What dosing weight should be used for IV acyclovir in patients with a BMI greater than 40?

Comment by InpharmD Researcher

Limited data exists on the optimal dosing weight for intravenous (IV) acyclovir in patients with a body mass index (BMI) greater than 40 kg/m^2. One retrospective study suggested that adjusted body weight (AdjBW) dosing resulted in reduced drug exposure compared to ideal body weight (IBW) dosing, while another study indicated lower acyclovir exposure in obese patients dosed on IBW compared to normal-weight patients dosed on total body weight (TBW), suggesting potential similarity in exposure with AdjBW dosing in obese patients. Clinical studies specifically investigating AdjBW dosing are lacking. Overall, more data is needed to establish the appropriate dosing strategy for this specific patient population.

Background

A poster abstract describing a 2020 retrospective observational chart review assessed the impact of different dosing strategies of intravenous (IV) acyclovir in obese patients. The study included 51 adult patients with a body mass index (BMI) greater than or equal to 30 kg/m^2 who received at least 48 hours of high-dose IV acyclovir therapy. Efficacy analysis was conducted by stratifying patients into ideal body weight (IBW), adjusted body weight (AdjBW), and total body weight (TBW) groups. Treatment failure was observed in 3 out of 51 patients (1 patient in IBW group, 2 patients in AdjBW group, p= 0.445). Median length of stay (p= 0.977) and median duration of IV therapy (p= 0.78) did not show significant differences. Nephrotoxicity occurred in 22.2%, 19.2%, and 22.7% of patients in the IBW, AdjBW, and TBW groups, respectively (p= 1). The study suggested that, while comparing different dosing modalities, there were no significant differences in the outcome of infection, duration of therapy, or length of stay. However, dosing patients according to AdjBW resulted in smaller doses of acyclovir, reducing drug exposure. It is important to interpret the results with caution due to the small sample size and the limited available information based on a poster abstract. [1]

An abstract published on the Eshelman School of Pharmacy website describes a retrospective study that assessed the nephrotoxicity of IV acyclovir between traditional dosing and BMI-based dosing at a single institution center. Patients with BMI ≥ 40 kg/m^2 were dosed using AdjBW while patients with BMI less than 40 kg/m^2 were dosed using actual body weight (ABW). Nephrotoxicity was defined as an increase of 2x or greater in serum creatinine (SCr) from baseline. When patients were divided by BMI groups, those between 30 to 39 kg/m^2 experienced the highest rate of nephrotoxicity compared to traditional protocol dosing (9.5% vs 0%), although there were only a total of 4 of 70 events in the BMI-based protocol group. The rate for those with BMI ≥ 40 kg/m^2 were not published. The dosing protocol for IV acyclovir was also not specified within the abstract. [2]

References:

[1] Mulvey N, Jain S, Falsetta K, Doan TL. 196. Assessing the Clinical Impact of Intravenous Acyclovir Dosing in Obese Patients: Should We Be Using Ideal, Adjusted, or Total Body Weight?. Open Forum Infect Dis. 2020;7(Suppl 1):S102-S103. Published 2020 Dec 31. doi:10.1093/ofid/ofaa439.240
[2] Smith, M. Keith, A. Abstract only. Published 2020. Accessed June 7, 2023. https://pharmacy.unc.edu/wp-content/uploads/sites/1043/2020/06/Smith-Mary.pdf
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What dosing weight should be used for IV acyclovir in patients with a BMI > 40?

Please see Tables 1-2 for your response.

Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

Design

Prospective, open-label, matched-pair, pharmacokinetic study

N= 14

Objective

To evaluate the pharmacokinetics of intravenous (IV) acyclovir in morbidly obese patients utilizing dosing recommendations from the manufacturer's prescribing information

Study Groups

Morbidly obese (n= 7)

Normal weight (n= 7)

Inclusion Criteria

Age ≥18 years; requiring IV acyclovir as part of routine clinical care

Exclusion Criteria

Serum creatinine >1.4 mg/dL; exhibited clinical instability (intensive care unit [ICU] admission or use of vasopressor support); receiving medications known to interact with acyclovir; received acyclovir or valacyclovir within the previous 24 hours

Methods

Consistent with manufacturer recommendations, patients received intravenous acyclovir 5 mg/kg using ideal body weight if morbidly obese and total body weight if normal weight. Acyclovir was prepared in 100 mL of normal saline and infused over 60 min via an infusion pump.

Blood samples were collected serially immediately prior to the first dose of acyclovir and at 30, 60, 75, 90, 120, 180, 300, 420, 540, and 720 min following initiation of the infusion for analysis. Samples were analyzed by high-performance liquid chromatography separation using positive-ion electrospray tandem mass spectrometry (LC-MS/MS) for detection and quantitation.

Duration

 Up to 12 hours after the first acyclovir dose

Outcome Measures

 Pharmacokinetic parameters

Baseline Characteristics

  

Morbidly obese (n= 7)

Normal weight (n= 7)

 p-value

Age, years

 54.3 ± 9.6 53.0 ± 16.3 0.87

Female

85.7% 85.7% 1.0

White

 100% 100% 1.0

Body weight, kg

Body mass index, kg/m2

120.5 ± 15.7

45.0 ± 3.4

61.2 ± 5.1

22.5 ± 2.2

0.016

0.016

Glomerular filtration rate, mL/min/1.73 m2

93.4 ± 24.9

93.7 ± 25.7

0.94

All patients in the morbidly obese group were classified as class III obesity (body mass index [BMI] ≥40 kg/m2).

Results

 

Morbidly obese (n= 7)

Normal weight (n= 7)

p-value

Acyclovir dose, mg

 285 ± 44 303 ± 26 0.55

Cmax, mg/L

 5.8 ± 0.9 8.2 ± 1.3 0.031

AUC0-∞, mg*h/L

 15.2 ± 2.9 24.0 ± 9.4 0.011

Systemic clearance, L/h

 19.4 ± 5.3 14.3 ± 5.4 0.047

Volume of distribution

 31.8 ± 9.9 25.9 ± 10.4 0.29

Time above 0.5625 mg/L

Time above 1.125 mg/L

402.6 ± 204.2

264.9 ± 54.5

524.3 ± 253.0

373.1 ± 181.6

0.22

0.08

Cmax: maximum concentration; AUC: area under the curve from time 0 to infinity

Adverse Events

None reported

Study Author Conclusions

 These data suggest that morbidly obese patients treated with IV acyclovir dosed by ideal body weight experience substantially decreased overall exposure compared to normal weight patients dosed by total body weight.

InpharmD Researcher Critique

This study is limited by the small sample size, use of a low acyclovir dose (5 mg/kg), and single-dose observation; however, the authors state the kinetics observed are likely to be similar if dosed over several days. Included patients were receiving acyclovir for prophylaxis and were not actively infected or critically ill; altered pharmacokinetics are often present in critically ill patients. Patients with BMI ranges from 25.0 to 39.9 kg/m2 were not evaluated, so these results should not be generalized to them.

 

References:

Turner RB, Cumpston A, Sweet M, et al. Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients. Antimicrob Agents Chemother. 2016;60(3):1830-1833. Published 2016 Jan 11. doi:10.1128/AAC.02010-15

 

Comparison of Dosing Strategies in Obese Patients Prescribed Intravenous Acyclovir and Evaluation of Rate of Acute Kidney Injury

Design

Retrospective cohort review

N= 94

Objective

To compare adjusted body weight (AdjBW) to ideal body weight (IBW) dosing in obese patients prescribed IV acyclovir and determine if AdjBW dosing results in higher rates of acute kidney injury (AKI)

Study Groups

IBW (n= 61)

AdjBW (n= 33)

Inclusion Criteria

Age ≥18 years with a BMI ≥30 kg/m² prescribed IV acyclovir from July 1, 2014 to August 31, 2021

Exclusion Criteria

Patients on renal replacement therapy, AKI prior to acyclovir, missing information in the electronic medical record (lack of dosing weight, or serum creatinine prior to or during therapy), patients who received both IBW and AdjBW dosing of acyclovir and those prescribed acyclovir for prophylaxis 

Methods

 Patients who met the inclusion criteria were divided into groups according to the dosage administered, either using IBW or AdjBW. Following the institution's protocol, AdjBW was calculated as IBW + 0.4 (TBW-IBW).

Duration

January 1, 2014 to August 31, 2021

Outcome Measures

 AKI rates

Baseline Characteristics

  

IBW (n= 61)

AdjBW (n=33)

  

Age, years

 54.6 52.8  

Female

54.1% 57.6%  

Caucasian

 68.9%  63.6%  

BMI, kg/m2

 34.8 (31.5 to 40.6) 34.6 (32.7 to 39.6)   

Comorbidities

Hypertension

Diabetes mellitus

Chronic kidney disease

Renal transplant

Heart failure

Human immunodeficiency virus

Cancer

Cirrhosis

Immunocompromised status

 

67.2%

32.8%

3.3%

1.6%

6.6%

11.5%

24.6%

1.6%

4.9%

 

63.6%

27.3%

3.0%

3.0%

3.0%

3.0%

24.2%

0

9.1%

  

ICU admission when acyclovir initiated

34.4%

33.3%

  

ICU length of stay, days

8.0

9.0

  

Hospital length of stay, days

9.0

8.0

  

Results

Endpoint

IBW (n= 61)

AdjBW (n=33)

p-value
Dose, mg/dose

600 (500-700)

 800 (700-850) <0.0001
Doses per day

3.0 (3.0-3.0)

 3.0 (3.0-3.0) 0.2024

Dosing interval

Every 12 hours

Every 8 hours

 

3 (4.9%)

58 (95.1%)

 

0 

33 (100.0%)

 --

Duration, days

5.0 (4.0-7.0)

5.0 (4.0-8.0)

 >0.99

Renal parameters

AKI

Baseline SCr, mg/dL

Urine output, mL/kg/hr

Dehydration status (BUN/Scr >20:1)

Concomitant fluids

Fluid bolus during acyclovir

 

8 (13.1%)

0.81 (0.71-0.97)

1.6 (1.1-2.2)

15 (24.6%)

34 (55.7%)

19 (31.1%)

 

0

0.84 (0.68-0.96)

1.3 (0.9-1.6)

9 (27.3%)

18 (54.5%)

4 (12.1%)

 

--

0.704

0.100

0.776

0.916

0.041

There was no difference in the use of concomitant nephrotoxic agents between groups. Overall, the most common nephrotoxins were vancomycin (64.9%), radiocontrast dye (48.9%), loop diuretics (33%), ACEi/ARBs (28.7%) and NSAIDS (17%).

Adverse Events

See results

Study Author Conclusions

In this study, 8.5% of all obese patients receiving acyclovir developed AKI. Further studies are needed to confirm dosing recommendations.

InpharmD Researcher Critique

Limitations include a smaller sample size compared to previous studies, difficulty accounting for all AKI-associated factors due to the retrospective design (e.g., lack of information on fluid mL/hour rate), and the impracticality of conducting a logistic regression due to a limited number of AKI cases. Only a few patients exceeded the 40 kg/m2 BMI in the IBW group, while none surpassed this limit in the AdjBW group.



References:

Zelnicek TD, Siegrist EA, Miller JL, Neely SB, Higuita NIA, White BP. Comparison of Dosing Strategies in Obese Patients Prescribed Intravenous Acyclovir and Evaluation of Rate of Acute Kidney Injury [published online ahead of print, 2023 May 29]. Int J Antimicrob Agents. 2023;106871. doi:10.1016/j.ijantimicag.2023.106871