% of patients). Filter types are provided in the appendix. The mean blood flow rate was 14.6 L/h and dialysate flow rate was similar for all patients in the study (≈30 L/h). Population Analysis

2.2 (10.8-15.3) 0.5 (2-5) 19.9 (20-102) 29.5 (1-144)

a. Dry weight. b. Calculated using the Cockcroft and Gault formula using ideal body weight.

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. RESULTS Forty-six patients were included in the NONMEM analysis, 20 were enrolled prospectively, and 26 patients were enrolled retrospectively. The patients’ ages ranged from 18 to 83 years, with a mean of 57.3

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). 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

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GENTAMICIN IN PATIENTS WITH ESRD RECEIVING HEMODIALYSIS

Table II

Parameter Values Estimated With the Base, Base Hemodialysis (HD), and Final Covariate Model

Parameter

CL, L/h CLNHD, L/h CLHD V, L *ΩCL *ΩV Σ proportional** additive**

Base Model

Base HD Model

Final Model (SE%)

0.604 — — 22.5 0.271 0.0637 0.133 3.54 ×10–10

— 0.388 4.74 24.3 0.406 0.0537 0.0625 0.0495

— 0.453 × CLCR/0.53 (0.9) 4.69 (0.86) 23.5 (0.91) 0.264 (0.59) 0.0256 (0.45) 0.0804 (1.77) 0.00659 (3.05)

CL, clearance; CLNHD, nonhemodialysis clearance; CLHD, clearance during hemodialysis; Vd, volume of distribution; *Ω refers to the lognormal variance of η (measure for BSV) corresponding to CLNHD (CL base model) and Vd. **variance.

A Observed concentrations(DV)

14 12 10 8 6 4 2 0 0

2

4 6 8 Predicted concentrations

10

12

B

Observed concentrations(DV)

14 12

observed versus predicted concentrations for the base and final model are shown in Figure 1. 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. Dose Individualization

10 8 6 4 2 0 0

2

4

6

8

10

Predicted concentrations

Figure 1. Observed versus population predicted concentration for (A) base model and (B) final model.

Multiple dosing schedules were evaluated based on the final covariate model. The best dosing schedule identified for gentamicin through the simulations was 300 mg as a first dose, 240 mg as a second dose, and 220 mg as a third dose, immediately before hemodialysis occurring every 48 hours, with up to 4 hours flexibility between the dose and hemodialysis. This dosing schedule achieved treatment success for all 3 criteria for all 3 doses in 23.4% of patients and resulted in a satisfactory peak concentration in more than 90% of patients for all 3 doses, with 85% of patients achieving a maximum value of AUC

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TEIGEN ET AL

reduced from that of the first dose when the doses are administered predialysis. DISCUSSION

Figure 2. Observed peak concentrations with postdialysis dosing (n = 38).

(AUCmax) below 240 mg·h/L at all times through the 6-day course of treatment (see Table III and Figure 3). 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

Table III

Criteria

Predialysis dosing 1. 300 mg 2. 240 mg 3. 220 mg Postdialysis dosing 1. 160 mg 2. 120 mg 3. 120 mg

The model developed in this study describes the pharmacokinetics of gentamicin in hemodialysis patients and was used to explore dosing regimens aiming to improve the efficacy-toxicity profile when administered to patients with ESRD receiving hemodialysis. 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

Percentage of Success Rate Achieved With the Simulated Dosing Schedules

Cmax ≥ 8 mg/L

97 97 91 0 0.7 6.1

Success in All Criteria on All Doses (overall success)

AUCmin ≥ 140 mg·h/L/48h

AUCmax ≤240 mg·h/L/48h

77 75 70

92 85 89

23

89 84 82

93 77 76

0

Cmax, maximum concentration; AUCmin, minimum value of the area under the concentration time curve; AUCmax, maximum value of the area under the concentration time curve.

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GENTAMICIN IN PATIENTS WITH ESRD RECEIVING HEMODIALYSIS

A Cmax 1. dose predialysis dosing

Cmax 2. dose predialysis dosing

250

250

200

200

150

150

100

100

50

50

0

0 6

8

10

12

14

6

8

10

12

14

Cmax 3. dose predialysis dosing

300 250 200 150 100 50 0 6

8

10

12

14

16

B AUC 1. dose predialysis dosing

AUC 2. dose predialysis dosing

250

250

200

200

150

150

100

100

50

50

0

0 0

100

200

300

400

0

100 200 300 400 500

AUC 3. dose predialysis dosing

300 250 200 150 100 50 0 0

100 200 300 400 500

Figure 3. Histogram of the simulated criteria values compared to target values (vertical lines) for predialysis dosing for (A) maximum concentration (Cmax) and (B) area under the concentrationtime curve (AUC) for a dose of 300 mg for the first dose, 240 mg for the second dose, and 220 mg for the third dose.

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,

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TEIGEN ET AL

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.

We wish to acknowledge assistance from medical and nursing staff in the hemodialysis units, pathology, and pharmacy departments at Princess Alexandra Hospital through the course of the study. Financial disclosure: We also wish to acknowledge the University of Queensland for financial support through an ECR Grant (2003).

APPENDIX Filter Types Used for Patients in This Study Filter Type

Fresenius F10 HPS Low Flux 2.4 Fresenius F7 HPS Low Flux 1.6 Fresenius F7 Low Flux 1.6 Fresenius F8 HPS Low Flux 1.8 Fresenius F8 Low Flux 1.8 Fresenius FX80 Fresenius FX80 S 1.8 Fresenius HF80 1.8 Fresenius HF80 S 1.8 Gambro Allwal GFS/GEH Plus 11 (Haemophan) Gambro Polyflux 140 H Gambro Polyflux 170H Gambro Polyflux 210H

Number of Patients

11 3 1 3 1 2 3 10 1 1 3 5 2

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