Table 4.

Hepatic and visual adverse events (related to study drug) versus corresponding observed voriconazole exposure parameters in children^a

Event type and subject	Adverse events (related to study drug)f	AE onset study day	Period	AUC0-12 (μg·h/ml)	Cmax (μg/ml)	Cmin (μg/ml)
Hepatic
17b,c	Severe hyperbilirubinemia	8	IV	34.3	5.81	1.33
19b	Moderate increase in hepatic enzyme	6	IV	33.0	4.30	0.94
24b	Mild hepatomegaly; severe increase in hepatic enzyme	18	IV	36.7	5.66	1.65
26	Mild increase in transaminases	22	IV	52.0	7.52	2.52
30b,d	Severe increase in ALT; moderate increase in AST	3	IV			2.28
32	Mild increases in ALT and AST	6	IV	81.4	9.71	4.59
32	Mild increase in GGT	14 (day 7 of oral treatment)	Oral	48.6	7.39	1.86
33e	Severe increases in ALT and AST	11 (day 5 of oral treatment)	Oral	203	18.0	12.8
Visual
38	Mild change in color vision	7	IV	11.4	2.35	0.17
	Mild reduction in visual acuity	20 (day 1 of oral treatment)	Oral
	Mild astigmatism, mild myopia, mild lacrimation decrease	24 (day 4 of oral treatment)	Oral	20.1	4.53	0.43

^aSteady-state IV and oral voriconazole exposures were used as the estimates for AEs that occurred on nonpharmacokinetic days.

^bAdverse event(s) resulted in permanent discontinuation.

^cThis subject received esomeprazole throughout the study.

^dThis subject was the CYP2C19 PM, who discontinued on day 4, and these events were resolved on days 5 and 6.

^eThese events were also reported as serious AEs, which were resolved on oral treatment day 10 without any alteration of the study drug.

^fALT, alanine aminotransferase; AST, aspartate aminotransfearse; GGT, gamma glutamyltransferase.