Revisiting Acyclovir Dosing for Adult Viral Encephalitis Using a Full Bayesian LeiCNS PBPK Modeling Approach

Figures

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  Fig. 1. Overview of the approaches. μ and Ʃ2, the mean and the variance of the selected parameter; 50%fT > IC50, drug concentrations at the steady state > IC50 for 12 h during 24 h treatment; Cmin > IC50, drug trough concentration at the steady state during the whole treatment; MCMC, Markov chain Monte Carlo; PTA, probability of drug target attainment.

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  Fig 2. Posterior predictive check (PPC) for the Bayesian LeiCNS3.0 model. Simulated acyclovir data over time in plasma and brain subarachnoid space (SAS) are shown (line, median; middle band color, 50% interval; outer band, 95% interval) against the observations (dots, mean values).

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  Fig. 3. Simulated acyclovir concentrations over time in different compartments [plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS)] for the standard dosing regimen of 10 mg/kg administered three times daily (TID). The solid lines represent median predicted concentrations, with the shaded areas indicating the 95% confidence intervals. The area under the curve over 8 h (AUCτ), the median maximum concentration at the steady state (Cssmax), the median trough concentration (Cssmin), and the median half-life (t1/2) were calculated on the basis of predicted concentrations in each compartment.

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  Fig. 4. A Probability of target attainment (PTA) of acyclovir in treating herpes simplex virus (HSV) and varicella-zoster virus (VZV) in plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS) at different doses (10 mg/kg, 15 mg/kg, 20 mg/kg) and dosing frequencies (TID: three times per day; QID: four times per day). The red dashed line marks the PTA of 90%, the threshold defined to indicate adequate acyclovir dose regimens. B Simulated plasma concentrations of acyclovir over time for different dose regimens (15–20 mg/kg with TID or QID dosing). The solid line represents the median value of predicted concentration, with the shaded area representing the 95% confidence interval. The red dashed line represents the threshold concentration (25 mg/L or 50 mg/L) associated with side effects.

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  Fig. 5. A Probability of target attainment (PTA) for acyclovir against herpes simplex virus (HSV) and varicella-zoster virus (VZV) across plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS), assessed at varying infusion durations (1, 1.5, and 2 h) and dosing frequencies (TID: three times daily; QID: four times per day) under the higher dose of 20 mg/kg. The horizontal red dashed line indicates a PTA threshold of 90%. B Simulated concentration–time profiles of acyclovir in plasma under different infusion durations (1, 1.5, and 2 h) and dosing frequencies (TID and QID) under the higher dose of 20 mg/kg. Solid lines represent median predicted concentrations, while shaded areas indicate the 95% confidence intervals of predictions. The horizontal red dashed line indicates the concentration threshold (25 mg/L or 50 mg/L) linked with adverse events