tetano
Editor, Senior Moderator
Clin Transl Sci
. 2025 Apr;18(4):e70184.
doi: 10.1111/cts.70184. Comparison of Molnupiravir Exposure-Response Relationships for Virology Response and Mechanism of Action Biomarkers With Clinical Outcomes in Treatment of COVID-19
Akshita Chawla[SUP] 1 [/SUP], Ruthie Birger[SUP] 1 [/SUP], Brian M Maas[SUP] 1 [/SUP], Youfang Cao[SUP] 1 [/SUP], Hong Wan[SUP] 1 [/SUP], Julie Strizki[SUP] 1 [/SUP], Arthur Fridman[SUP] 1 [/SUP], Amanda Paschke[SUP] 1 [/SUP], Carisa de Anda[SUP] 1 [/SUP], Wei Gao[SUP] 1 [/SUP], Matthew L Rizk[SUP] 1 [/SUP], Wendy Painter[SUP] 2 [/SUP], Wayne Holman[SUP] 2 [/SUP], Susanne Sardella[SUP] 3 [/SUP], George Painter[SUP] 4 [/SUP], Julie A Stone[SUP] 1 [/SUP]
Affiliations
Molnupiravir, an orally administered drug for the treatment of mild-to-moderate COVID-19, is a prodrug of the ribonucleoside β-D-N4-hydroxycytidine (NHC). NHC incorporation in the SARS-CoV-2 RNA strand causes an accumulation of deleterious errors in the genome, resulting in reduced viral infectivity and replication. Exposure-response (E-R) analyses for viral RNA mutation rate and virologic outcomes were conducted using data from three phase 2/3 studies of molnupiravir (P006, MOVe-IN, and MOVe-OUT). Three dose levels (200, 400, and 800 mg every 12 hours [Q12H]) and placebo were evaluated. E-R datasets were generated for SARS-CoV-2 RNA mutation and longitudinal SARS-CoV-2 RNA viral load. E-R models were defined for RNA mutation rate and viral load change from baseline at days 5 and 10. The models supported plasma NHC AUC[SUB]0-12[/SUB] as the appropriate pharmacokinetic driver for assessing E-R relationships. The highest percentage of participants with > 20 low-frequency nucleotide substitutions (LNS) per 10,000 bases, a measure of likely meaningful drug effect, was predicted in the 800 mg Q12H treatment group. A strong drug effect on the reduction of viral load was observed on days 5 and 10. E-R relationships were best represented by an E[SUB]max[/SUB] structural model with reasonable consistency in the estimated AUC[SUB]50[/SUB]s (~2.3-fold), across the models, of 10,260 and 4390 nM*hr. for day 5 viral load change from baseline and LNS error rate, respectively. These biomarker E-R curves support the choice of 800 mg Q12H as providing near-maximal drug effect, consistent with findings from the previously published molnupiravir E-R model of clinical outcomes.
Keywords: NHC; SARS‐CoV‐2; exposure‐response; low‐frequency nucleotide substitutions; pharmacokinetics‐pharmacodynamics; viral load; virologic outcomes; β‐D‐N4‐hydroxycytidine.
. 2025 Apr;18(4):e70184.
doi: 10.1111/cts.70184. Comparison of Molnupiravir Exposure-Response Relationships for Virology Response and Mechanism of Action Biomarkers With Clinical Outcomes in Treatment of COVID-19
Akshita Chawla[SUP] 1 [/SUP], Ruthie Birger[SUP] 1 [/SUP], Brian M Maas[SUP] 1 [/SUP], Youfang Cao[SUP] 1 [/SUP], Hong Wan[SUP] 1 [/SUP], Julie Strizki[SUP] 1 [/SUP], Arthur Fridman[SUP] 1 [/SUP], Amanda Paschke[SUP] 1 [/SUP], Carisa de Anda[SUP] 1 [/SUP], Wei Gao[SUP] 1 [/SUP], Matthew L Rizk[SUP] 1 [/SUP], Wendy Painter[SUP] 2 [/SUP], Wayne Holman[SUP] 2 [/SUP], Susanne Sardella[SUP] 3 [/SUP], George Painter[SUP] 4 [/SUP], Julie A Stone[SUP] 1 [/SUP]
Affiliations
- PMID: 40138219
- DOI: 10.1111/cts.70184
Molnupiravir, an orally administered drug for the treatment of mild-to-moderate COVID-19, is a prodrug of the ribonucleoside β-D-N4-hydroxycytidine (NHC). NHC incorporation in the SARS-CoV-2 RNA strand causes an accumulation of deleterious errors in the genome, resulting in reduced viral infectivity and replication. Exposure-response (E-R) analyses for viral RNA mutation rate and virologic outcomes were conducted using data from three phase 2/3 studies of molnupiravir (P006, MOVe-IN, and MOVe-OUT). Three dose levels (200, 400, and 800 mg every 12 hours [Q12H]) and placebo were evaluated. E-R datasets were generated for SARS-CoV-2 RNA mutation and longitudinal SARS-CoV-2 RNA viral load. E-R models were defined for RNA mutation rate and viral load change from baseline at days 5 and 10. The models supported plasma NHC AUC[SUB]0-12[/SUB] as the appropriate pharmacokinetic driver for assessing E-R relationships. The highest percentage of participants with > 20 low-frequency nucleotide substitutions (LNS) per 10,000 bases, a measure of likely meaningful drug effect, was predicted in the 800 mg Q12H treatment group. A strong drug effect on the reduction of viral load was observed on days 5 and 10. E-R relationships were best represented by an E[SUB]max[/SUB] structural model with reasonable consistency in the estimated AUC[SUB]50[/SUB]s (~2.3-fold), across the models, of 10,260 and 4390 nM*hr. for day 5 viral load change from baseline and LNS error rate, respectively. These biomarker E-R curves support the choice of 800 mg Q12H as providing near-maximal drug effect, consistent with findings from the previously published molnupiravir E-R model of clinical outcomes.
Keywords: NHC; SARS‐CoV‐2; exposure‐response; low‐frequency nucleotide substitutions; pharmacokinetics‐pharmacodynamics; viral load; virologic outcomes; β‐D‐N4‐hydroxycytidine.