Purpose: The antiviral nucleoside analogue ganciclovir is a potent inhibitor of replication in herpes viruses and is effective against cytomegalovirus infections in immunocompromised patients. Ganciclovir is also used in cancer gene therapy studies that utilize the herpes simplex virus thymidine kinase gene (HSV-TK). The pharmacokinetics of ganciclovir in adults and children have been described previously but there are no detailed studies of the CNS pharmacology of ganciclovir. We studied the pharmacokinetics of ganciclovir in plasma and CSF in a nonhuman primate model that is highly predictive of the CSF penetration of drugs in humans.
Methods: Ganciclovir, 10 mg/kg i.v., was administered over 30 min to three animals. Ganciclovir concentrations in plasma and CSF were measured using reverse-phase HPLC.
Results: Peak plasma ganciclovir concentrations ranged from 18.3 to 20.0 microg/ml and the mean plasma AUC was 1075+/-202 microg/ml x min. Disappearance of ganciclovir from the plasma was biexponential with a distribution half-life (t(1/2)alpha) of 18+/-7 min and an elimination half-life (t(1/2)beta) of 109+/-7 min. Total body clearance (ClTB) was 9.4+/-1.6 ml/min/kg. The mean CSF ganciclovir AUC was 168+/-83 microg/ml x min and the mean peak CSF concentration was 0.7+/-0.3 microg/ml. The ratio of the AUCs in CSF and plasma was 15.5+/-7.1%.
Conclusions: Ganciclovir penetrates into the CSF following i.v. administration. This finding will be useful in the design of gene therapy trials involving the HSV-TK gene followed by treatment with ganciclovir in CNS or leptomeningeal tumors.