Summary of the in vitro induction parameters obtained with the human cryopreserved hepatocyte lots RCP and Hu4026, based on mRNA
Compound | Lot RCP | Lot Hu4026 | Projected % Midazolam AUC Decrease | Observed Decrease in Midazolam AUC | Projected % EE AUC Decrease | Observed Decrease in EE AUC | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| EC50 | Emax | RIS | EC50 | Emax | RIS | Lot RCP | Lot Hu4026 | Lot RCP | Lot Hu4026 | |||||||||
| μM | μM | |||||||||||||||||
| Carbamazepine | 60 | 10.2 | 1.3 | 55.8 | 34.3 | 4.5 | 94 | 94 | 95 | 55 | 56 | 42 | ||||||
| Nifedipine | 16.6 | 104 | 0.09 | 18 | 34.3 | 0.03 | 17 | 4.9 | No DDI | 14 | 3.1 | No DDI | ||||||
| Phenobarbital | 153 | 14.4 | 2.1 | 159 | 49 | 6.9 | 94 | 95 | N.D. | 56 | 56 | 70 | ||||||
| Phenytoin | 3.7 | 8.8 | 5.2 | 24 | 15.8 | 2.8 | 95 | 93 | 94 | 56 | 56 | 49 | ||||||
| Pioglitazone | 13.3 | 37.5 | 0.08 | 2.0 | 7.0 | 0.10 | 11 | 21 | 26 | 12 | 16 | 11 | ||||||
| Pleconaril | 16.4 | 33 | 0.12 | 16.5 | 51 | 0.18 | 30 | 38 | 35 | 20 | 28 | 28 | ||||||
| Rifampicin | 2.6 | 14.9 | 7.3 | 0.57 | 33 | 27.2 | 95 | 96 | 93 | 56 | 57 | 64 | ||||||
| Rosiglitazone | 14.3 | 5.4 | 0.001 | 13.6 | 23.9 | 0.005 | 0.0 | 0.5 | No DDI | 0.0 | 0.2 | No DDI | ||||||
| Troglitazone | 2.0 | 9.8 | 0.30 | 8.5 | 23 | 0.17 | 84 | 36 | N.D. | 43 | 27 | 32 | ||||||
| Aprepitant | 2.0 | 13 | 0.20 | 2.0 | 34.1 | 0.51 | 66 | 69 | Clinical inhibition | 34 | 47 | 45 | ||||||
No DDI, no observed induction in clinical DDI studies; EE, ethinyl estradiol; N.D., no clinical in vivo data with midazolam.