Table 5.
All-causality hepatic and visual adverse events versus corresponding observed voriconazole exposure parametersa
| Event type and subject (age [yr], sex) | Adverse event(s) | AE onset study day | Treatment period and day | AUC0–12 (μg·h/ml) | Cmax (μg/ml) | Cmin (μg/ml) |
|---|---|---|---|---|---|---|
| Hepaticb | ||||||
| 1 (14, M) | Moderate increase in GGT | 8 | IV, 8 | 10.4 | 2.5 | 0.22 |
| 3 (14, M) | Mild increase in AST (intermittent) | 7 | IV, 7 | 64.8 | 7.48 | 4.73 |
| Moderate ascites | 20 | Oral, 1 | NA | NA | NA | |
| Severe hyperbilirubinemiac | 20 | Oral, 1 | NA | NA | NA | |
| 4 (14, M) | Mild increase in transaminases (intermittent) | 12 | Oral, 5 | 5.59 | 0.81 | 0.17 |
| 5 (13, F) | Moderate hyperbilirubinemia | 8 | IV, 8 | 95.3 | 9.99 | 7.78 |
| 8 (13, F) | Mild cholelithiasis | 9 | IV, 9 | 37 | 8.74 | 1.93 |
| Moderate hyperbilirubinemia | 11 | IV, 11 | 37 | 8.74 | 1.93 | |
| 12 (13, F) | Moderate increase in transaminases | 18 | IV, 18 | 16.7 | 2.61 | 0.71 |
| 16 (16, M) | Mild jaundice | 9 | IV, 9 | 45.3 | 8.35 | 2.34 |
| Mild hyperbilirubinemia | 10 | IV, 10 | 45.3 | 8.35 | 2.34 | |
| 19 (16, F) | Severe increase in hepatic enzymed | 6 | IV, 6 | 6.82 | 1.71 | 0.14 |
| 22 (13, M) | Mild hyperbilirubinemia | 10 | IV, 10 | 6.24 | 1.89 | NA |
| Moderate increase in hepatic enzyme (intermittent) | 10 | IV, 10 | NA | NA | NA | |
| 25 (13, M) | Mild increase in hepatic enzyme | 7 | IV, 7 | 8.29 | 2.44 | 0.11 |
| 26 (12, M) | Moderate hyperbilirubinemiae | 24 | IV, 24 | NA | NA | NA |
| Visual | ||||||
| 12 (13, F) | Moderate visual impairment (dark spots in lateral visual fields in left eye) | 23 | Oral, 1 | NA | NA | NA |
| 16 (16, M) | Mild color blindness (trouble distinguishing between black and blue)f | 29 | Oral, 7 | 24.1 | 2.93 | 1.3 |
| 17 (16, M) | Moderate photophobia | 22 | Oral, 15 | 46.5 | 4.39 | 2.72 |
| 24 (13, M) | Mild blurring of vision | 1 | IV, 1 | NA | NA | NA |
AST, aspartate aminotransferase; F, female; GGT, gamma glutamyltransferase; IV, intravenous; M, male; NA, not available.
Two subjects were not included because the hepatic AEs occurred during the follow-up period.
This subject discontinued study treatment on day 21 (day 2 of oral treatment) due to severe hyperbilirubinemia (treatment related).
This subject discontinued study treatment on day 8 of IV treatment due to a severe increase in hepatic enzyme (treatment related).
This subject inadvertently received phenytoin up to day 5 IV, AUC0-12 on day 7 IV was 2.47 μg·h/ml, but it could not be used to estimate the exposure on day 24 IV.
Treatment related.