Distribution of acyclovir in central nervous system compartments: a porcine pharmacokinetic model

Herpes simplex virus (HSV) encephalitis is a severe infection with high mortality and neurological sequelae if untreated. Intravenous acyclovir (ACV) is the standard treatment, but its central nervous system (CNS) penetration is not fully understood. To evaluate the distribution of ACV in various CNS compartments in a porcine pharmacokinetic model, 12 female pigs were divided into two groups: group I receiving a single ACV dose (10 mg/kg) and group II receiving three doses over 24 h. Microdialysis sampled unbound ACV concentrations in cortical and subcortical extracellular fluid (ECF), ventricular cerebrospinal fluid (CSF), and cisternal CSF. The ACV target concentration was defined as peak concentration (fC_max)  > inhibitory concentration 50% (IC₅₀) for HSV-1 at 0.56 µg/mL. Pharmacokinetic parameters, including fC_max, time above IC₅₀ (T > IC₅₀), and area under the curve (AUC), were analyzed. The target ACV concentration (fC_max > 0.56 µg/mL) was achieved in all ECF and CSF compartments during the second and third dosing intervals. The T > IC₅₀ and AUC increased from the first to the third dose and were consistent across compartments. Intracerebral penetration ratios (fAUC_tissue/fAUC_plasma) during the third dose ranged from 0.18 to 0.32 within the CNS compartments. In conclusion, ACV administered intravenously at 10 mg/kg every eighth hour achieved therapeutic levels in porcine CNS compartments after the second dose, suggesting that current dosing regimens are effective in treating HSV encephalitis. However, the first dose may not reach therapeutic levels, suggesting that higher initial dosages or prolonged infusions should be considered. Further studies under inflammatory conditions are warranted to extrapolate these findings.