What are the potential drug interactions with letermovir?

Letermovir Drug Interactions: Clinical Management Guide

Letermovir has numerous significant drug interactions that require careful monitoring and management, particularly when used in transplant recipients and immunocompromised patients. As a cytomegalovirus (CMV) terminase inhibitor, letermovir's complex interaction profile stems from its role as both a substrate and inhibitor of multiple drug transporters and metabolizing enzymes 1.

Key Interaction Mechanisms

Letermovir functions as:

• Substrate of:

  • OATP1B1/3 transporters
  • P-glycoprotein (P-gp)
  • UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3)

• Inhibitor of:

  • CYP3A (moderate inhibitor)
  • CYP2C8 (inhibitor)
  • OATP1B1/3 transporters (inhibitor)

Critical Drug Interactions Requiring Management

Immunosuppressants

• Cyclosporine:

  • Cyclosporine increases letermovir AUC by 2.1-fold 2
  • Letermovir dose must be reduced to 240 mg daily when co-administered with cyclosporine 1, 2
  • Letermovir increases cyclosporine exposure by 1.7-fold 2

• Tacrolimus:

  • Letermovir increases tacrolimus AUC by 2.4-fold 2
  • Frequent monitoring of tacrolimus levels and dose adjustment is required 2

• Sirolimus:

  • Letermovir increases sirolimus AUC by 3.4-fold 2
  • Frequent monitoring of sirolimus levels and dose adjustment is required 2

• Mycophenolate mofetil (MMF):

  • No clinically significant interaction with mycophenolic acid levels 2
  • No dose adjustment needed

Anticoagulants

• Warfarin:
  • Letermovir may decrease warfarin levels 1
  • Frequent INR monitoring is recommended 1

Statins

• HMG-CoA reductase inhibitors:
  • Potential for increased statin exposure due to OATP1B1/3 inhibition 1, 3
  • Dose reduction may be needed; monitor for myopathy

Antimicrobials

• Rifampin:

  • Complex interaction with acute inhibitory and chronic inductive effects 4
  • Co-administration is not recommended due to potential for loss of letermovir efficacy 1

• Nafcillin:

  • May decrease letermovir levels 1
  • Co-administration is not recommended

Antiepileptics

• Carbamazepine, phenytoin, phenobarbital:
  • May significantly decrease letermovir levels 1
  • Co-administration is not recommended

Antiarrhythmics

• Amiodarone:
  • Letermovir may increase amiodarone levels 1
  • Close clinical monitoring for adverse events and amiodarone concentration monitoring is recommended 1

Herbal Products

• St. John's Wort:
  • May decrease letermovir levels 1
  • Co-administration is not recommended

Special Populations and Considerations

Renal Impairment

• No dose adjustment required for renal impairment 1
• Letermovir AUC is approximately 1.9-fold higher in moderate renal impairment and 1.4-fold higher in severe renal impairment 1

Hepatic Impairment

• Letermovir AUC is approximately 1.6-fold higher in moderate hepatic impairment (Child-Pugh B) and 3.8-fold higher in severe hepatic impairment (Child-Pugh C) 1
• Monitor more closely in patients with hepatic impairment

Clinical Management Approach

1. Before initiating letermovir:

   • Complete medication reconciliation
   • Identify potential interactions
   • Make necessary dose adjustments to concomitant medications

2. During letermovir therapy:

   • Monitor drug levels for narrow therapeutic index drugs (tacrolimus, sirolimus, cyclosporine)
   • Adjust doses as needed
   • Monitor for adverse effects related to increased drug exposure

3. After discontinuing letermovir:

   • Readjust doses of concomitant medications that were modified due to letermovir 1
   • Continue monitoring drug levels until stable

Practical Recommendations

• For transplant recipients: Carefully manage immunosuppressant doses with frequent therapeutic drug monitoring 3, 2
• For patients on anticoagulants: Monitor INR more frequently when starting or stopping letermovir 1
• For patients on multiple medications: Consider consultation with clinical pharmacist to manage complex interactions 3

Common Pitfalls to Avoid

• Failure to adjust letermovir dose when co-administered with cyclosporine
• Overlooking the need to readjust concomitant medication doses after discontinuing letermovir
• Not recognizing the potential for three-way drug interactions in transplant patients on multiple medications 3
• Assuming interactions are immediate - some may develop over time due to enzyme induction effects

By understanding and proactively managing these interactions, clinicians can optimize the safety and efficacy of letermovir therapy while minimizing adverse events related to drug interactions.