Table 2.
Pharmacokinetic parameters of midazolam following intravenous and oral administration in 16 healthy elderly volunteers before and after clarithromycin (500 mg bid ×7 days) administration. Presented as mean (95% confidence interval)
| Control | ||||
|---|---|---|---|---|
| N | Female, 8 | Male, 8 | P-value, male vs. female | All 16 |
| Cmax,iv (µg l−1)† | 58 (48, 68) | 59 (53, 64) | 0.88 | 58 (53, 64) |
| AUCiv (µg l−1 h−1)† | 118 (96, 140) | 142 (112, 171) | 0.23 | 130 (111, 149) |
| CLiv (l h−1) | 36.0 (29.5, 42.8) | 30.4 (24.5, 36.3) | 0.22 | 33.2 (28.7, 37.8) |
| t1/2iv (h) | 2.5 (2.0, 2.9) | 4.0 (3.0, 5.0) | 0.018 | 3.2 (2.6, 3.9) |
| Vdβ (l) | 126 (100, 152) | 162 (133, 192) | 0.09 | 144 (123, 165) |
| tmax,po (h)‡ | 0.88 (0.25, 2) | 0.5 (0.5, 3) | 0.88 | 0.75 (0.25, 3) |
| Cmax,po (µg l−1)† | 12 (7.2, 17) | 12 (8.0, 15) | 0.86 | 12 (9.0, 15) |
| AUCpo (µg l−1 h−1)† | 46 (27, 65) | 48 (21, 75) | 0.90 | 47 (31, 63) |
| CLpo (l h−1) | 124 (71, 177) | 119 (76, 161) | 0.88 | 121 (88, 154) |
| Percent of dose recovered in the urine as 1'-hydroxymidazolam | ||||
| Intravenous dose (%) | 73 (63, 83) | 63 (46, 80) | 0.35 | 68 (58, 78) |
| Oral dose (%)* | 70 (67, 74) | 69 (56, 83) | 0.89 | 70 (63, 77) |
| P.o./i.v. dose (%)§ | 98 (85, 113) | 115 (92, 145) | 0.26 | 106 (93, 123) |
| Clarithromycin treatment | |||||
|---|---|---|---|---|---|
| N | Female, 8 | Male, 8 | P-value, male vs. female | All 16 | P-value, control vs. treatment |
| Cmax,iv (µg l−1)† | 70 (54, 85) | 66 (50, 82) | 0.75 | 68 (57, 79) | 0.13 |
| AUCiv (µg l−1 h−1)† | 409 (311, 507) | 397 (291, 503) | 0.87 | 403 (333, 473) | <0.00001 |
| CLiv (l h−1) | 10.6 (8.6, 12.6) | 12.4 (7.0, 17.9) | 0.55 | 11.5 (8.7, 14.4) | <0.00001 |
| t1/2iv (h) | 13.5 (9.1, 17.9) | 12.5 (8.5, 16.5) | 0.74 | 13.0 (10.1, 15.9) | <0.00001 |
| Vdβ (l) | 189 (153, 224) | 180 (144, 215) | 0.73 | 184 (160, 208) | 0.011 |
| tmax,po (h)‡ | 0.63 (0.5, 1.5) | 0.5 (0.5, 1.5) | 0.88 | 0.5 (0.5, 1.5) | 0.29 |
| Cmax,po (µg l−1)† | 34 (28, 40) | 31 (27, 35) | 0.40 | 33 (29, 36) | <0.00001 |
| AUCpo (µg l−1 h−1)† | 304 (183, 426) | 290 (205, 375) | 0.86 | 297 (226, 369) | <0.00001 |
| CLpo (l h−1) | 16.2 (11.6, 20.7) | 18.6 (9.2, 28.0) | 0.65 | 17.4 (12.3, 22.5) | <0.00001 |
| Percent of dose recovered in the urine as 1'-hydroxymidazolam | |||||
| Intravenous dose (%) | 31 (25, 37) | 38 (24, 53) | 0.33 | 34 (27, 42) | 0.00001 |
| Oral dose (%)* | 38 (30, 45) | 48 (41, 56) | 0.07 | 43 (37, 49) | <0.00001 |
| P.o./i.v. dose (%)§ | 124 (98, 156) | 141 (115, 189) | 0.51 | 132 (115, 151) | 0.04 |
| Extent of interaction | |||||
| AUCiv ratio | 3.6 (2.8, 4.4) | 2.9 (2.0, 3.7) | 0.22 | 3.2 (2.7, 3.8) | |
| AUCpo ratio | 8.2 (4.8, 11.6) | 7.7 (4.5, 11) | 0.85 | 8.0 (5.7, 10.2) | |
*
Oral dose recovered as 1'-hydroxy-15N3-midazolam.
†
Normalized to a dose of 4 mg.
‡
Median (range).
§
Logarthmic average (95% CI) of individual oral to intravenous 1'-hydroxymidazolam recovery ratio.