Acyclovir Pharmacokinetic Dosing Information

Acyclovir-Induced Renal Failure

Incidence: Acyclovir induced renal failure occurs in greater than 10% of cases, range 10-48%, with crystal obstruction being the most common cause.

Mechanism: Crystal nephropathy is characterized by a decrease in renal function with a rapid rise in serum creatinine. Dialysis may be needed in severe cases.

Acyclovir is filtered by glomeruli and secreted in renal tubules producing high tubular concentrations. It is relatively insoluble in urine. Intra-tubular crystals obstruct the nephron leading to acute renal failure.

Timing: Crystalluria usually develops within 24-72 hours of initiation of therapy. Severe intra-parenchymal crystals may cause interstitial congestion and hemorrhage.

Risk Factors: Higher concentrations are produced in the tubules when there is decreased urine flow, dehydration, IV administration rather than oral, and rapid IV administration.

Laboratory Findings: Increasing serum creatinine, hematuria, pyuria, and urine crystals which may be seen under polarizing light microscopy.

Pharmacokinetic Parameters

Molecular Weight 225 Da
Plasma Protein Binding Low (9-33%)
Volume of Distribution (Vd) 0.6 L/kg lean body weight
Distribution Distributed into the lean body compartment
Partition Coefficient (log P) -1.56 (hydrophilic nature)
Solubility Maximum solubility at physiological pH is 2.5 mg/ml
Elimination 60-90% renally eliminated unchanged by glomerular filtration and tubular secretion
Renal Clearance Approximately 3 fold higher than creatinine clearance
Peak Urinary Concentration Highest during IV administration and several hours post administration due to renal clearance
Urine Flow Rate Threshold Urine flow rates less than 100 ml/hour are more likely to produce acyclovir urine concentrations above the solubility point producing precipitants
Conversion Unit: 1 µM = 0.225 µg of acyclovir. Most studies measure serum levels in µM/L or nM/ml.

Clinical Indications (Adults)

Acyclovir intravenous intermittent infusion is indicated in adults for:

  • Herpes Simplex infections in immunocompromised: 5 mg/kg Q8H for 7 days
  • Initial episodes of Herpes Genitalis: 5 mg/kg Q8H for 5 days
  • Herpes Simplex Encephalitis: 10 mg/kg Q8H for 10 days
  • Varicella-Zoster infections in immunocompromised: 10 mg/kg Q8H for 7 days

Pharmacodynamic Parameters

  • Time > EC50%: Time concentration remains above the 50% inhibitory concentration
  • AUC: Area under the curve
  • Encephalitis Trough Target: Trough above 2-4 mg/L is recommended

Pharmacokinetic Studies: Blum 1982 (Intermittent Infusion)

Study Population: Pooled results of 7 acyclovir single and multiple dose intermittent infusion pharmacokinetic studies in adults by Blum at Burroughs Wellcome Laboratories. Seventy patients, age 16-68 years old, with varying degrees of renal function.

Key Findings:
  • Total Body Clearance (L/hour/1.73 m²): 0.2022 × CrCl per 1.73 m² + 1.722, R² = 0.34
  • Vd Steady State: Approximately 48 L/1.73 m²
  • Central Volume of Distribution: 21 L/1.73 m²
Package Insert Dosing Basis: This study forms the basis of the package insert dosing recommendations for renal dysfunction, which were designed to maintain similar AUC ranges over a 24 hour period of 45-101 mg·hour/liter per 24 hours for 5 mg/kg doses.

Pharmacokinetic Studies: Spector (Continuous Infusion)

Study Population: 16 immunocompromised patients with Varicella Zoster infections, age 17-66 years

Infusion Rates and Steady State Levels:
Infusion Rate (mg/kg/day) Infusion Rate (mg/hr) Average SS Serum Level (µg/ml) Average Urinary Concentration (mg/ml)
7.2150.90.09
14.428.82.30.33
21.643.24.60.67
28.857.63.20.68
36725.60.97
43.286.48.20.84

Urine Solubility Limit: 1.3 mg/ml

Clearance Equation:

Total Body Clearance (L/hour/1.73 m²): 0.091 × CrCl per 1.73 m² + 7.52, R² = 0.45

Clinical Outcomes:
  • Seven of thirteen patients had no new vesicle formation after three days
  • All patients stopped new vesicle formation after five days of therapy
  • No clinical or laboratory signs of systemic toxicity or infusion site reactions
Key Advantage: Continuous infusion of the same total daily dose given as intermittent infusions produces much lower peak urinary levels with a reduction of risk of crystalluria.

Pharmacokinetic Studies: Fletcher (Continuous Infusion - Life Threatening Infections)

Study Population: 13 patients with life threatening HSV, EBV, or CMV infections, age 4-57 years old

Infusion Rate: 0.45-9.7 mg/kg/hour (25-280 mg/hour)

Target Goal Levels:
  • HSV: 4.5-9 mg/L
  • EBV: 6.8-13.5 mg/L
  • CMV: 9-18 mg/L
Clinical Outcomes:
  • Two of five patients with CMV had clinical improvement and resolution
  • Three of three with HSV had clinical improvement and resolution
  • Two of four with EBV had clinical improvement and resolution
  • Three patients developed neutropenia
  • Nephrotoxicity was not observed
Clearance Equation:

Total Body Clearance (L/hour/1.73 m²): 0.178 × CrCl per 1.73 m² + 2.92, R² = 0.88

Dosing in Obesity

Note: Few pharmacokinetic studies are available in obese adult patients. There are no clinical trials of herpes viral infections treated with IV acyclovir comparing efficacy by dosing weight (lean, adjusted, total) in obese adults patients.
Davis 1991 Study:

Population: 7 morbidly obese patients and 5 normal weight patients

Findings:

  • Similar pharmacokinetic profiles between groups
  • Vd of 43 liters
  • Dosing using actual body weight resulted in serum levels twice as high in obese patients
  • Recommendation: Authors recommended dosing by IBW
Turner 2016 Study:

Population: 14 patients given prophylactic dose of 5 mg/kg based on IBW

  • Average age: 54 years
  • BMI > 40 in 7 patients, BMI 22.5 in 7 patients

Findings:

  • Clearance, AUC, and peak levels were statistically different for obese versus non-obese
  • Time above HSV inhibitory therapeutic break points were NOT statistically different

Conclusion: While not directly studied, dosing by adjusted body weight in morbid obesity more closely approximates the exposure seen in normal weight patients. Further research is needed to validate their results and clarify the proper dosing in obese patients.

Risk Factors for Acyclovir-Induced Nephrotoxicity

Ryan 2018 Study (269 patients):

AKI Rate: 13%. All doses were given over at least 60 minutes.

Factors Associated with AKI:

  • CKD (Chronic Kidney Disease)
  • Diabetes Mellitus (DM)
  • Higher daily doses (2173 vs 1819 mg/day)

Recommendation: Dosing based on IBW

Lee 2018 Study (287 patients):

Independent Risk Factors for AKI:

  • Diabetes Mellitus (DM)
  • NSAID use
  • Vancomycin use
Barber 2019 Study (115 patients):

Nephrotoxicity Rate: 21%

Median Acyclovir IV Dose: 10.1 mg/kg based on ideal body weight (range 9.8-11.4 mg/kg)

Independent Risk Factors:

  • Obesity (BMI > 30)
  • Concomitant vancomycin use

Toxicity Definition: RIFLE criteria

Kim 2015 Study (216 patients):

Study Design: Compared effect of IV hydration on renal function in patients with normal renal function treated for CNS HSV infection with 10 mg/kg infused over one hour Q8H

Baseline and Day 3 Renal Function Parameters:

Hydration Status Average SCr Pre (mg/dL) Average SCr Day 3 (mg/dL) Average eGFR Pre (ml/min) Average eGFR Day 3 (ml/min)
No hydration 0.73 2.22 104 53
< 2 liters/day 0.84 1.7 87 60
> 2 liters/day 0.79 0.87 107 89

Conclusion: Outcomes for patients with hydration > 2 liters per day were significantly better (P < 0.05) than those with less than 2 liters per day or no IV hydration.

Summary: AKI is more frequent in patients with DM, obesity, renal dysfunction, and concomitant NSAIDs or vancomycin.

Strategies to Minimize IV Acyclovir-Induced Nephrotoxicity

Optimal dosing and administration are needed to minimize the risk of nephropathy. Risks may be reduced by:

  • Maintaining Euvolemia: Institution of a hydration protocol
  • Urine Flow Rates: 100-150 ml/hour (approximately 1.5 ml/kg/hour based on acyclovir dosing weight)
  • IV Hydration: > 2 liters per day while receiving IV acyclovir
  • Slow Infusion: Administering IV doses over 2 hours (rather than 1 hour) in 250 ml of fluid
  • Dilution: Dilute doses of 10 mg/kg in 250 ml rather than 100 ml for intermittent infusions
  • Dose Adjustment: Adjusting the dose for renal function
  • Avoid Concomitant Nephrotoxins: Avoiding other nephrotoxins
  • Early Discontinuation: Based on viral PCR tests
  • Alternative Administration: Continuous infusion of the total daily dose may be used to improve efficacy and decrease risk of nephrotoxicity
Treatment of Acyclovir Nephrotoxicity:
  • IV fluids to maintain high urine flow rate greater than 150 ml/hour
  • Loop diuretics
  • Discontinuation of acyclovir or dosage reduction
  • Dialysis may be needed in severe cases

Dosing Weight Controversy in Obesity

Manufacturer Guidance: Dosing of acyclovir per manufacturer guidelines is by total body weight but there is a warning against using total body weight in obesity where ideal body weight is recommended. The product was released in 1982 long before obesity was common.
Mathematical Dosing Inconsistency:

Using adjusted body weight for patients BMI > 30 and total body weight for all others causes patients with a BMI of < 30 to get larger doses than patients with a BMI > 30, with a dosing error of 15-20%. The higher the BMI breakpoint, the greater the resulting dosing error.

Example (70-inch tall male): The total body weight needs to increase by 32 kg for the obese patient dosed by adjusted body weight to receive the same dose as the patient who has a BMI of 30 dosed by total body weight.

  • An 82 kg patient dosed by total body weight gets the same dose as a 95 kg patient dosed by adjusted body weight
  • A 94 kg patient dosed by total body weight gets the same dose as a 125 kg patient dosed by adjusted body weight
Problem: This type of dosing is mathematically illogical as smaller patients are given larger doses than heavier patients.
Calculation Formula:

The following equation may be used to calculate the increase in total body weight required for an obese patient dosed by adjusted body weight to be given the same dose as a patient who is dosed by total body weight who is just before the breakpoint for BMI:

Weight (kg) = 1.5 × BMI Breakpoint × (Inches in height × 2.54/100)² - 1.5 × ((Inches in height - 60) × 2.3 + 50)

Recommended Approach:
  • If adjusted body weight is used, it should be used on all patients weighing more than their ideal weight
  • If a BMI breakpoint is used, a lower BMI breakpoint such as BMI of 25 should be used, as it causes less dosing discrepancies

Review of Institutional Renal Dosing Protocols (Accessed 6/8/22)

Finding: A review of online institutional renal dosing protocols reveals a lack of standardization with a wide array of dosing recommendations.
Dosing Weight Strategies by Institution:
Institution Dosing Weight Strategy
Centegra HealthSystem, CCKM@uwhealth.org Ideal body weight
UNMC.edu Dosing weight not mentioned
Nebraska Medicine Adjusted body weight
Wake Forest - WakeHealth.edu Adjusted body weight for BMI > 30, ideal for non-obese
University of Michigan, Stanford Health Care Adjusted body weight for BMI > 30, total body weight for non-obese
Asp.nm.org Adjusted body weight for BMI > 35, actual body weight others
University of California San Francisco Adjusted body weight if weight > 120% of ideal, total body weight if weight ≤ 120% of ideal
University of Toledo Adjusted body weight if > 190% of IBW, IBW if overweight (> 130-190% of IBW)
Washington.edu (HMC/UWMC) Adjusted body weight for BMI > 40 and life threatening, ideal body weight for BMI > 30

Recommendations to Minimize IV Acyclovir-Induced Nephrotoxicity in Adults

Conservative Approach Warranted: As there are few pharmacokinetic studies in obese adults, published studies have conflicting results, and there are no outcomes studies comparing the use of different dosing weights on efficacy in obese adult patients with HSV infections, a conservative approach is warranted. Nephrotoxicity is dose related and occurs at higher rates in obese patients even when dosed by IBW. Unnecessarily increasing the dose may place patients at higher risk of nephrotoxicity.
Key Recommendations:
  1. Dosing by adjusted body weight, if used, should be uniformly applied to all patients who weigh more than their ideal body weight. If a BMI breakpoint is used, a value of 25 is suggested to minimize dosing discrepancies.
  2. Obese patients (BMI > 30) should NOT be dosed by total body weight.
  3. Patients should receive IV hydration of > 2 liters per day while receiving IV acyclovir and maintain urine flow rates of 100-150 ml/hour or approximately 1.5 ml/kg/hour urine flow based on acyclovir dosing weight.
  4. Doses should be administered over 2 hours, rather than 1 hour, if possible. Continuous infusion of the total daily dose may be used to improve efficacy and decrease risk of nephrotoxicity.
  5. Dilute doses of 10 mg/kg in 250 ml rather than 100 ml for intermittent infusions.
  6. Early discontinuation of acyclovir is recommended if viral tests are negative.
  7. Monitor renal function and CBC daily.
Research Need: A large prospective pharmacokinetic study in obese patients treated for severe HSV infections is needed to validate pharmacokinetic parameters, efficacy and toxicity rates using different dosing weights. Use of nephrotoxicity reducing measures should be included to evaluate their impact on toxicity.

References

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  3. Sallevelt BTGM, et al. Acute renal and neurotoxicity due to weight-based dosing of intravenous acyclovir: How to dose in obese patients? Clinical Infection in Practice. 2020;7-8:100046.
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  8. Yildiz C, et al. Acute kidney injury due to acyclovir. Eur J Pediatr. 2013 May;2(1):38-40. PMID: 28509218
  9. Fleischer R, et al. Acyclovir nephrotoxicity: a case report highlighting the importance of prevention, detection, and treatment of acyclovir-induced nephropathy. Case Rep Med. 2010;2010:602783. PMID: 20862348
  10. Wurtz R, et al. Antimicrobial dosing in obese patients. Clin Infect Dis. 1997 Jul;25(1):112-8. PMID: 9243045
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  12. Lee EJ, et al. The incidence, risk factors, and clinical outcomes of acute kidney injury (staged using the RIFLE classification) associated with intravenous acyclovir administration. Ren Fail. 2018 Nov;40(1):687-692. PMID: 30741619