Optimization of antiviral dosing in Herpesviridae encephalitis: a promising approach to improve outcome?

Abstract

Despite established antiviral therapy for herpes simplex (HSV), varicella zoster (VZV) and cytomegalovirus (CMV) encephalitis, outcome remains poor. To assess pharmacokinetic (PK) and -dynamic (PD) data of antiviral drugs in the central nervous system (CNS) to optimize treatment of Herpesviridae encephalitis. PUBMED search 1950 to September 2024, terms 1. "encephalitis" and ("HSV" or "VZV" or "CMV") or 2. cerebrospinal and ["(val)acyclovir" or "(val)ganciclovir" or "foscarnet" or "cidofovir"]. Antivirals against herpes viruses apparently act in a time-dependent manner. To suppress viral replication, drug concentration in the extracellular space at the site of the infection should be kept above the concentrations active in cell cultures for 24h per day. Most data reflect delayed drug entry into lumbar cerebrospinal fluid (CSF). Ratios of the areas of the concentration/time curves (AUC) in CSF and serum (AUCCSF/AUCS) of acyclovir, ganciclovir and foscarnet are 0.15-0.3 in the absence of meningeal inflammation and increase in severe meningoencephalitis. Elimination half-lives (t1/2β) are longer in CSF than in plasma. CSF concentrations are rough approximations of drug concentrations in the cerebral extracellular fluid (ECF). Lumbar CSF concentrations usually are higher than ventricular or cisternal CSF concentrations tending to overestimate cerebral ECF concentrations. Provided the availability of adequate measurements in individual CNS compartments - antiviral concentrations and efficacy may be predicted by future PK/PD modeling. Probenecid holds potential to reduce efflux of antiviral drugs from the CNS. The long t1/2β of antiviral drugs in CSF suggest relatively uniform steady state CSF levels at dosing intervals ≤12h and accumulation after repeated dosing. Probenecid is of unproven utility. To rapidly attain effective concentrations in the infected tissue, physiologically based pharmacokinetic (PBPK) and PK/PD modeling may be helpful. Until reliable PK/PD data are available, doubling the first dose should be considered.