What is the dose of letermovir and its modification in patients with impaired renal function?

Letermovir Dosing and Renal Dose Modifications

The standard dose of letermovir is 480 mg once daily, which should be reduced to 240 mg once daily when co-administered with cyclosporine. No dosage adjustment is required for patients with renal impairment, including those with severe renal impairment or end-stage renal disease. 1

Standard Dosing Recommendations

• Without cyclosporine: 480 mg orally or intravenously once daily
• With cyclosporine: 240 mg orally or intravenously once daily
• Duration: Typically initiated between day 0 and day 28 post-allogeneic hematopoietic stem cell transplant (HSCT) and continued through day 100 post-transplantation 2

Renal Impairment Considerations

Unlike many antiviral medications, letermovir does not require dose adjustment based on renal function:

• Mild renal impairment (eGFR 60-89 mL/min/1.73m²): No dose adjustment
• Moderate renal impairment (eGFR 30-59 mL/min/1.73m²): No dose adjustment
• Severe renal impairment (eGFR <30 mL/min/1.73m²): No dose adjustment
• End-stage renal disease on dialysis: No dose adjustment 1

While pharmacokinetic studies have shown that letermovir AUC is approximately 1.9-fold and 1.4-fold higher in patients with moderate and severe renal impairment respectively, these changes do not warrant dose modifications 1.

Special Populations and Considerations

Hepatic Impairment

• Mild to moderate hepatic impairment (Child-Pugh Class A or B): No dose adjustment
• Severe hepatic impairment (Child-Pugh Class C): Not recommended due to 3.8-fold higher AUC 1

Drug Interactions

• Cyclosporine: Reduces letermovir dose to 240 mg once daily due to significant drug interaction 1
• OATP1B1/3 inhibitors: May increase letermovir plasma concentrations 1

Pediatric Patients

• Dosing for adolescents (12-18 years) is the same as adults: 480 mg once daily (240 mg with cyclosporine) 3

Clinical Efficacy and Safety

Letermovir has demonstrated significant efficacy in preventing CMV infection in high-risk populations. In a phase 3 trial, letermovir prophylaxis resulted in significantly lower risk of clinically significant CMV infection compared to placebo (37.5% vs 60.6%, P<0.001) 4.

The medication is generally well-tolerated with adverse events similar to placebo. Common side effects include:

• Vomiting (18.5%)
• Edema (14.5%)
• Atrial fibrillation/flutter (4.6%) 4

Monitoring Recommendations

While specific dose adjustments aren't required for renal impairment, monitoring is recommended:

• Monitor serum creatinine in patients with CrCl <50 mL/min 2
• Watch for breakthrough CMV infections, particularly in high-risk patients 5

Key Clinical Pearls

1. Unlike other antiviral agents used for CMV (such as ganciclovir or valganciclovir), letermovir does not require renal dose adjustment, making it particularly valuable in transplant recipients with renal dysfunction.

2. Letermovir has a novel mechanism of action (inhibition of the CMV terminase complex) and does not show cross-resistance with other anti-CMV agents 2.

3. Be vigilant about drug interactions, particularly with cyclosporine, which necessitates a 50% dose reduction of letermovir.

4. Ensure proper timing of administration in relation to immunosuppressive medications in transplant recipients.