TABLE 1

Parameter estimates for the PD mechanism-based mathematical model of favipiravir, interferon alpha, and ribavirin against Zika virus

ParameterSymbol (unit of measure)Population mean estimate (SE [%])CVc of estimate for between-curve variability (SE [%])
PD parameters
    Log10 of 2nd-order infection rate constantkinfect−4.10 (2.39)0.0841 (128b)
    Synthesis rate constant of virusksyn (1/h)9.35 (7.09)0.068 (219)
    Mean delay time until release of virus in the absence of drugTDelay = 5/ktr (h)40.0 (2.56)0.0238 (97)
    Mean survival time of infected cellsMSTInfected = 1/kdeath (h)70.5 (8.92)0.152 (141)
    Mean survival time for extracellular virusMSTVirus = 1/kloss,virus (h)14.3 (10.4)0.172 (112)
    Log10 initial no. of uninfected cellsLog_U6.30 (fixed)0 (fixed)
    Log10 initial no. of infected cellsLog_I3.38 (2.66)0.365 (29)
    Maximum extent of inhibition by FAVImaxFAV (normal scale)0.9999 (∼0.9992–1.00a)0.793a (88.8)
    FAV concn causing 50% ImaxIC50_FAV (μM)41.7 (2.55)0.039 (180)
    Hill coefficient of FAVHillFAV2.79 (4.53)0.1 (fixed)
    Maximum extent of inhibition by RBVImaxRBV (normal scale)0.954 (∼0.924–0.973a)0.44a (120)
    RBV concn causing 50% ImaxIC50_RBV (μg/ml)7.86 (9.99)0.491 (84.3)
    Hill coefficient of RBVHillRBV2.90 (16.5)0.1 (fixed)
    Maximum extent of inhibition by IFNImaxIFN (normal scale)0.99997 (∼0.99990–1.00a)0.859a (62.4)
    IFN concn causing 50% ImaxIC50_IFN (IU/ml)4.12 (15.9)0.131 (383)
    Hill coefficient of IFNHillIFN2.00 (fixed)0.1 (fixed)
    Interaction factor between FAV and RBVPSI = 1 if monotherapy, PSI = SYNANTd if combination therapy1.37 (8.21)0.05 (427)
    Maximum extent of cytotoxicity by RBVMSTTOX = 1/SmaxRBV (h)11.9 (7.21)0.354 (39.3)
    RBV concn causing 50% SmaxSC50_RBV (μg/ml)150 (11.3)0.226 (110)
    Hill coefficient of RBV for toxicityHillRBVTOX (normal scale)4.16 (12.5)0.1 (fixed)
Residual-error parameter
    Additive error for viral load on log10 scaleSDin0.333 (4.67)
  • a Imax was assumed to be normally distributed on a logistically transformed scale (ImaxTransformed). The population mean value of Imax is reported on a normal scale (i.e., from 0 to 1), whereas the between-curve variability is presented as the standard deviation of a normal distribution on a logistically transformed scale.

  • b Between-curve variability was included and required in this population PD model to account for minor biological differences between experimental curves on separate days. The uncertainty (percent standard error) for the estimated between-curve variability tended to be large for some parameters. However, this has only a minor or no effect on the predictive performance of the model, as shown by the NPDE.

  • c CV, coefficient of variation.

  • d SYNANT, synergy or antagonism.