Treatment of FeLV-induced immunodeficiency syndrome (FeLV-FAIDS) with controlled release capsular implantation of 2′,3′-dideoxycytidine

Abstract

2′,3′-dideoxycytidine (ddC) inhibits replication of the immunodeficiency inducing strain of feline leukemia virus (FeLV-FAIDS) in vitro at concentrations ranging from 1–10 μg/ml. Additive antiviral effect is achieved when ddC is combined with either human recombinant alpha interferon (IFNα) or tumor necrosis factor (TNF) plus IFNα. Initial in vivo pharmacokinetic studies in cats, utilizing bolus intravenous administration of ddC (20 mg/kg), resulted in peak plasma concentrations of 15 μg/ml 1 min after administration and a half-life of approximately 1 h. These values could not be augmented with high levels of the deaminase blocker tetrahydrouridine administered prior to or concurrently with ddC. In vivo trials utilizing multiple, daily intravenous injections of ddC could not prevent the development of persistent viremia in cats infected with FeLV-FAIDS. To enhance ddC pharmacokinetics and antiviral activity, controlled release capsular implants were developed by blending ddC with a copolymer consisting of DL-lactide glycolide and hydroxypropyl cellulose, which was melt-spun into fibers and encapsulated in a sheath of polyethylene glycol for subcutaneous implantation. Pharmacokinetic studies, conducted in cats receiving an average dose of 600 mg of ddC, indicated an average peak plasma concentration of 17 μg/ml achieved at 6 h post implantation with 3.5 μg/ml noted at 48 h; and an extension of plasma half-life from 1.5 (bolus subcutaneous injection) to 20 h. Sustained plasma concentrations of 1.5 to 10 μg/ml, equivalent to ddC levels previously shown to have anti-FeLV activity in vitro, were maintained throughout a 72 h period. Implantation devices could be replenished every 48 h and elevated plasma levels were sustained for four weeks without signs of clinical toxicity, sepsis or significant alterations in the hemogram. Initial clinical trials employing controlled release capsular ddC implants in vivo indicate significant retardation of FeLV-FAIDS replication throughout a four week treatment period.