Effect of Co-administration of Tacrolimus on the Pharmacokinetics of Multiple Subcutaneous Administered Interferon-Alpha in Rats

Abstract

Intravenous co-administration of tacrolimus (0.001 mg/kg) may be a promising way to assess crossover pharmacokinetic study of human or humanized proteinic formulations with multiple dosing schedules in an experimental animal.

Co-administration of Tacrolimus Suppresses Pharmacokinetic Modulation of Multiple Subcutaneously Administered Human Interferon-alpha in Beagle Dogs

“…3), whereas 0.001 mg/kg was effective in rats in our previous study. 8) Eiras et al 11) reported that tacrolimus shows similar immunosuppressive effects in rat and dog lymphocytes. It is well known that tacrolimus is mainly metabolized by the cytochrome P450 subfamily in the liver.…”

“…We recently reported that co-administration of the immunosuppressant tacrolimus suppressed specific antibody production following multiple administrations of protein-based drug h-IFN in rats. 8) In general, large animal species such as dogs or monkeys, which are close to humans, are used to evaluate the PK profiles of novel drug formulations. In the present study, we therefore extended our previous study to a larger experimen- tal animal, i.e., beagle dogs.…”

“…13) In addition, subcutaneously administered h-IFN was found to be eliminated with relatively longer terminal half-lives of 2.7-4.7 hr in dogs in the present study ( Table 1) compared with 0.9-1.5 hr in rats in our previous study. 8) Taken together, the differences in metabolism of tacrolimus and h-IFN between rats and dogs, rather than the sensitivities of the corresponding T lymphocytes to tacrolimus, may be the major cause of the different immunosuppressive effects of tacrolimus. This suggests that in crossover studies of protein-based formulations, the optimal tacrolimus dosage must be set up in advance according to the species of experimental animal involved.…”

“…21) These findings are consistent with our current study and previous observations. 8) If caused by additives such as solubilizers, severe anaphylaxis-like symptoms may modulate the PK profile of the main drug and thereby the crossover study must be terminated. If the experimental animals show marked reactivity to additives in the formulation, premedication with a steroid, H1-blocker and H2-blocker 22) might be effective for preventing such severe anaphylaxis-like symptoms during the crossover study.…”

“…8) This observation suggests that crossover PK studies of protein-based formulations can be achieved in experimental animal models under the conditions created by co-administration of tacrolimus. For preclinical studies, it is preferable to carry out PK evaluations in larger animals such as dogs and monkeys because these animals can accept the same dosage forms and dosing devices as those required for human use.…”