Distribution

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 (t) 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.

Special Populations

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 Insufficiency

Vorinostat was not eva luated in patients with hepatic impairment. [See 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 effects of vorinostat with other agents

Vorinostat is not an inhibitor of CYP drug metabolizing enzymes in human liver microsomes at steady state C of the 400 mg dose (Cof 1.2 µM vs ICof >75 µM). Gene expression studies in human hepatocytes detected some potential for suppression of CYP2C9 and CYP3A4 activities by vorinostat at concentrations higher (≥10 µM) than pharmacologically relevant. Thus, vorinostat is not expected to affect the pharmacokinetics of other agents. As vorinostat is not eliminated via the CYP pathways, it is anticipated that vorinostat will not be subject to drug-drug interactions when co-administered with drugs that are known CYP inhibitors or inducers. However, no formal clinical studies have been conducted to eva luate drug interactions with vorinostat.

In vitro studies indicate that vorinostat is not a substrate of human P-glycoprotein (P-gp). In addition, vorinostat has no inhibitory effect on human P-gp-mediated transport of vinblastine (a marker P-gp substrate) at concentrations of up to 100 μM. Thus, vorinostat is not likely to inhibit P-gp at t