Foscarnet penetrates the blood-brain barrier: rationale for therapy of cytomegalovirus encephalitis

Abstract

Foscarnet (phosphonoformate) is a potent virustatic drug against herpes-like viruses and is widely used in the therapy of cytomegalovirus infections in immunosuppressed patients. To obtain data on its penetration across the blood-brain barrier, we determined concentrations of foscarnet in cerebrospinal fluid and in plasma specimens from 26 patients with human immunodeficiency virus (stages 2 to 6 by Walter Reed Army Institute of Research classification) after a single infusion of 90 mg of foscarnet per kg of body weight and at steady state by electrochemical detection by high-pressure liquid chromatography. Penetration coefficients were correlated with the integrity of the blood-brain barrier. After a single infusion of foscarnet, levels in plasma ranged from 297 to 1,775 ,i.g/ml (990 to 5,920 ,umol/liter), with a mean of 766 + 400 ,ug/ml. Corresponding levels in cerebrospinal fluid were 57 to 225 ,ug/ml (190 to 750 ,umol/liter), with a mean of 131 + 52 ,ug/ml. The penetration coefficient was 0.05 to 0.72 (mean, 0.23 + 0.16). At steady state, mean foscarnet levels in plasma were 464 + 219 ,ug/ml (1,553 ,umollliter) and mean levels in cerebrospinal fluid were 308 ± 155 ,ug/ml (1,023 ,umol/liter). The penetration coefficient was 0.66 ± 0.11. Although penetration coefficients were highly variable after a single administration and at steady state, the concentrations of foscarnet attained in cerebrospinal fluid are sufficient for complete inhibition of cytomegalovirus replication in vitro. In conclusion, we show that foscarnet seems to be the drug of choice for the treatment of cytomegalovirus encephalitis, because it penetrates the blood-brain barrier and is found in the cerebrospinal fluid in virustatic concentrations. Foscarnet might be considered for additive therapy for human immunodeficiency virus encephalitis in combination with zidovudine or dideoxyinosine.

Cytomegalovirus Ventriculoencephalitis in a Bone Marrow Transplant Recipient Receiving Antiviral Maintenance: Clinical and Molecular Evidence of Drug Resistance

“…Inefficient penetration of ganciclovir and foscarnet into the brain may not be sufficient to suppress viral replication completely and may lead to viral resistance and progression of disease [1,10,13,14]. Varying concentrations of ganciclovir and foscarnet in CSF have been demonstrated in adult patients [16,17]. Pharmacokinetic profiles in children are not known.…”

Focal Neurological Disease in Patients with Acquired Immunodeficiency Syndrome

“…Ganciclovir, the mainstay of treatment for CMV retinitis, reaches lower concentrations in the CSF and brain than it does in serum [79,87], and it is associated with poor responses [75,85]. Foscarnet, a pyrophosphate analogue with better CSF penetration, is synergistic with ganciclovir and has been used to treat retinitis and polyradiculopathy [79,[88][89][90][91][92]. An open-label study of combined foscarnet-ganciclovir therapy in 31 patients with neurological CMV disease revealed a median duration of survival of 94 days, compared with 42 days for a group of historical controls who had mostly received CMV monotherapy [74,77].…”

Relevance of clinical and laboratory findings in the diagnosis of cytomegalovirus encephalitis in patients with AIDS

“…The prognosis of patients with an ante mortem diagnosis of encephalitis is poor, as already reported (14,18,30), probably because the treatment with ganciclovir can reduce, but not suppress, viral replication in CMV encephalitis (33). Both ganciclovir and foscarnet can penetrate the blood-brain barrier, but their concentrations in CSF are either lower than those in blood or highly variable (19,(34)(35)(36)(37). This could render the standard doses ineffective during CMV encephalitis.…”