Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates

Purpose: The antiviral nucleoside analogue ganciclovir is a potent inhibito r of replication in herpes viruses and is effective against cytomegalovirus infections in immunocompremised patients. Ganciclovir is also used in canc er gene therapy studies that utilize the herpes simplex virus thymidine kin ase gene (HSV-TK). The pharmacokinetics of ganciclovir in adults and childr en have been described previously but there are no detailed studies of the CNS pharmacology of ganciclovir. We studied the pharmacokinetics of gancicl ovir in plasma and CSF in a nonhuman primate model that is highly predictiv e of the CSF penetration of drugs in humans, Methods: Ganciclovir, 10 mg/kg i.v., was administered over 30 min to three animals. Ganciclovir concentra tions in plasma and CSF were measured using reverse-phase HPLC, Results: Pe ak plasma ganciclovir concentrations ranged from 18.3 to 20.0 mu g/ ml and the mean plasma AUC was 1075 +/- 202 mu g/ ml min. Disappearance of gancicl ovir from the plasma was biexpenential 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 (Cl-TB) was 9.4 +/- 1.6 ml/min/kg. The mean C SF ganciclovir AUC was 168 +/- 83 mu g/ml . min and the mean peak CSF conce ntration was 0.7 +/- 0.3 mu g/ml. The ratio of the AUCs in CSF and plasma w as 15.5 +/- 7.1%. Conclusions: Ganciclovir penetrates into the CSF followin g i.v. administration. This finding will be useful in the design of gene th erapy trials involving the HSV-TK gene followed by treatment with ganciclov ir in CNS or leptomeningeal tumors.