Molnupiravir

by Michael S. Saag, M.D. last updated 2022-02-19 15:33:08.013845-05:00 © Antimicrobial Therapy, Inc.
Lagevrio

Usage and Dosing

  • Molnupiravir (Lagevrio), a prodrug, is a new antiviral agent for treatment of COVID-19.
  • Nucleoside antiviral agent similar to dideoxycytidine (ddC; previously used in HIV treatment).  Molnupiravir is a prodrug, which is metabolized to the ribonucleoside analogue N-hydroxycytidine (NHC) during or after absorption; in the cells NHC is phosphorylated to the active moiety,  NHC-triphosphate.
  • NHC-triphosphate  incorporated into SARS-CoV-2 RNA (as NHC-monophosphate) by viral RNA polymerase. This results in an accumulation of errors in the viral genome leading to inhibition of replication, known as viral error catastrophe or viral lethal mutagenesis.
  • Best used if given within 2 - 3 days of onset of symptoms.  Not very effective when given > 5 days after onset of symptoms.  Patients should be advised to test for SARS-CoV-2 as soon as possible after onset of symptoms and notify their provider ASAP after symptoms develop
  • No significant drug-drug interactions are anticipated.  Capsules can be administered with or without food.
  • Prior to initiating treatment with molnupiravir, assess whether an individual of childbearing potential is pregnant or not, if clinically indicated.
  • Initially, preliminary release of clinical trial data indicated a very robust 50% reduction in hospitalization or death; however, with the final study analysis, only a 30% reduction was observed.  
  • On December 23, 2021, the US FDA issued an EUA authorizing use for the treatment of mild-to-moderate COVID-19 in adults with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate. The drug should be initiated ASAP after diagnosis of COVID-19 and within five days of symptom onset.
  • On November 4, 2021, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK authorized the use of molnupiravir for use in people who have:
    • Been symptomatic for no more than 3-5 days
    • Have mild to moderate COVID-19 and
    • Have at least one risk factor for developing severe illness. Such risk factors include obesity, older age (>60 years), diabetes mellitus, and  heart disease.
  • References: N Engl J Med 2022;386:509 and editorial N Engl J Med 2022;386:592

Adult Dose

  • 800 mg (four 200 mg capsules) po q12h for five days, with or without food.
  • Capsules should not be open, crushed, or chewed.

Pediatric Dose

  • Safety and efficacy in patients under 18 years of age not established.
  • Bone and cartilage toxicity observed in rats after repeated dosing.

Renal Adjustment

  • No dosage adjustment in renal impairment required.

Hepatic Adjustment

  • No dosage adjustment in hepatic impairment required.

Adverse Effects

  • Diarrhea (2%)
  • Nausea (2%)
  • Dizziness (1%)
  • Headache (1%)
  • Rash, urticaria

Pharmacology

Class  Ribonucleoside analog
PK/PD Index  No data
Pharmaceutical
Preparation		  200 mg capsules
Usual Adult Dose  800 mg q12h x5 days
Pregnancy Risk Summary
  Not recommended during pregnancy (embryo-fetal toxicity in animals, no human data)
Food Effect1  Take with or without food
Oral
Absorption2 (%)		  No data
Tmax (hr)  1.5
Peak Serum Level3
(μg/mL)		  2.33 (SS)
Protein Binding
(%)		 ≈0
Average Serum
Half-life4 (hr)		 3.3 (NHC)
Elimination (of NHC) Metabolism to uridine and/or cytidine
Biliary Penetration5 (%)  No data
CSF/Blood
Penetration6 (%)		  No data
Therapeutic Levels in CSF7  No data
Volume of Distribution8
(Vd)		  142 L
AUC9 (μg*hr/mL)  8.26 (AUC0-12hr)
CYP450, Transporter
Interactions		 None known
  • Notes:
    • 1 Adult preparations unless otherwise noted.
    • 2 Absorption under optimal conditions.
    • 3 Total drug; adjust for protein binding to determine free drug concentration.
      • SD = after single dose
      • SS = steady state after multiple doses
    • 4 Assumes CrCl > 80 mL/min
    • 5 Peak concentration in bile/peak concentration in serum x 100
    • 6 CSF levels with inflammation
    • 7 Judgment based on drug dose & organism susceptibility. CSF concentration ideally ≥10x above MIC.
    • 8 Volume of Distribution (Vd):
      • V/F = Vd/oral bioavailability
      • Vss = Vd at steady state
      • Vss/F = Vd at steady state/oral bioavailability
    • 9 Area under the plasma concentration versus time curve

Major Drug Interactions

  • No data