Revisiting acyclovir dosing for viral encephalitis using a Bayesian PBPK modeling approach

medRxiv

Abstract

Abstract 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 with high mortality and morbidity, following current dosing guidelines. Given the lack of alternative therapies, there is a pressing need to optimize acyclovir dosing, especially since initial regimens were developed in the 1980s with incomplete pharmacokinetic data in the CNS. This study aimed to evaluate both current and alternative acyclovir dosing regimens using a full Bayesian physiologically-based pharmacokinetic (PBPK) model tailored for viral encephalitis. We developed a CNS PBPK model to simulate acyclovir concentrations in plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS). Drug efficacy was assessed using two pharmacokinetic targets, 50% f T>IC 50 and C min >IC 50 , with a safety threshold set at 25 mg/L in plasma. The standard dosing regimen (10 mg/kg TID) yielded sufficient acyclovir exposure in plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS) compartments based on the 50% f T>IC 50 target. However, it did not consistently meet the C min >IC 50 target, indicating potential suboptimal exposure in these compartments when evaluated against this criterion. Notably, a higher probability of target attainment (PTA) was generally observed in the brain ECF and SAS compared to plasma. Increasing the dosing frequency to QID improved target attainment but exceeded the toxicity threshold at 20 mg/kg. Our findings suggest that a dosing regimen of 10 mg/kg or 15 mg/kg QID may offer a more effective and safer approach for managing CNS infections compared to the other tested alternative dosing regimens.

Authors 6

1. Ming Sun Aachen Leiden Academic Centre for Drug Research Systems Pharmacology and Pharmacy

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands;

   Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

2. Martijn L. Manson Aachen Leiden Academic Centre for Drug Research Systems Pharmacology and Pharmacy

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands;

   Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

3. Anne‐Grete Märtson Aachen Leiden Academic Centre for Drug Research Systems Pharmacology and Pharmacy

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands;

   Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

4. Jacob Bodilsen

   Aalborg University Hospital · Aalborg University

   Affiliation as printed

   Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

   Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark

5. Elizabeth C. M. de Lange Aachen Leiden Academic Centre for Drug Research Systems Pharmacology and Pharmacy

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands;

   Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

6. Tingjie Guo corresponding Aachen Leiden Academic Centre for Drug Research Systems Pharmacology and Pharmacy

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands;

   Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands

   Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands