Summary of drug interaction predictions using inactivation parameter estimates from various sources
Predictions were performed using Simcyp version 9.10.
| Diltiazem SR-Midazolam p.o. | Verapamil SR-Midazolam p.o. | Clarithromycin-Midazolam p.o. | Erythromycin-Midazolam p.o. | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mercka | Zhaob | Simcypc | Xud | Mercka | Simcypb | Xud | Mercka | Mayhewe | Xud | Yamanof | Simcyp | Zhaob | Xud | Mercka | |
| HLM (mg/ml) | 1 | 0.2 | <0.5 | 1 | 1 | <0.5 | 1 | 1 | 0.2 | 1 | 5 | N.A. | 0.2 | 1 | 1 |
| Dilution | 1:10 | 1:10 | N.A. | 1:20 | 1:10 | N.A. | 1:20 | 1:10 | 1:10 | 1:20 | 1:20 | N.A. | 1:10 | 1:20 | 1:10 |
| Substrate conc. (μM) | TEST | MDZ | TEST | MDZ | TEST | TEST | MDZ | TEST | MDZ | MDZ | MDZ | N.A. | MDZ | MDZ | TEST |
| (250) | (100) | (50) | (20) | (250) | (50) | (20) | (250) | (200) | (20) | (10) | (100) | (20) | (250) | ||
| fu, mic | 0.71g | 0.9 | 0.9 | 0.821 | 0.373g | 0.77 | 0.59 | 0.804g | 0.954g | 0.32 | 0.53 | 0.972 | 0.925 | 0.871 | 0.804g |
| kinact (h−1) | 1.38 | 0.72 | 4.2 | 1.14 | 3.48 | 5.3 | 3.18 | 1.8 | 4.3 | 3.78 | 3.93 | 1.49 | 4.32 | 1.02 | 2.16 |
| KI (μM) | 1.9 | 0.53h | 3.3 | 0.67 | 4.4 | 1.8 | 3.5 | 4.56 | 5.49 | 15.72 | 81.8 | 13.4 | 15.2 | 1.7 | 3.5 |
| Predicted AUC Ratioi | 3.0 ± 1.6 | 3.5 ± 1.9 | 3.7 ± 2.1 | 4.2 ± 2.5 | 2.9 ± 2.0 | 3.9 ± 3.1 | 2.5 ± 1.5 | 6.9 ± 4.7 | 9.1 ± 6.9 | 9.1 ± 7.0 | 4.0 | 3.9 | 3.8 | 11.5 | 12.9 |
| (1.4 − 6.3) | (1.5 − 7.4) | (1.6 − 8.0) | (1.6 − 9.4) | (1.3 − 6.9) | (1.4 − 10) | (1.3 −5.5) | (1.8 − 17) | (2.0 − 22) | (2.0 − 23) | ||||||
| Observed AUC ratioj | 3.5 ± 0.9 | 4.1 ± 2.4 | 8.0 ± 4.4 | 4.4k | |||||||||||
| (1.8 − 4.4) | (1.7 − 11.7) | (3.8 − 14.8) | |||||||||||||
| Study reference | l | Wang et al., 2005 | Wang et al., 2004a | Olkkola et al., 1993 | |||||||||||
HLM, human liver microsomes; TEST, testosterone; MDZ, midazolam; N.A., not available.
↵a Merck unpublished data;
↵b Data from Zhao et al., 2005;
↵c Data from Yeo and Yeo, 2001;
↵d Data from Xu et al., 2009;
↵e Data from Mayhew et al., 2000;
↵f Data from Yamano et al., 2001;
↵g Simcyp-predicted;
↵h Back-calculated by assuming free fraction in microsomal incubation;
↵i Mean ± S.D. (5th–95th percentile);
↵j Mean ± S.D. (range);
↵k S.D. and range were not available;
↵l Friedman EJ, Fraser IP, Wang YH, Bergman A, Li CC, Larson P, Chodakewitz J, Wagner JA, and Stoch SA, manuscript submitted for publication.