2. Albany College of Pharmacy and Health Sciences, Albany, NY, USA

Transcription

1 AAC Accepted Manuscript Posted Online 17 August 2015 Antimicrob. Agents Chemother. doi: /aac Copyright 2015, American Society for Microbiology. All Rights Reserved. 1 Optimizing the Initial Amikacin Dosage in Adults 2 Bryan P. White, Pharm.D. 1 ; Ben Lomaestro, Pharm.D. 1 ; and *Manjunath P. Pai, Pharm.D Albany Medical Center, Albany, NY, USA Albany College of Pharmacy and Health Sciences, Albany, NY, USA Running Head: Optimizing the Amikacin Dosage *Corresponding Author: Manjunath P. Pai, Pharm.D. Professor Department of Pharmacy Practice Albany College of Pharmacy and Health Sciences 106 New Scotland Avenue Albany, NY (T): ; (F): ; (E): amit.pai@acphs.edu Word Count: Abstract (66 words), Main Text (1,417) Tables: 2 Figures:

2 Abstract: We report on the pharmacokinetics and pharmacodynamics (PK-PD) of high-dose (>15 mg/kg/day) amikacin. A mean (SD) C max and AUC 24 of 101 (49.4) mg/l and 600 (387) mg h/l, respectively, were observed (n= 73) with 28.0 (8.47) mg/kg/day doses. An initial amikacin dose of 2500 mg in adults weighing 40 kg to 200 kg with therapeutic drug monitoring to adjust the maintenance dose will optimize its PK-PD. Downloaded from on October 8, 2018 by guest 2

3 Amikacin is an important component of an initial empiric antimicrobial treatment strategy against major Gram-negative pathogens associated with serious infections. The regulatory approved dose of this aminoglycoside is 15 mg/kg/day as 2-3 divided doses (1). Aminoglycoside dosing has shifted from divided daily dosing to single daily dosing in order to optimize its concentration-dependent pharmacokinetic-pharmacodynamic (PK-PD) profile (2, 3). This dosing paradigm seeks to achieve a C max /MIC of 8-10 and an AUC/MIC of 75 (3-5). As a consequence, currently accepted standard doses of aminoglycosides such as tobramycin are now 5-10 mg/kg once daily in patients with normal kidney function that is roughly two-fold higher than the regulatory approved dose of 3-5 mg/kg/day in divided doses (5). The typical four-fold higher MIC 90 (4-8 mg/l) of amikacin against Pseudomonas aeruginosa compared to tobramycin (1-2 mg/l) coupled with dose-proportionality of aminoglycosides led our institution to adopt an initial empiric amikacin dose of 24 mg/kg in non-critically ill patients and mg/kg in critically ill patients. Two amikacin concentrations are measured 1 to 2 hours and the second 8 to 10 hours after the end of infusion of this first dose to permit dose individualization (6). Recent clinical studies corroborate this approach by suggesting that an initial amikacin dose 25 mg/kg is likely needed as empiric therapy of certain Gram-negative infections (7-10). Herein, we report on the amikacin exposure profile observed in our patients with this higher than regulatory approved amikacin treatment strategy (1). We also provide a clear rationale for consideration of an alternate empiric fixed amikacin dosing strategy in line with the current clinical adult total body weight (TBW) distribution. After institution review board approval, patients 21 years of age who received at least one dose of amikacin from 1/1/2012 to 6/30/2014, had two serial amikacin measurable 3

4 concentrations, and an estimated creatinine clearance (CLcr) >30 ml/minute based on the Cockcroft-Gault equation were included (11). Information pertaining to patient demographics, laboratory values, amikacin dose, administration and infusion times, amikacin concentration and sample collection times were collected. Amikacin concentrations were measured by an automated turbidometry immunoassay using the UniCel DxC 880i Synchron Access Clinical System (Beckman Coulter, Brea, CA). Serum creatinine concentrations were quantified based on an isotopic dilution mass spectrometry referenced method that was not modified during the study period. The concentration-time data were fit by population PK analyses (ADAPT 5, BMSR, Los Angeles, CA) using a 1-compartment model and a 2-compartment model (12). The relationship of amikacin PK parameters and exposure to body size were evaluated by visual inspection of scatter plots followed by regression. The final model was selected based on the Akaike Information Criterion (13). The final model was used to generate empirical Bayesian estimates of individual AUC 24, C max, and C min. The C max was the estimated concentration at the end of infusion and the C min was the estimated concentration 24 hours from the start of infusion. Classification and regression tree analysis (CART) was used to identify amikacin doses associated with achievement of C max /MIC 10 and AUC 24 /MIC 75 based on an MIC 90 of 8 mg/l. These results were used to define doses (1 hour infusion) for Monte Carlo Simulation (MCS) and permit calculation of the cumulative fraction of response (CFR) for C max /MIC 10 and AUC 24 /MIC 75 targets and the EUCAST MIC distribution of amikacin against P. aeruginosa (14, 15). Some institutions define amikacin doses based on a calculated Dosing Weight (DW) algorithm of; 1) TBW if less than ideal body weight (IBW); 2) IBW if TBW<1.2 fold higher than IBW; 3) adjusted body weight (ABW) if TBW 1.2 fold higher than IBW (2). As a result, we also 4

5 tested the CFR associated with amikacin doses that may be calculated by DW. Descriptive statistics, CART analyses, CFR computation, and figures were generated using STATA SE, version A total of 218 adult cases received amikacin and 145 cases were excluded due to an absence of two measurable amikacin concentrations (n=120), doses <15 mg/kg of TBW/day (n=8), amikacin administration time not charted (n=5), and creatinine clearance <30 ml/minute (n=10). Two cases were excluded as outliers due to a very low serum creatinine value and incorrect body size data to appropriately estimate CLcr. A 2-compartment model was selected as the final model (AIC decreased from 1780 to 1767) with a mean (relative standard error) CL, Vc, CLd, and Vp of 3.22 L/h (12.3%), 17.7 L (22.0%), 3.52 L/h (36.1%), and 22.5 L (41.7%), respectively, with excellent model prediction of individual concentrations (R 2 = 0.90). Patient demographics and Bayesian estimates of amikacin exposures (n=73) are reported in Table 1 based on receipt of a mean (SD) dose of 2262 (869) mg or 28.0 (8.47) mg/kg (TBW) or 31.8 (9.60) mg/kg (DW). A majority of patients in the study were white (92.9 %), male (65.9 %), and 45.3% were critically ill. About 37.0% of patients were obese based on a body mass index (BMI) 30 kg/m 2. Most of the patients were <80 kg (46.6%) or 80-<120 kg (45.2%) of TBW and <60 kg (32.8%) or 60-<90 kg (56.2%) of DW. The relationship of amikacin Vc and Vp and TBW or DW was weak (R 2 <0.1) and not significant (p>0.1). Similarly, amikacin CL was correlated to age and serum creatinine but not TBW or DW. Consistent with this observation, amikacin C max and AUC 24 were better correlated to amikacin dose in mg (R 2 < 0.32 and 0.39) compared to the dose in mg/kg (TBW or DW) (R 2 <0.13). The relative hazard ratio (RHR) by CART analyses to achieve or not achieve a C max /MIC 10 was 0.50 and 1.46 for doses above and 5

6 below 2200 mg. Similarly, the RHR to achieve or not achieve AUC 24 /MIC 75 was 0.38 and 1.89 for doses above and below 2500 mg. Only 63.0% and 36.9% of our patients achieved these C max /MIC and AUC 24 /MIC targets, respectively. The mean (SD) MCS predicted C max and AUC 24 values and CFR are provided in Table 2 centered on TBW-, DW- based doses and a fixed dosing approach. The CFR exceeds 90% for a C max /MIC 10 when the amikacin dose is 30 mg/kg of TBW, 40 mg/kg of DW or 2500 mg. However, the CFR is consistently higher with a fixed dose approach compared to weight-based dosing for AUC 24 /MIC 75. Figure 1 illustrates the observed (dose normalized for comparison) and predicted AUC 24 with a single dose of 30 mg/kg or 2500 mg and shows that AUC 24 increases across the weight categories but is lower in the kg group (45% of the sample) when dosed on TBW. The same trend was observed when comparing 40 mg/kg of DW to the 2500 mg dosage (data not illustrated). Our observations are consistent with the pharmacometric analyses conducted by Rughoo and colleagues in a sample of 872 patients treated with amikacin (16). Their analysis elegantly demonstrates the relationship of amikacin volume of distribution and weight to be weak, and to not serve as a good scalar for dosing (10). We clearly show that the regulatory approved dose of 15 mg/kg/day is expected to be suboptimal based on PK-PD targets. Recent studies have suggested that doses of 25 mg/kg are necessary to optimize the PK-PD profile (7-10). However, they have not simulated the effect of a fixed dose in their population models even though weight is not shown to be a proportionate scalar of key PK parameters (7, 8). We illustrate the predicted effects of both approaches that match our observations (Figure 1). If rapid target attainment and short-term use of amikacin is the empiric goal to optimize effect 6

7 and safety, respectively, then use of a single initial 2500 mg dose of amikacin followed by TDM to individualize the dose is suggested (17). This suggestion if validated by other groups is not only simpler across the clinical weight distribution but should increase the likelihood of effect against serious Gram-negative pathogens. Our study has several limitations that would be expected of a retrospective design. We included a heterogeneous clinical population who received weight-based doses of amikacin and not a fixed dose as is proposed by these results. Our model is based on a small and heterogeneous study population but closely matches the PK system parameters reported by recent studies (7, 8). Based on our results, an initial dose of at least 2500 mg of amikacin increases the expected CFR and this mathematical expectation can be validated by other research groups. The increasing use of this agent against serious multidrug resistant Gramnegative infections and availability of a commercial assay makes this suggested shift in the dosing paradigm testable by other research groups prior to broad implementation. Acknowledgements The authors would like to acknowledge Tim Lesar, Pharm.D. for his insights and Robert Davis, MS for informatics support. 7

8 References 1. Amikacin Sulfate [package insert]. Sellersville, PA: Teva Pharmaceutical USA, Inc; Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39(3): Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger AN, Louie A. Back to the future: using aminoglycosides again and how to dose them optimally. Clin Infect Dis Sep 15;45(6): Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155(1): Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother. 1999;43(3): Sawchuk RJ, Zaske DE. Pharmacokinetics of dosing regimens which utilize multiple intravenous infusions: gentamicin in burn patients. J Pharmacokinet Biopharm. 1976;4(2): de Montmollin E, Bouadma L, Gault N, Mourvillier B, Mariotte E, Chemam S, Massias L, Papy E, Tubach F, Wolff M, Sonneville R. Predictors of insufficient amikacin peak concentration in critically ill patients receiving a 25 mg/kg total body weight regimen. Intensive Care Med. 2014;40(7):

9 Burdet C, Pajot O, Couffignal C, Armand-Lefèvre L, Foucrier A, Laouénan C, Wolff M, Massias L, Mentré F. Population pharmacokinetics of single-dose amikacin in critically ill patients with suspected ventilator-associated pneumonia. Eur J Clin Pharmacol. 2015;71(1): Taccone FS, Laterre PF, Spapen H, Dugernier T, Delattre I, Layeux B, De Backer D, Wittebole X, Wallemacg P, Vincent JL, and Jacobs F. Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock. Crit Care. 2010;14(2):R Duszynska W, Taccone FS, Hurkacz M, Kowalska-Krochmal B, Wiela-Hojeńska A, Kübler A. Therapeutic drug monitoring of amikacin in septic patients. Crit Care ;17(4):R Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1): D'Argenio DZ, Schumitzky A, and Wang X ADAPT 5 user's guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles, California. 13. Akaike H A Bayesian extension of the minimum AIC procedure of autoregressive model fitting. Biometrika 66: Amikacin: Rationale for the EUCAST clinical breakpoints, version Amikacin_rationale_1.2_0906.pdf [Accessed April 4, 2015] 9

10 Mouton JW, Dudley MN, Cars O, Derendorf H, Drusano GL. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. J Antimicrob Chemother. 2005;55(5): Rughoo L, Bourguignon L, Maire P, Ducher M. Study of relationship between volume of distribution and body weight application to amikacin. Eur J Drug Metab Pharmacokinet. 2014;39(2): Drusano GL, Louie A. Optimization of aminoglycoside therapy. Antimicrob Agents Chemother. 2011;55(6): Downloaded from on October 8, 2018 by guest 10

11 Table 1. Summary of population demographics, kidney function, and amikacin exposure Parameter Mean SD Minimum Maximum Age Height (cm) Total Body Weight (kg) Dosing Weight (kg) Body Mass Index (kg/m 2 ) Creatinine Clearance (ml/min) C max (mg/l) C min (mg/l) AUC 24 (mg h/l)

12 Table 2. Mean (SD) maximum concentration (Cmax) and area under the curve over 24 hours (AUC 24 ) and cumulative fraction of response (CFR) predicted based on model based simulation of amikacin weight-based, fixed doses, and the EUCAST P.aeruginosa MIC distribution. 192 Initial Amikacin Dose Total Body Weight C max CFR AUC 24 CFR (mg/l) C max /MIC 10 (mg h/l) AUC 24 /MIC mg/kg 65.0 (35.9) 72.5% 370 (217) 29.5% 20 mg/kg 86.6 (47.9) 81.8% 494 (289) 41.4% 30 mg/kg 130 (71.9) 90.7% 741 (433) 58.7% 40 mg/kg 173 (95.8) 94.6% 987 (577) 70.2% Dosing Weight 15 mg/kg 52.9 (25.0) 66.3% 301 (155) 22.1% 20 mg/kg 70.6 (33.3) 77.6% 401 (206) 33.3% 30 mg/kg 106 (49.9) 88.2% 602 (309) 51.5% 40 mg/kg 141 (66.6) 93.1% 802 (413) 64.0% Fixed Dose 1500 mg 78.5 (37.5) 81.4% 435 (194) 69.0% 2000 mg 105 (50.0) 88.1% 580 (259) 80.0% 2500 mg 131 (62.5) 92.5% 725 (324) 85.7% 3000 mg 157 (75.0) 94.7% 870 (389) 89.3% 12

13 Simulation of 5000 subjects using the population model and covariance matrix with parameter truncation to match observed data distributions. The median [minimum, maximum] simulated values were: CL 3.28 [0.423, 9.36] L/h, Vc 18.2 [1.71, 35.1] L, CLd 3.47 [0.0783, 8.085] L/h, Vp 22.0 [1.95, 43.5] L, Total Body Weight 83.6 [40.0, 189] kg and a matching distribution of 40-<80 kg (45.0%) or 80-<120 kg (43.6%), Dosing Weight 69.7 [30, 124] and a matching distribution of 30-<60 kg (28.9%) or 60-<90 kg (59.2%) Downloaded from on October 8, 2018 by guest 13

14 Figure 1. Box and whisker plot of the area under the curve over 24 hours (AUC(0-24)) based on observed (n=73) values normalized to total body weight and fixed doses (A), and predicted (n=5000) values based on simulated weight-based and fixed doses (B). 203 Observed AUC(0-24) mg*h/l ,200 1,800 2,400 A Predicted AUC(0-24) mg*h/l ,200 1,800 2,400 3,000 3, <80 kg 80-<120 kg 120-<160 kg 160-<200 kg 30 mg/kg (dose normalized) 2500 mg (dose normalized) B 40-<80 kg 80-<120 kg 120- <160 kg kg 30mg/kg 2500 mg

15 Observed AUC(0 24) mg*h/l ,200 1,800 2,400 A 40 <80 kg 80 <120 kg 120 <160 kg 160 <200 kg 30 mg/kg (dose normalized) 2500 mg (dose normalized)

16 Predicted AUC(0 24) mg*h/l ,200 1,800 2,400 3,000 3,600 B 40 <80 kg 80 <120 kg 120 <160 kg kg 30mg/kg 2500 mg