Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals. ATC code: not yet assigned.
Pharmacology: Pharmacodynamics: Mechanism of action: Molnupiravir is a prodrug that is metabolised to the ribonucleoside analogue N-hydroxycytidine (NHC) which distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP acts by a mechanism known as viral error catastrophe. NHC-TP incorporation into viral RNA by the viral RNA polymerase, results in an accumulation of errors in the viral genome leading to inhibition of replication.
Antiviral Activity: NHC was active in cell culture assays against SARS-CoV-2 with 50% effective concentrations (EC50) ranging between 0.67 to 2.66 μM in A-549 cells and 0.32 to 2.03 μM in Vero E6 cells. NHC had similar activity against SARS-CoV-2 variants B.1.1.7 (Alpha), B.1351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) with EC50 values of 1.59, 1.77 and 1.32 and 1.68 μM, respectively. No impact was observed on the in vitro antiviral activity of NHC against SARS-CoV-2 when NHC was tested in combination with abacavir, emtricitabine, hydroxychloroquine, lamivudine, nelfinavir, remdesivir, ribavirin, sofosbuvir, or tenofovir.
Pharmacodynamic effects: The relationship between NHC and intracellular NHC-TP with antiviral efficacy has not been evaluated clinically.
Resistance: No amino acid substitutions in SARS-CoV-2 associated with resistance to NHC have been identified in Phase 2 clinical trials evaluating molnupiravir for the treatment of COVID-19. Studies to evaluate selection of resistance to NHC with SARS-CoV-2 in cell culture have not been completed.
Pharmacokinetics: Molnupiravir is a 5'-isobutyrate prodrug that is hydrolysed to NHC prior to reaching systemic circulation. The pharmacokinetics of NHC are similar in healthy subjects and patients with COVID-19.
Absorption: Following twice daily oral administration of 800 mg molnupiravir, the median time to peak plasma NHC concentrations (Tmax) was 1.5 hours.
Distribution: NHC does not bind to plasma proteins.
Elimination: The effective half-life of NHC is approximately 3.3 hours. The fraction of dose excreted as NHC in the urine was <3% in healthy participants.
Other special populations: Gender, Race, Age: Population pharmacokinetic analysis showed that age, gender, race and ethnicity do not meaningfully influence the pharmacokinetics of NHC.
Paediatric Patients: MOLNUPAC 200 has not been studied in paediatric patients.
Renal Impairment: Renal clearance is not a meaningful route of elimination for NHC. No dose adjustment in patients with any degree of renal impairment is needed. In a population PK analysis, mild or moderate renal impairment did not have a meaningful impact on the pharmacokinetics of NHC. The pharmacokinetics of molnupiravir and NHC has not been evaluated in patients with eGFR less than 30 mL/min or on dialysis.
Hepatic Impairment: The pharmacokinetics of molnupiravir and NHC has not been evaluated in patients with hepatic impairment. Preclinical data indicate that hepatic elimination is not expected to be a major route of NHC elimination therefore hepatic impairment is unlikely to affect NHC exposure. No dose adjustment in patients with hepatic impairment is needed.