Effect of co-administration of tacrolimus on the pharmacokinetics of multiple subcutaneous administered interferon-alpha in rats.
OBJECTIVE
Repeated administration of exogenous proteinic compounds triggers the production of specific antibodies. This reaction is limits not only pharmacokinetic studies in animal but also development of human or humanized proteins as drugs. We investigated the effect of co-administration of tacrolimus on pharmacokinetic of human interferon-alpha (h-IFN) following multiple subcutaneous administration in rats.


METHODS
h-IFN was administered at a dose of 5 million IU/kg. For some experiments, tacrolimus was also either subcutaneously or intravenously injected in rats at a dose of 0.001 or 0.5 mg/kg as well as with administration of h-IFN.


RESULTS
Multiple administration of h-IFN without co-administration of tacrolimus induced IgG response at 2 or 3 weeks following first administration in the short dosing interval (daily, once per 3 days, or once per a week), irrespective of the dosing interval. Both intravenous and subcutaneous administration of tacrolimus (0.5 mg/kg) with multiple h-IFN injections successfully suppressed IgG response against h-IFN. Interestingly, in lower doses (0.001 mg/kg), intravenous co-administration of tacrolimus showed much stronger suppressive effect than subcutaneous co-administration.


CONCLUSIONS
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.
Yamazaki
Hiroyuki
H
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan.
Miyake
Masateru
M
Nishibayashi
Toru
T
Mukai
Tadashi
T
Odomi
Masaaki
M
Ishida
Tatsuhiro
T
Kiwada
Hiroshi
H
D000818:Animals; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000008:administration & dosage*
D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D016559:Tacrolimus