The 14-day repeated-dose toxicity studies of a fixed-dose combination, QXOH/levobupivacaine, via subcutaneous injection in mice.

Abstract

QXOH-LB, a fixed-dose combination (35 mM QXOH and 10 mM levobupivacaine) has been shown to induce a long duration of local anesthesia in animal efficacy testing, which indicates potential for postoperative pain management. In this study, we evaluated the potential toxicity of QXOH-LB in NIH mice under the Guidance on the repeated-dose toxicity published by the China Food and Drug Administration. Mice (n = 30 per sex per group) were subcutaneously injected 5, 10, 20 mg/kg QXOH-LB, 5, 10, 20 mg/kg QXOH, and 5mg/kg levobupivacaine (LB) once a day for 14 days with sacrifice of main study animals; remaining mice (n = 10 per sex per group) were monitored for an additional 4-week recovery period. Mice in the 10 and 20 mg/kg QXOH, and 20 mg/kg QXOH-LB died, which was considered due to excessive respiratory inhibition. The doses of 10mg/kg QXOH-LB and 5mg/kg QXOH were well tolerated without any clinical signs of toxicity. Therefore, the no-observed-adverse-effect level (NOAEL) of QXOH-LB and QXOH was considered to be 10 and 5mg/kg/day, respectively. In the dose range from 5 to 20 mg/kg, the exposure of QXOH and LB in QXOH-LB was equal to each agent used alone at the same dose in NIH mice. There was no gender difference on exposure and no evidence of accumulation.