Intravitreal, retinal, and central nervous system foscarnet concentrations after rapid intravenous administration to rabbits.

Retinal, vitreous humor, brain, and cerebrospinal fluid (CSF) foscarnet levels were measured by high-performance liquid chromatography after administration of an intravenous dose of 120 mg/kg of body weight to 32 pigmented rabbits. A pharmacokinetic analysis was done using a two-compartment model. The penetration ratios, defined as ratios of retinal, vitreous humor, brain, and CSF areas under the concentration-time curve from 0 to 2 h were 110% +/- 1%, 12.3% +/- 0.7%, 118% +/- 1%, and 20.2% +/- 2.2%, respectively. These results suggest a good penetration of foscarnet into the retinal and brain tissues, reaching higher concentrations than those estimated from vitreous humor and CSF levels.

Penetration of foscarnet into cerebrospinal fluid of AIDS patients.

The diffusion of foscarnet into cerebrospinal fluid (CSF) was studied in 27 patients with AIDS. Foscarnet was administered intravenously at various dosages at 12-h intervals. Concentrations in plasma and CSF at the end of foscarnet infusion or 1, 3, 5, 6, and 12 h after infusion were determined by high-performance liquid chromatography. Thirty-seven samples were obtained. The median concentration of foscarnet in CSF was 80 mumol/liter (range, 0 to 500 mumol/liter). The CSF foscarnet concentration was greater than the 50% inhibitory concentration for human immunodeficiency virus type 1 and was equal to or greater than the 50% inhibitory concentration for cytomegalovirus in most cases. The penetration of foscarnet into CSF, as expressed by the ratio of the concentration in CSF to the simultaneous concentration in plasma, ranged from 0 to 3.4 (median, 0.27) and was highly correlated with the presence of cells within CSF and the length of foscarnet therapy. Good diffusion of foscarnet in CSF allows evaluation of this drug in central nervous system cytomegalovirus and human immunodeficiency virus infections in patients with AIDS.

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

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 micrograms/ml (990 to 5,920 mumol/liter), with a mean of 766 +/- 400 micrograms/ml. Corresponding levels in cerebrospinal fluid were 57 to 225 micrograms/ml (190 to 750 mumol/liter), with a mean of 131 +/- 52 micrograms/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 micrograms/ml (1,553 mumol/liter) and mean levels in cerebrospinal fluid were 308 +/- 155 micrograms/ml (1,023 mumol/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.