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Factors Influencing COVID-19 Risk: Insights From Molnupiravir Exposure-Response Modeling of Clinical Outcomes.
Chawla, Akshita; Birger, Ruthie; Wan, Hong; Cao, Youfang; Maas, Brian M; Paschke, Amanda; De Anda, Carisa; Rizk, Matthew L; Stone, Julie A.
  • Chawla A; Merck & Co., Inc., Rahway, New Jersey, USA.
  • Birger R; Merck & Co., Inc., Rahway, New Jersey, USA.
  • Wan H; Merck & Co., Inc., Rahway, New Jersey, USA.
  • Cao Y; Merck & Co., Inc., Rahway, New Jersey, USA.
  • Maas BM; Merck & Co., Inc., Rahway, New Jersey, USA.
  • Paschke A; Merck & Co., Inc., Rahway, New Jersey, USA.
  • De Anda C; Merck & Co., Inc., Rahway, New Jersey, USA.
  • Rizk ML; Merck & Co., Inc., Rahway, New Jersey, USA.
  • Stone JA; Merck & Co., Inc., Rahway, New Jersey, USA.
Clin Pharmacol Ther ; 113(6): 1337-1345, 2023 06.
Article in English | MEDLINE | ID: covidwho-2254467
ABSTRACT
Molnupiravir (MOV) is an oral antiviral for the treatment of coronavirus disease 2019 (COVID-19) in outpatient settings. This analysis investigated the relationship between ß-D-N4-hydroxycytidine (NHC) pharmacokinetics and clinical outcomes in patients with mild to moderate COVID-19 in the phase III part of the randomized, double-blind, placebo-controlled MOVe-OUT trial. Logistic regression models of the dependency of outcomes on exposures and covariates were constructed using a multistep process. Influential covariates were identified first using placebo arm data, followed by assessment of exposure-dependency in drug effect using data from both the placebo and MOV arms. The exposure-response (E-R) analysis included 1,313 participants; 630 received MOV and 683 received placebo. Baseline viral load, baseline disease severity, age, weight, viral clade, active cancer, and diabetes were identified as significant determinants of response using placebo data. Absolute measures of viral load on days 5 and 10 were strong on-treatment predictors of hospitalization. An additive area under the curve (AUC)-based maximum effect (Emax ) model with a fixed Hill coefficient of 1 best represented the exposure-dependency in drug effect and the AUC50 was estimated to be 19,900 nM hour. Patients at 800 mg achieved near maximal response, which was larger than for 200 or 400 mg. The final E-R model was externally validated and predicted that the relative reduction in hospitalization with MOV treatment would vary with patient characteristics and factors in the population. In conclusion, the E-R results support the MOV dose of 800 mg twice daily to treat COVID-19. Many patient characteristics and factors impacted outcomes beyond drug exposures.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Humans Language: English Journal: Clin Pharmacol Ther Year: 2023 Document Type: Article Affiliation country: Cpt.2895

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Humans Language: English Journal: Clin Pharmacol Ther Year: 2023 Document Type: Article Affiliation country: Cpt.2895