Distribution of ganciclovir in the porcine central nervous system

Abstract

Ganciclovir is often used compassionately for encephalitis due to cytomegalovirus (CMV) and human herpes virus 6b (HHV-6b). Ganciclovir pharmacokinetic studies in the central nervous system (CNS) generally rely on single measurements in the cerebrospinal fluid (CSF) or homogenized brain tissue. Therefore the objective was to compare brain extracellular fluid (ECF) concentrations of ganciclovir with plasma and CSF concentrations in a porcine model, using microdialysis during a 24 h period. Six Danish landrace pigs (female, age 4 months, 31-37 kg) received two weight-adjusted intravenous doses of ganciclovir. Unbound ganciclovir concentrations were determined by microdialysis over 24 h in five compartments: CSF (lateral ventricle, cisterna magna, and lumbar) and brain ECF (cortical and subcortical). Data were compared with paired plasma samples. Ganciclovir concentrations >IC₅₀ for CMV (1.6 µg/mL) were achieved in all compartments. Concentrations >IC₉₀ for CMV (8.3 µg/mL) were only achieved in plasma and the lumbar CSF compartment. The concentration time curves indicated higher lumbar and cisternal CSF concentrations than ECF concentrations. The ECF compartments achieved greater maximum concentration (C_max), area under the concentration time curve (AUC), and time >IC₅₀ after the second dose, and an accumulation ratio (R_ac) >1. The greater C_max, AUC, time >IC₅₀, and R_ac >1 in the ECF compartments with repeated dosages suggest that therapeutic concentrations may be achieved during long-term treatment. A higher loading dose might be warranted to improve early viral inhibition.

Keywords: CNS; animal models; antiviral agents; antiviral pharmacology; ganciclovir; microdialysis; pharmacokinetics.

Fig 1

Median concentrations in plasma, ventricular CSF, lumbar CSF, cisternal CSF, cortical ECF, and subcortical ECF in healthy adult pigs after two intravenous bolus infusions of 5 mg/kg ganciclovir at an interval of 12 h. IC₅₀ is defined as 1.6 µg/mL and IC₉₀ is defined as 8.3 µg/mL.