Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 µg/mL.
Metabolism

The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively.

In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).
Excretion

Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. The mean urinary recovery of two pharmacologically inactive metabolites at steady state was 16±5.8% of vorinostat dose as the O‑glucuronide of vorinostat, and 36±8.6% of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary recovery of vorinostat and these two metabolites averaged 52±13.3% of vorinostat dose. The mean terminal half-life (t½) was ~2.0 hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.
Specific Populations
Gender, Race & Age

Based upon an exploratory analysis of limited data, gender, race and age do not appear to have meaningful effects on the pharmacokinetics of vorinostat.
Pediatric

Vorinostat was not eva luated in patients <18 years of age.
Hepatic Impairment

The single dose pharmacokinetics of a 400 mg ZOLINZA dose was eva luated in patients with non-CTCL cancers with varying degrees of hepatic impairment. The mean AUC of vorinostat in patients with mild (bilirubin > 1 to 1.5 × ULN or AST > ULN but bilirubin ≤ ULN) and moderate (bilirubin 1.5 to ≤ 3 × ULN) hepatic impairment increased by 50% compared to the AUC of vorinostat in patients with normal hepatic function. The mean vorinostat AUC in patients with severe hepatic impairment (bilirubin > 3 x ULN) increased by 66% compared to the AUC of patients with normal hepatic function.

The safety of multiple daily doses of ZOLINZA was also eva luated in patients with non-CTCL cancers with varying degrees of hepatic impairment. The highest dose studied in mild, moderate and severe hepatic impairment was 400, 300 and 200 mg daily respectively. The incidence of Grade 3 or 4 adverse reactions was similar among the hepatic function groups. The most common Grade 3 or 4 adverse reaction was thrombocytopenia.

Reduce the dose in patients with mild to moderate hepatic impairment. There is not enough data in patients with severe hepatic impairment to recommend a dose modification. [See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]
Renal Insufficiency

Vorinostat was not eva luated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat. [See Use in Specific Populations (8.7).]
Pharmacokinetic