PK/PD parameters, which enable a description of the whole-time course of bacterial kill and growth, can be determined in an in silico model (Nielsen and Friberg, 2013 (link)). Dose fractions of 0, 2.5, 5, 10, 15, 20, and 25 mg/kg for single administration and twice-daily administration were inputted in the PBPK/PD model. Concentration–time curves of ADP and bacterial count–time curves can be simulated. PK/PD parameters (AUC/MIC and %T > MIC) are directly calculated by the PBPK model (Mi et al., 2023 (link)). The cumulative area under the curve of the total bacterial count over 24 h (AUC0-24h (Bacterial count)) was used as a bacteriological effect (Pelligand et al., 2019 (link); Ronaghinia et al., 2021 (link)). PK/PD parameters (AUC/MIC and %T > MIC) versus the bacteriological effect, AUC0-24h (Bacterial count), were fitted with an inhibitory sigmoid model (Eq. 4 ). Curve fitting was performed in Phoenix (version 8.3, Certara, United States), and the best PK/PD parameter related to bacteriological effect was selected.
where E0 was the effect under a drug concentration of zero. The maximum possible observed effect is Imax. INDEX was the value of the PK/PD parameters (AUC24h/MIC or %T > MIC). INDEX50 was the value of AUC24h/MIC or %T > MIC, producing a 50% reduction in Imax, and N was the Hill coefficient that described the steepness of the curve.
where E0 was the effect under a drug concentration of zero. The maximum possible observed effect is Imax. INDEX was the value of the PK/PD parameters (AUC24h/MIC or %T > MIC). INDEX50 was the value of AUC24h/MIC or %T > MIC, producing a 50% reduction in Imax, and N was the Hill coefficient that described the steepness of the curve.
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