Drug Jelly Dosage as an Alternative to Gavage for Long-Term Oral Drug Administration in Rhesus Monkeys

Abstract

Introduction: Rhesus monkeys are often used as recipients in preclinical transplantation studies. The long-term oral administration of immunosuppressive agents to transplanted rhesus monkeys is one of the major challenges in such studies. Gavage, a frequently employed method, has the disadvantage of producing stress in restrained animals. To avoid this problem, we tested an alternative method for oral dosing of sirolimus (SRL) in rhesus monkeys. Methods: An oral solution of SRL was mixed with gelatin stock at 45°C and then cooled to 4°C to form a jelly dosage. Animal behavior of jelly dosing technique and gavage dosing technique was observed, the oral bioequivalence of these two dosage forms was evaluated, and the whole blood levels of SRL for long-term drug delivery were assayed. For the bioequivalence study, 4 rhesus monkeys were enrolled in a two-phase randomized crossover design. In each phase, the animals received SLR oral solution or jelly at a dosage of 0.6 mg/kg. 10 monkeys were then given either SRL oral solution or jelly for one month at a dosage of 0.2 mg/kg/day. After the administration, whole blood SRL concentrations were measured by high-performance liquid chromatography assay (HPLC). Results: The jelly dosing technique appears to enhance the compliance of the animals to gavage, and all the animals in the SRL jelly group learned to voluntarily consume the jelly after a short period of training. The jelly dosage form of SRL displayed sustained release and bioequivalence to the oral solution. The SRL whole blood level for long-term drug delivery was 2.97±1.91 ng/mL in the jelly group and 3.13±2.03 ng/mL in the oral solution group. The difference between these two means was not significant.[Figure 1][Figure 2]Conclusion: The jelly dosing technique described here is convenient and effective for oral administration of SRL in rhesus monkeys and may be adapted for administration of other drugs.