Background and Objective <p>Acyclovir is a primary treatment for central nervous system (CNS) infections caused by herpes simplex virus (HSV) and varicella-zoster virus (VZV). However, patient outcomes remain suboptimal, despite acyclovir treatment. Given the lack of alternative therapies, there is a pressing clinical need to revisit acyclovir dosing for viral encephalitis. This study aimed to evaluate current and alternative acyclovir dosing regimens using a Bayesian CNS physiologically based pharmacokinetic (PBPK) modeling approach.</p> Method <p>A full Bayesian analysis was performed using LeiCNS3.0 model to describe acyclovir’s CNS distribution. Simulations were performed for standard dosing (10 mg/kg TID) and various alternative dosing regimens. Drug efficacy was evaluated using 50%fT &gt; IC₅₀ (50% of the dosing interval with drug concentration above IC₅₀) and C_min &gt; IC₅₀ (minimum concentration of the drug exceeding IC₅₀). A toxicity threshold of 25 mg/L for plasma peak concentration was applied.</p> Results <p>The standard regimen (10 mg/kg TID) achieved the 50%fT &gt; IC₅₀ target but failed to consistently meet the C_min &gt; IC₅₀ target, particularly for VZV. Alternative regimens of increasing the dosing frequency to QID or extending infusion durations to 1.5 h or 2 h improved efficacy while maintaining safety. Prolonged infusion durations reduced peak plasma concentration thus lowered toxicity risks</p> Conclusions <p>The Bayesian CNS PBPK modeling approach demonstrated robust predictive capacity for CNS PK. Current acyclovir dosing regimens may be inadequate for treating HSV and VZV encephalitis. Alternative dosing strategies involving increased frequency or extended infusion durations appear more effective and safer. Future efforts should focus on refining the PK/pharmacodynamic (PD) relationship between acyclovir exposure and antiviral efficacy to improve therapeutic outcomes.</p>