TABLE 4.

IL‐6 threshold levels prediction for anti‐IL‐6 therapeutic proteins to cause significant CYP‐mediated TP‐DI based on FDA DDI classification

Substrate	IL‐6 level (pg/ml) Bioequivalence AUC ↓<20%	IL‐6 level (pg/ml) Weak inducer 20%≤AUC ↓<50%	IL‐6 level (pg/ml) Moderate inducer 50%≤UC ↓<80%	IL‐6 level (pg/ml) Strong inducer AUC ↓≥80%
Omeprazole (CYP2C19)	<19	19–89	89–279	>279
S‐warfarin (CYP2C9)	<21	21–81	81–264	>264
Midazolam (CYP3A)	<12	12–69	69–197	>197
Substrate	IL−6 level (pg/ml) Bioequivalence AUC↑<1.25‐fold	IL−6 level (pg/ml) Weak inhibitor 1.25<AUC↑<2‐fold	—	—
Caffeine (CYP1A2)	<10	10–1000	—	—

Abbreviations: AUC, area under plasma concentration versus time curves; DDI, drug‐drug interaction; FDA, US Food and Drug Administration; TP‐DI, therapeutic protein drug interaction; UC, ulcerative colitis.

↑: Increase in exposure metrics after anti‐IL‐6 treatment; ↓: Decrease in exposure metrics after anti‐IL‐6 treatment.