What are the considerations and dosing guidelines for using Cidofovir in pediatric patients?

Cidofovir Use in Pediatric Patients

Primary Recommendation

Cidofovir should be dosed at 5 mg/kg IV once weekly for 2 consecutive weeks as induction therapy in pediatric patients with severe viral infections (particularly adenovirus in immunocompromised hosts), followed by 5 mg/kg IV every 2 weeks for maintenance, with mandatory probenecid and aggressive saline hydration to mitigate nephrotoxicity. 1, 2

Clinical Context and Indications

Cidofovir is primarily used in pediatric patients for:

• Severe adenovirus infections in immunocompromised children (particularly post-hematopoietic stem cell transplantation), where the German Society of Hematology and Oncology specifically recommends its use 1
• CMV retinitis (FDA-approved indication) 3
• Vaccinia-related complications as second-line therapy under CDC IND protocol when VIG fails 3
• Resistant herpesvirus infections and polyomavirus-BK in transplant recipients 4, 5

Dosing Algorithm

Standard Dosing Protocol

Induction Phase:

• 5 mg/kg IV once weekly for 2 consecutive weeks 1, 2
• Infuse over 60 minutes at a constant rate 1, 2

Maintenance Phase:

• 5 mg/kg IV every 2 weeks until 3 consecutive negative viral samples from all previously involved sites 1

Alternative Modified Dosing:

• 1 mg/kg/dose three times weekly may be considered to reduce nephrotoxicity risk, particularly in patients with baseline renal compromise 5
• This modified regimen showed lower nephrotoxicity rates (4% vs 15%) compared to conventional dosing 5

Critical Caveat for Pediatric Dosing

The CDC explicitly states that insufficient data exists for appropriate pediatric dosing, and dosages must be determined in consultation with CDC or DoD specialists, particularly for vaccinia complications. 3, 2 However, the 5 mg/kg weekly regimen has become the de facto standard based on extrapolation from adult CMV dosing and pediatric adenovirus treatment experience 1.

Mandatory Nephroprotective Measures

Probenecid Protocol (Total 4 grams per cidofovir dose)

• 2 grams orally 3 hours before cidofovir infusion 2
• 1 gram orally 2 hours after infusion completion 2
• 1 gram orally 8 hours after infusion completion 2

Important: Probenecid should be used with caution in children and those with sulfa drug allergy 3

Saline Hydration Protocol

• Minimum 1 liter 0.9% normal saline IV over 1-2 hours immediately before cidofovir 1, 2
• Second liter (if tolerated) at the start of or immediately after cidofovir infusion, over 1-3 hours 2

Note: In smaller children, hydration volumes should be adjusted to 10-20 mL/kg per liter equivalent, maintaining the same timing principles 5

Nephrotoxicity Risk Stratification and Monitoring

Risk Profile

Dose-dependent nephrotoxicity is the major dose-limiting toxicity, with acute renal failure requiring dialysis possible after as few as 1-2 doses. 1, 2 However, recent data suggests nephrotoxicity rates may be lower in immunocompetent children than previously reported 6.

Comparative Nephrotoxicity Rates

• Conventional dosing (5 mg/kg weekly): 15% nephrotoxicity rate 5
• Modified dosing (1 mg/kg three times weekly): 4% nephrotoxicity rate 5
• Immunocompetent children: Only 1 of 23 patients (4%) developed acute kidney injury during treatment 6
• HSCT recipients: 2 of 12 patients (17%) developed acute kidney injury after first dose 4

Monitoring Algorithm

Before each dose:

• Serum creatinine and calculated GFR 3
• Urinalysis for proteinuria (early indicator of nephrotoxicity) 1, 2
• Complete blood count (monitor for neutropenia) 3

Proteinuria may be an early indicator of nephrotoxicity, and continued administration can lead to Fanconi syndrome. 1, 2

Dose adjustment required if:

• Serum creatinine increases ≥0.5 mg/dL from baseline 3
• Proteinuria ≥2+ develops 2
• Consider discontinuation if creatinine doubles from baseline 7

Additional Toxicities to Monitor

Beyond nephrotoxicity, cidofovir is associated with:

• Neutropenia (monitor CBC) 3, 2
• Decreased intraocular pressure/ocular hypotony and anterior uveitis/iritis 3, 2
• Metabolic acidosis 3, 2
• Carcinogenicity in animal studies (mammary adenocarcinomas in rats at 0.04 times human exposure) 3, 2
• Teratogenicity and hypospermia in animal studies 3, 2

Clinical Efficacy Data

Adenovirus Infections

• 4 of 7 patients (57%) with adenovirus infection successfully cleared infections in HSCT recipients 4
• 5 of 8 antigenemic patients (63%) responded completely to cidofovir as second-line therapy for CMV 7
• Mortality rate of 13% in immunocompetent children with severe adenovirus, unrelated to cidofovir toxicity 6

Safety Profile

Cidofovir was well tolerated in the majority of patients across 234 infusions in 23 high-risk pediatric patients, with only 3 patients suffering adverse events (2 related to hydration regimen). 8

Pharmacokinetic Considerations

• Mean drug half-life in children is 9.5 hours, significantly longer than in adults 4
• No correlation exists between nephrotoxicity and plasma maximum concentration, clearance, or half-life 4
• Pharmacokinetics are otherwise similar to adults 4

Critical Clinical Pitfalls

When NOT to Use Cidofovir

• Baseline serum creatinine >1.5 mg/dL or proteinuria ≥2+ (relative contraindication) 2
• Concurrent use of other nephrotoxic agents increases risk, though not an absolute contraindication if benefits outweigh risks 8
• Sulfa drug allergy (due to probenecid component) requires careful consideration 3

Common Errors to Avoid

• Omitting probenecid or inadequate hydration dramatically increases nephrotoxicity risk 1, 2
• Failure to monitor renal function before each dose can lead to irreversible renal failure 1, 2
• Continuing therapy despite rising creatinine or proteinuria risks progression to Fanconi syndrome 1, 2
• Infusing too rapidly (must be over 60 minutes minimum) 1, 2

Special Populations

Vaccinia Complications

For smallpox vaccine-related adverse events, cidofovir is only released under CDC IND protocol when: 3

1. Patient fails to respond to VIG treatment
2. Patient is near death
3. All VIG inventories exhausted

Pediatric dosing for vaccinia complications specifically requires consultation with CDC/DoD specialists due to insufficient data. 3, 2

Immunocompetent vs. Immunocompromised

Recent evidence suggests cidofovir-related nephrotoxicity rates in immunocompetent children may be substantially lower than in severely immunocompromised populations (4% vs 15-17%), potentially expanding the risk-benefit calculus 6.