4-Week repeated dose rat GLP toxicity study of oncolytic ECHO-7 virus Rigvir administered intramuscularly with a 4-week recovery period

The oncolytic ECHO-7 virus Rigvir was registered in Latvia in 2004 and later in Georgia, Armenia and Uzbekistan. No severe adverse events have been observed. During drug development good laboratory practice (GLP) pre-clinical toxicology studies are generally required by regulatory agencies. Since such studies had previously not been performed, the aim of this 4-week repeated dose GLP toxicity study was to determine the potential toxicity, and reversibility of any findings after a 4-week treatment-free period. Han-Wistar rats were randomly assigned to control, Rigvir (2×10(6), 1×10(7) and 2×10(7) TCID(50)) groups. Intramuscular administration was on days 1-3, 8-10, 15-17, and 22-24. Clinical signs, average food-intake, body weights, ophthalmology, clinical pathology parameters, bioanalysis, gross necropsy, organ weights, biodistribution and histopathology were evaluated. There were no unscheduled deaths, adverse clinical signs, no changes in body weight, body weight gain, food intake, ophthalmoscopy, clinical pathology, urine volume or composition, or organ weights. Slightly higher numbers of eosinophils in Rigvir treated animals returned to normal after recovery. Rigvir biodistributed to the spleen. Low incidence of inflammatory cell infiltration at administration sites and increased lymphoid cellularity at the regional (inguinal and popliteal) lymph nodes were observed; after recovery, only those in popliteal lymph nodes remained. Therefore, 4-week Rigvir at 2×10(7) TCID(50) administration was well tolerated in rats. The no-observed-adverse-effect level (NOAEL) was the highest dose tested, 2×10(7) TCID(50). OBJECTIVES: The objectives of this study were to determine the potential toxicity of Rigvir, an ECHO-7 oncolytic virus, when administered intramuscularly for 4 weeks to rats, with a 4-week recovery period, and to evaluate the reversibility of any potential findings. In addition, the biodistribution of Rigvir in selected tissues was determined.