Revisiting Acyclovir Dosing for Adult Viral Encephalitis Using a Full Bayesian LeiCNS PBPK Modeling Approach
Clinical Pharmacokinetics, vol. 64, pp. 1413–1423
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, 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. 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 > IC 50 (50% of the dosing interval with drug concentration above IC 50 ) and C min > IC 50 (minimum concentration of the drug exceeding IC 50 ). A toxicity threshold of 25 mg/L for plasma peak concentration was applied. The standard regimen (10 mg/kg TID) achieved the 50%fT > IC 50 target but failed to consistently meet the C min > IC 50 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 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.
Authors 6
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Leiden University · European Society of Clinical Microbiology and Infectious Diseases
Affiliation as printed
ESCMID Study Group for Infectious Diseases of the Brain (ESGIB), Basel, Switzerland
Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
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Affiliation as printed
Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
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Anne‐Grete Märtson Aachen Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
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Aalborg University Hospital · European Society of Clinical Microbiology and Infectious Diseases · Aalborg University
Affiliation as printed
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark
ESCMID Study Group for Infectious Diseases of the Brain (ESGIB), Basel, Switzerland
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Elizabeth C. M. de Lange Aachen Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Affiliation as printed
Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
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Tingjie Guo corresponding Aachen Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research
Leiden University · European Society of Clinical Microbiology and Infectious Diseases
Affiliation as printed
ESCMID Study Group for Infectious Diseases of the Brain (ESGIB), Basel, Switzerland. t.guo@lacdr.leidenuniv.nl
Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands. t.guo@lacdr.leidenuniv.nl
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