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Favipiravir causes mutagenesis in RNA viruses, and it is currently unknown whether it may have a measurable effect on the virus in humans. In this study, we report the secondary endpoints from the phase 2a randomized, double\u2010blind, 2\u2009\u00d7\u20092 factorial placebo\u2010controlled FLARE trial, which studied the combination of favipiravir and lopinavir\u2013ritonavir.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Population pharmacokinetic and viral dynamic models including data from 59 and 235 participants respectively were developed to assess the drug effect of favipiravir in combination with lopinavir\u2013ritonavir. Viral whole\u2010genome sequencing was performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The final joint model consisted of a slope\u2013intercept exponential decay viral dynamic model and a one\u2010compartment model with first\u2010order absorption and elimination for favipiravir pharmacokinetics. The mean death rate of infected cells (\n                      <jats:italic>\u03b4<\/jats:italic>\n                      ) was 0.96\u2009day\n                      <jats:sup>\u22121<\/jats:sup>\n                      . Favipiravir mean apparent clearance (\n                      <jats:italic>CL<\/jats:italic>\n                      \/\n                      <jats:italic>F<\/jats:italic>\n                      ) and mean apparent volume of distribution were 1.73\u2009L\/h and 22.1\u2009L, respectively. Favipiravir co\u2010administration with lopinavir\u2013ritonavir increased\n                      <jats:italic>CL<\/jats:italic>\n                      \/\n                      <jats:italic>F<\/jats:italic>\n                      by twofold, representing an unexpected drug\u2013drug interaction. Favipiravir and lopinavir\u2013ritonavir drug effects on\n                      <jats:italic>\u03b4<\/jats:italic>\n                      did not improve model fit in the final joint model, indicating that neither drug has any antiviral effect against SARS\u2010CoV\u20102. Viral sequencing did not show a clear mutagenic signature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that favipiravir does not have antiviral activity at the dose used in our study, and further work to understand the mechanistic basis of the drug\u2013drug interaction with lopinavir\u2013ritonavir is required.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70507","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T10:05:50Z","timestamp":1774260350000},"page":"2390-2402","source":"Crossref","is-referenced-by-count":1,"title":["Population pharmacokinetic\/pharmacodynamic modelling to evaluate favipiravir in combination with lopinavir\u2013ritonavir in patients with 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