Effect of dosing schedule on pharmacokinetics of alpha interferon and anti-alpha interferon neutralizing antibody in mice.
The influences of dosing time and dosing schedule on the plasma alpha interferon (IFN-alpha) concentration and the production of anti-IFN-alpha neutralizing antibodies were investigated in ICR male mice adapted to cycles of 12 h of light and 12 h of dark. In mice pretreated with IFN-alpha for 21 days, the plasma IFN-alpha concentrations were significantly lower than those in control mice (P < 0.01). The clearance of IFN-alpha and its volume of distribution obtained at steady state were significantly higher in the animals with IFN-alpha pretreatment than in the mice without IFN-alpha pretreatment. The area under the concentration-time curve and the mean residence time of IFN-alpha were significantly smaller in IFN-alpha-pretreated animals than in control animals. The plasma IFN-alpha levels (measured 2 h after dosing) were significantly lower in mice treated daily with IFN-alpha, while the anti-IFN-alpha neutralizing antibody levels (measured 24 h after dosing) were significantly increased on days 15 and 21 of treatment. Plasma IFN-alpha levels were significantly decreased in association with the production of anti-IFN-alpha neutralizing antibodies in mice treated with IFN-alpha daily at either 0900 or 2100 h. By contrast, the plasma IFN-alpha levels (measured 2 h after dosing) remained stable in mice treated with IFN-alpha at 0900 h on alternate days, while they were significantly lower after 21 days of treatment in mice treated with IFN-alpha at 2100 h on alternate days. These changes were associated with a significant increase in the levels of anti-IFN-alpha neutralizing antibodies in the latter group. The present findings suggest that an appropriate dosing schedule and/or dosing time for IFN-alpha may reduce the level of production of anti-IFN-alpha neutralizing antibodies in experimental and clinical situations.
Wang
D S
DS
Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Graduate School, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
Ohdo
S
S
Koyanagi
S
S
Takane
H
H
Aramaki
H
H
Yukawa
E
E
Higuchi
S
S
D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism*; D000998:Antiviral Agents / Q000276:immunology / Q000493:pharmacokinetics*; D019540:Area Under Curve; D006207:Half-Life; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000276:immunology / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011994:Recombinant Proteins
D019138:Antibodies, Blocking; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins