Intravitreal, Retinal, and Central Nervous System Foscarnet Concentrations after Rapid Intravenous Administration to Rabbits

Abstract

Retinal, vitreous humor, brain, and cerebrospinal fluid (CSF) foscarnet levels were measured by highperformance 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.Foscarnet is a drug used extensively in the treatment of retinitis and neurological conditions caused by cytomegalovirus (CMV) in patients with AIDS, and there are data supporting the use of foscarnet with aciclovir or ganciclovir in the treatment of retinitis caused by other herpesviruses (4,15,19). It has been suggested that intravenous ganciclovir or foscarnet maintenance therapy of CMV retinitis may result in subtherapeutic intraocular concentrations, a factor implicated in the progression of this disease (1). However, there are few data on concentrations of foscarnet in tissue, and the levels in retina or brain have not been described for either humans or experimental models. The intraocular penetration of foscarnet has been assessed only in vitreal samples from a few patients with CMV retinitis (1). Likewise, the penetration of foscarnet into the central nervous system has been evaluated only from single determinations in cerebrospinal fluid (CSF) and single ratios of concentrations in CSF to concentrations in plasma in samples obtained at variable and arbitrary intervals from patients with nonuniform dosages. Consequently, the results have been very variable, 13 to 340% of the simultaneous concentration in plasma (11,(21)(22)(23). Moreover, to assume that retinal and brain foscarnet levels are similar to those measured in vitreous humor and CSF may be erroneous. Due to the difficulties in obtaining tissue samples from humans, we used a rabbit model for evaluating the retinal and brain penetration of foscarnet after its intravenous administration. The ratios of the areas under the concentration-time curve (AUCs) for tissues and CSF to the AUCs for serum were used to obtain more accurate results (16). We have also determined whether the concentrations detected in retina and brain are similar to those in vitreous humor and CSF. In humans, no significant differences were observed in plasma concentrations between single-and multiple-dose administration (25); therefore, the study was designed to obtain samples after a single dose of the drug.Study design, drug administration, and sampling. Thirtytwo healthy, pigmented rabbits with a mean weight of 3 kg were used. The study was conducted according to the Ministerio de Agricultura guidelines. After animals were anesthetized with an intramuscular injection of xylazine (12 mg/kg of body wei...

Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development

“…34 V ss, ivt and CL ivt values were determined from the available literature on intravitreal drug administra- 35 tion using compartmental models and curve fitting. A simple QSPR model for CL ivt of small molecular 36 weight compounds was obtained with two descriptors: Log D 7.4 and hydrogen bond donor capacity.…”

Efeitos do Foscarnet sobre a infecção pelos herpesvírus bovino tipos 1 e 5 em coelhos

“…A redução nos índices de morbidade e mortalidade pelo tratamento com PFA nos coelhos inoculados com o BoHV-5 pode também ter sido influenciada pela interferência do fármaco com a replicação do vírus no encéfalo. Estudos anteriores demonstraram que o PFA apresenta uma boa penetração no líquor, atingindo concentrações considerá-veis no SNC de coelhos (López-Cortés et al 2000). Portanto, além de restringir a replicação viral no sítio de entrada, é possível que o fármaco tenha reduzido os níveis da replicação da população de vírus que invadiu o encéfalo, reduzindo assim a carga e disseminação viral no tecido nervoso.…”

Factors affecting delivery of antiviral drugs to the brain

“…The drug is negatively charged and its experimental partition coefficient measured at physiological pH is not known. Human trials [63] and animal experiments [64] have shown that foscarnet reaches the CSF to some extent, and this drug has also been shown to cross the BBB easily in animals. Following a single i.v.…”