Effect of dosing schedule on pharmacokinetics of alpha interferon and anti-alpha interferon neutralizing antibody in mice

Abstract

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.

FIG. 1

Influence of IFN-α pretreatment on plasma IFN-α concentrations after administration of a single dose of IFN-α (1 MIU/kg i.v.) at 0900 h on day 22. ○, without IFN-α pretreatment; ●, pretreatment with a single dose of IFN-α (1 MIU/kg s.c.) daily for 21 days. Each point represents the mean ± standard error of six observations. ∗∗, P < 0.01 when the data for the two groups are compared.

FIG. 2

Time course of plasma IFN-α concentration 2 h after dosing and plasma anti-IFN-α antibody levels 24 h after dosing in mice given a single dose of IFN-α (1 MIU/kg s.c.) at 0900 h daily for 21 days. ○, plasma IFN-α concentration; ●, anti-IFN-α antibody level. Each point represents the mean ± standard error of six observations. ∗, P < 0.05; ∗∗, P < 0.01 compared with the level on day 1.

FIG. 3

Influence of dosing time on plasma IFN-α concentration 2 h after dosing in mice given a single dose of IFN-α (1 MIU/kg s.c.) daily (A) or on alternate days (B) for 21 days. ○, dosing at 0900 h; ●, dosing at 2100 h. Each point represents the mean ± standard error of six observations. a, P < 0.05 when the levels on day 1 are compared; b, P < 0.05 when the data for the two groups are compared.

FIG. 4

Influence of dosing time on plasma anti-IFN-α antibody levels 24 h after administration of the last dose in mice given a single dose of IFN-α (1 MIU/kg s.c.) daily (A) or on alternate days (B) for 21 days. □, dosing at 0900 h; ■, dosing at 2100 h. Each column represents the mean ± standard error of six observations. ∗, P < 0.05 when the data for the two groups are compared.