Mechanism Of Action
Vorinostat inhibits the enzymatic activity of histone
deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar
concentrations (IC50<86 nM). These enzymes catalyze the removal of acetyl
groups from the lysine residues of proteins, including histones and transcription
factors. In some cancer cells, there is an overexpression of HDACs, or an
aberrant recruitment of HDACs to oncogenic transcription factors causing
hypoacetylation of core nucleosomal histones. Hypoacetylation of histones is
associated with a condensed chromatin structure and repression of gene
transcription. Inhibition of HDAC activity allows for the accumulation of
acetyl groups on the histone lysine residues resulting in an open chromatin
structure and transcriptional activation. In vitro, vorinostat causes the
accumulation of acetylated histones and induces cell cycle arrest and/or
apoptosis of some transformed cells. The mechanism of the antineoplastic effect
of vorinostat has not been fully characterized.
A randomized, partially-blind, placebo-controlled,
2-period crossover study was performed to assess the effects of a single 800-mg
dose of vorinostat on the QTc interval in 24 patients with advanced cancer.
This study was conducted to assess the impact of vorinostat on ventricular
repolarization. The upper bound of the 90% confidence interval of the
placebo-adjusted mean QTc interval change-from-baseline was less than 10 msec
at every time point through 24 hours. Based on these study results,
administration of a single supratherapeutic 800-mg dose of vorinostat does not
appear to prolong the QTc interval in patients with advanced cancer; however
the study did not include a positive control to demonstrate assay sensitivity.
In the fasted state, oral administration of a single 800-mg dose of vorinostat
resulted in a mean AUC and Cmax and median Tmax of 8.6±5.7 μM•hr and
1.7±0.67 μM and 2.1 (0.5-6) hours, respectively.
In clinical studies in patients with CTCL, three of 86
CTCL patients exposed to 400 mg once daily had Grade 1 (>450-470 msec) or 2
(>470-500 msec or increase of >60 msec above baseline) clinical adverse
reactions of QTc prolongation. In a retrospective analysis of three Phase 1 and
two Phase 2 studies, 116 patients had a baseline and at least one follow-up
ECG. Four patients had Grade 2 (>470-500 msec or increase of >60 msec
above baseline) and 1 patient had Grade 3 (>500 msec) QTc prolongation. In
49 non-CTCL patients from 3 clinical trials who had complete evaluation of QT
interval, 2 had QTc measurements of >500 msec and 1 had a QTc prolongation
of >60 msec.
The pharmacokinetics of vorinostat were evaluated in 23
patients with relapsed or refractory advanced cancer. After oral administration
of a single 400-mg dose of vorinostat with a high-fat meal, the mean ± standard
deviation area under the curve (AUC) and peak serum concentration (Cmax) and
the median (range) time to maximum concentration (Tmax) were 5.5±1.8
μM•hr, 1.2±0.62 μM and 4 (2-10) hours, respectively.
In the fasted state, oral administration of a single
400-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of
4.2±1.9 μM•hr and 1.2±0.35 μM and 1.5 (0.5-10) hours,
respectively. Therefore, oral administration of vorinostat with a high-fat meal
resulted in an increase (33%) in the extent of absorption and a modest decrease
in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted
state. However, these small effects are not expected to be clinically
meaningful. In clinical trials of patients with CTCL, vorinostat was taken with
At steady state in the fed-state, oral administration of
multiple 400-mg doses of vorinostat resulted in a mean AUC and Cmax and a median
Tmax of 6.0±2.0 μM•hr, 1.2±0.53 μM and 4 (0.5-14) hours,
Vorinostat is approximately 71% bound to human plasma
proteins over the range of concentrations of 0.5 to 50 μg/mL.
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-anilino4-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).
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.
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 evaluated in
patients <18 years of age.
The single dose pharmacokinetics of a 400 mg ZOLINZA dose
was evaluated 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 x ULN or AST > ULN but bilirubin ≤ ULN) and moderate (bilirubin
1.5 to ≤ 3 x 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
evaluated 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 and Use
In Specific Populations].
Vorinostat was not evaluated in patients with renal
impairment. However, renal excretion does not play a role in the elimination of
Pharmacokinetic Effects Of Vorinostat With Other Agents
Vorinostat is not an inhibitor of CYP drug metabolizing
enzymes in human liver microsomes at steady state Cmax of the 400 mg dose (Cmax
of 1.2 μM vs IC50 of >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 evaluate
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 the pharmacologically relevant serum concentration of
2 μM (Cmax) in humans.
Cutaneous T-cell Lymphoma
In two open-label clinical studies, patients with
refractory CTCL have been evaluated to determine their response rate to oral
ZOLINZA. One study was a single-arm clinical study and the other assessed
several dosing regimens. In both studies, patients were treated until disease
progression or intolerable toxicity.
In an open-label, single-arm, multicenter non-randomized
study (NCT00091559), 74 patients with advanced CTCL were treated with ZOLINZA
at a dose of 400 mg once daily. The primary endpoint was response rate to oral
ZOLINZA in the treatment of skin disease in patients with advanced CTCL (Stage
IIB and higher) who had progressive, persistent, or recurrent disease on or
following two systemic therapies. Enrolled patients should have received, been
intolerant to or not a candidate for bexarotene. Extent of skin disease was
quantitatively assessed by investigators using a modified Severity Weighted
Assessment Tool (SWAT). The investigator measured the percentage total body
surface area (%TBSA) involvement separately for patches, plaques, and tumors
within 12 body regions using the patient’s palm as a “ruler”. The total %TBSA
for each lesion type was multiplied by a severity weighting factor (1=patch,
2=plaque and 4=tumor) and summed to derive the SWAT score. Efficacy was
measured as either a Complete Clinical Response (CCR) defined as no evidence of
disease, or Partial Response (PR) defined as a ≥50% decrease in SWAT skin
assessment score compared to baseline. Both CCR and PR had to be maintained for
at least 4 weeks.
Secondary efficacy endpoints included response duration,
time to progression, and time to objective response.
The population had been exposed to a median of three
prior therapies (range 1 to 12).
Table 2 summarizes the demographic and disease
characteristics of the Study 1 population.
Table 2: Baseline Patient Characteristics (All Patients As Treated)
||60.0 (39.0, 83.0)
|Gender, n (%)
|CTCL stage, n (%)
|Racial Origin, n (%)
|Time from Initial CTCL Diagnosis (year)
||2.6 (0.0, 27.3)
|Number of prior systemic treatments, median (range)
||3.0 (1.0, 12.0)
The overall objective response rate was 29.7% (22/74, 95%
CI [19.7 to 41.5%]) in all patients treated with ZOLINZA. In patients with
Stage IIB and higher CTCL, the overall objective response rate was 29.5% Â (18/61).
One patient with Stage IIB CTCL achieved a CCR. Median times to response were
55 and 56 days (range 28 to 171 days), respectively in the overall population
and in patients with Stage IIB and higher CTCL. However, in rare cases it took
up to 6 months for patients to achieve an objective response to ZOLINZA.
The median response duration was not reached since the
majority of responses continued at the time of analysis, but was estimated to
exceed 6 months for both the overall population and in patients with Stage IIB
and higher CTCL. When end of response was defined as a 50% increase in SWAT
score from the nadir, the estimated median response duration was 168 days and
the median time to tumor progression was 202 days.
Using a 25% increase in SWAT score from the nadir as
criterion for tumor progression, the estimated median time-to-progression was
148 days for the overall population and 169 days in the 61 patients with Stage
IIB and higher CTCL.
Response to any previous systemic therapy does not appear
to be predictive of response to ZOLINZA.
In an open-label, non-randomized study, ZOLINZA was
evaluated to determine the response rate for patients with CTCL who were
refractory or intolerant to at least one treatment. In this study, 33 patients
were assigned to one of 3 cohorts: Cohort 1, 400 mg once daily; Cohort 2, 300
mg twice daily 3 days/week; or Cohort 3, 300 mg twice daily for 14 days
followed by a 7-day rest (induction). In Cohort 3, if at least a partial
response was not observed then patients were dosed with a maintenance regimen
of 200 mg twice daily. The primary efficacy endpoint, objective response, was
measured by the 7-point Physician's Global Assessment (PGA) scale. The
investigator assessed improvement or worsening in overall disease compared to
baseline based on overall clinical impression. Index and non-index cutaneous
lesions as well as cutaneous tumors, lymph nodes and all other disease
manifestations were also assessed and included in the overall clinical
impression. CCR required 100% clearing of all findings, and PR required at
least 50% improvement in disease findings.
The median age was 67.0 years (range 26.0 to 82.0).
Fifty-five percent of patients were male, and 45% of patients were female.
Fifteen percent of patients had Stage IA, IB, or IIA CTCL and 85% of patients
had Stage IIB, III, IVA, or IVB CTCL. The median number of prior systemic
therapies was 4 (range 0.0 to 11.0).
In all patients treated, the objective response was 24.2%
(8/33) in the overall population, 25% (7/28) in patients with Stage IIB or
higher disease and 36.4% (4/11) in patients with Sezary syndrome. The overall
response rates were 30.8%, 9.1% and 33.3% in Cohort 1, Cohort 2 and Cohort 3,
respectively. The 300 mg twice daily regimen had higher toxicity with no
additional clinical benefit over the 400 mg once daily regimen. No CCR was
Among the 8 patients who responded to study treatment,
the median time to response was 83.5 days (range 25 to 153 days). The median
response duration was 106 days (range 66 to 136 days). Median time to
progression was 211.5 days (range 94 to 255 days).