Pharmacokinetic parameters of midazolam, tacrolimus, and their primary metabolites in cohort A, stratified by CYP3A5 genotype
| Variable | Nonexpressors (n = 40) | Expressors (n = 10) | Difference | P |
|---|---|---|---|---|
| % | ||||
| Midazolam | ||||
| AUC0–8 (h⋅ng/ml) | 3373 ± 1764 | 3355 ± 1219 | 0.770 | |
| Tmax (h)a | 0.5 (0.3–0.5) | 0.5 (0.5–1.0) | 0.519 | |
| Cmax (ng/ml) | 16.8 ± 8.1 | 15.9 ± 7.2 | −5.4 | 0.811 |
| CL/F (ml/h) | 735 ± 324 | 673 ± 249 | −8.4 | 0.770 |
| Midazolam metabolites | ||||
| AUC1′-HOMDZ/AUCMDZ | 0.43 ± 0.22 | 0.39 ± 0.17 | −9.3 | 0.544 |
| AUC4-HOMDZ/AUCMDZ | 0.05 ± 0.01 | 0.04 ± 0.01 | −20.0 | 0.108 |
| Tacrolimus | ||||
| AUC0–24 (h⋅ng/ml) | 266.0 ± 66.3 | 291.8 ± 59.2 | +9.7 | 0.257 |
| Dose (mg/day) | 4.7 ± 2.2 | 10.5 ± 3.1 | +123.4 | <0.001 |
| Tmax (h)a | 2.0 (1.6–3.0) | 1.75 (1.0–3.0) | 1.000 | |
| Cmax (ng/ml) | 17.9 ± 5.0 | 25.6 ± 7.3 | +43.0 | 0.002 |
| CL/F (L/h) | 17.8 ± 7.6 | 35.6 ± 8.2 | +100.0 | <0.001 |
| Tacrolimus metabolites | ||||
| AUC13-DMT/AUCtacrolimus | 0.036 ± 0.012 | 0.100 ± 0.024 | +177.8 | <0.001 |
| AUC15-DMT/AUCtacrolimus | 0.031 ± 0.007 | 0.031 ± 0.007 | 0.814 | |
| AUC31-DMT/AUCtacrolimus | 0.003 ± 0.001 | 0.006 ± 0.001 | +100.0 | <0.001 |
| AUCmetabolites/AUCtacrolimus | 0.070 ± 0.017 | 0.136 ± 0.028 | +94.3 | <0.001 |
AUCmetabolites, sum of AUC for 13-DMT, 15-DMT, and 31-DMT; Tmax, time to reach maximum blood concentration.
↵a Median (interquartile range).