Tofacitinib was indicated dependence on the dose increase in both cases of intravenous administration and oral administration. One of the dose-dependent pharmacokinetic parameter, the area under the plasma tofacitinib concentration-time curve from time zero to infinity (AUC0-∞), was meaningfully higher at 50 mg/kg dose of tofacitinib than at 5, 10 and 20 mg/kg (283, 342, 381 and 776 ug∙min/mL for 5, 10, 20 and 50 mg/kg, respectively, dose-normalized at 10 mg/kg) in intravenous administration study. In oral administration study, also the AUC0-∞ was meaningfully higher at 100 mg/kg dose of tofacitinib than at 10, 20 and 50 mg/kg (99.4, 151, 228 and 413 ug∙min/mL for 10, 20, 50 and 100 mg/kg, respectively, dose-normalized at 10 mg/kg).
The absolute oral bioavailability (F) was about 29.1% at 10 mg/kg dose of todacitinib in rat. For first-pass effect study, the AUC0-∞ values were compared between these group which administered by intravenous, intraportal, intraportal, intraduodenal and intragastric route, respectively. The hepatic first-pass effect of tofacitinib was calculated about 41.9% and the intestinal first-pass effect of tofacitinib was calculated about 49.2% using rat model. The gastric first-pass effect was negligible. Consequently, the reasons of nonperfect F value were evaluated to be owing to the high hepatic and intestinal first-pass effect.
