Co-administration of tacrolimus suppresses pharmacokinetic modulation of multiple subcutaneously administered human interferon-alpha in Beagle dogs.
Specific antibody production is an important issue in crossover pharmacokinetic (PK) studies of protein-based formulations. We recently reported that intravenous co-administration of tacrolimus with multiple human interferon-alpha (h-IFN) administrations successfully suppressed the production of anti-h-IFN antibodies in rats. Since crossover PK studies are preferentially carried out using larger animals such as dogs or monkeys that are capable of accepting the same dosage formulations as those for clinical use, we extended our study of co-administration of tacrolimus with multiple h-IFN administrations to beagle dogs in the present study. Beagle dogs were subcutaneously administered 0.5 million IU/kg of h-IFN once a week for 4 weeks. In some experiments, tacrolimus at 0.01 or 0.1 mg/kg was intravenously co-administered at the same time as the h-IFN administration. Co-administration of the lower dose of tacrolimus (0.01 mg/kg) failed to suppress the anti-h-IFN IgG responses, while co-administration of the higher dose (0.1 mg/kg) successfully suppressed these responses. Moreover, co-administration of tacrolimus had little effect on the serum creatinine concentrations, suggesting that multiple administrations of tacrolimus at the concentrations examined did not cause severe renal disorders. Taken together, the present data confirm that co-administration of tacrolimus is a promising way to assess crossover PK studies of human or humanized proteinic formulations in beagle dogs.
Yamazaki
Hiroyuki
H
Department of Pharmacokinetics and Biopharmaceutics, Institute of Health Biosciences, The University of Tokushima.
Miyake
Masateru
M
Kamada
Naoki
N
Nishibayashi
Toru
T
Mukai
Tadashi
T
Odomi
Masaaki
M
Ishida
Tatsuhiro
T
Kiwada
Hiroshi
H
D000818:Animals; D004285:Dogs; D004347:Drug Interactions; D006801:Humans; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*
D016898:Interferon-alpha; D016559:Tacrolimus