Disposition, metabolism and mass balance of [(14)C]apremilast following oral administration.

Abstract

Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis. The pharmacokinetics and disposition of [(14)C]apremilast was investigated following a single oral dose (20 mg, 100 μCi) to healthy male subjects. Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean C(max), AUC(0-∞) and t(max) values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h. Apremilast was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and <7% of the excreted radioactivity. The predominant metabolite was O-desmethyl apremilast glucuronide, representing 39% of plasma radioactivity and 34% of excreted radioactivity. The only other radioactive components that represented >4% of the excreted radioactivity were O-demethylated apremilast and its hydrolysis product. Additional minor circulating and excreted compounds were formed via O-demethylation, O-deethylation, N-deacetylation, hydroxylation, glucuronidation and/or hydrolysis. The major metabolites were at least 50-fold less pharmacologically active than apremilast. Metabolic clearance of apremilast was the major route of elimination, while non-enzymatic hydrolysis and excretion of unchanged drug were involved to a lesser extent.

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Introduction
Apremilast [CC-10004; (+)-N-[2-[(1S)-1-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-
2,3-dihydro-1H-isoindol-4-yl]acetamide] (Figure 1) is an
oral agent that inhibits the activity of phosphodiesterase
type 4 (PDE4) and the production of multiple pro-inflam-
matory cytokines and chemokines in vitro, including
tumour necrosis factor (TNF)-α, interleukin (IL)-8, IL-12,
IL-23, CXCL9, CXCL10 and interferon-γ (Man et al. 2009;
Schafer et al. 2010). Apremilast has demonstrated anti-
inflammatory effects in vitro and has shown efficacy in
a pre-clinical mouse model for psoriasis (Schafer et al.
2010). Additionally, apremilast has shown clinical efficacy
in subjects with moderate-to-severe psoriasis (Papp et al.
2008). Apremilast is also under clinical development for
the treatment of other inflammatory autoimmune disor-
ders that involve elevated cytokine levels such as psori-
atic arthritis and Behçet disease.
The pharmacokinetics of apremilast in patients
with severe plaque-type psoriasis following multiple
daily doses showed rapid absorption (Tmax = 2 h) and a
moderately long half-life (8.2 h) (Gottlieb et al. 2008).
Co-administration of apremilast with ketoconazole
resulted in a 36% increase in apremilast AUC (Wu et al.
2006), not only indicating that CYP3A4/5 metabolism
plays an important role in apremilast clearance but also
RESEARCH ARTICLE
Disposition, metabolism and mass balance of [14C]apremilast
following oral administration
Matthew Hoffmann1, Gondi Kumar1, Peter Schafer2, Dorota Cedzik2, Lori Capone2, Kei-Lai Fong3,
Zheming Gu4, Dennis Heller4, Hao Feng4, Sekhar Surapaneni1, Oscar Laskin5, and Anfan Wu6
1Drug Metabolism and Pharmacokinetics Department, Celgene, Summit, NJ, USA, 2Translational Development
Department, Celgene, Summit, NJ, USA, 3Accellient Partners LLC, Berkeley, CA, USA, 4XenoBiotic Laboratories,
Plainsboro, NJ, USA, 5R2D Pharma Services LLC, Princeton, NJ, USA, and 6Exploratory Clinical Pharmacology
Department, Celgene, Summit, NJ, USA
Abstract
1. Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple
pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis
and psoriatic arthritis. The pharmacokinetics and disposition of [14C]apremilast was investigated following a single
oral dose (20 mg, 100 μCi) to healthy male subjects.
2. Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean Cmax, AUC0−∞
and tmax values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h. Apremilast was extensively
metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and
<7% of the excreted radioactivity.
3. The predominant metabolite was O-desmethyl apremilast glucuronide, representing 39% of plasma radioactivity
and 34% of excreted radioactivity. The only other radioactive components that represented >4% of the excreted
radioactivity were O-demethylated apremilast and its hydrolysis product. Additional minor circulating and
excreted compounds were formed via O-demethylation, O-deethylation, N-deacetylation, hydroxylation,
glucuronidation and/or hydrolysis. The major metabolites were at least 50-fold less pharmacologically active than
apremilast. Metabolic clearance of apremilast was the major route of elimination, while non-enzymatic hydrolysis
and excretion of unchanged drug were involved to a lesser extent.
Keywords: Apremilast, human, metabolism, phosphodiesterase type 4, tumour necrosis factor
Address for Correspondence: Matthew Hoffmann, PhD, Celgene, 86 Morris Ave, Summit, NJ 07901, USA. E-mail: mjhoffman@celgene.com
(Received 26 May 2011; revised 06 July 2011; accepted 08 July 2011)
Xenobiotica, 2011; 41(12): 1063–1075
© 2011 Informa UK, Ltd.
ISSN 0049-8254 print/ISSN 1366-5928 online
DOI: 10.3109/00498254.2011.604745

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1064 M. Hoffmann et al.
Xenobiotica
suggesting that other clearance pathways are present.
This study was performed to evaluate the pharmacokinet-
ics, metabolic disposition and mass balance of a single
oral suspension dose (20 mg, 100 μCi) of [14C]apremilast
to healthy male subjects.
Materials and methods
Standards and reagents
[14C]Apremilast (Figure 1) was prepared by Girindus
America, Inc (Bergisch Gladbach, Germany). The spe-
cific activity, radiochemical purity and chemical purity
of the material were 5 μCi/mg, >98% and >98%, respec-
tively. Reference standard for apremilast (99.1% chemi-
cal purity) was synthesized by Evotec (Oxfordshire, UK).
CC-10047 (M5, O-desethyl apremilast), CC-10055
(M7, N-deacetyl apremilast), CC-15091 (M1/M2,
phthalimide ring hydrolysis products of apremilast),
CC-16085 (M3, O-desmethyl apremilast), CC-16166
(M12, O-desmethyl apremilast glucuronide), CC-16401
(M17, acetamide hydroxy metabolite), CC-16557 (M16,
acetamide hydroxyl glucuronide) and CC-16793 (M14,
O-desmethyl, N-deacetyl apremilast glucuronide) were
synthesized by the Medicinal Chemistry and Process
Chemistry groups at Celgene (Summit, NJ). (3S-cis)-(+)-
Tetrahydro-3,7adiphenylpyrrolo[2, 1-b] oxazol-5(6H)-
one and β-glucuronidase (S8162) were obtained from
SigmaAldrich (Milwaukee, WI). All other reagents and
chemicals were obtained from commercial sources.
Study design and dose administration
This was an open-label, inpatient, single-dose study
conducted with six non-smoking healthy male volun-
teers, aged between 19 and 55 years, with body mass
index between 19 and 29 kg/m2. Before initiation of the
study, the protocol and consent form were reviewed and
approved by the institutional review board. All study
participants gave written informed consent before the
screening process was initiated. This study was conducted
in full accordance with the Declaration of Helsinki and
Good Clinical (GCP) as required by and described in 21
Code of Federal Regulations.
Each subject was administered a single oral suspen-
sion of 20 mg (100 μCi) of [14C]apremilast in distilled
water (240 mL total volume). Subjects were fasted for
8 h prior to and 4 h following dose administration. The
residual radioactivity in the dosing vials was determined
and accounted for approximately 0.3% of the total radio-
activity. Dose administration, sample collection, sample
processing and determination of total radioactivity
were conducted at MDS Pharma Services (Lincoln, NE).
Determination of apremilast in plasma, metabolite pro-
filing and metabolite characterization were performed at
XenoBiotic Laboratories, Inc. (Plainsboro, NJ).
Sample collection
Urine was collected pre-dose, 0−4, 4−8, 8−12, 12−24 and
every 24 h thereafter up to 216 h (9 days) following dose
administration and was stabilized with one volume of
pH 1.5 Sorensen’s citrate buffer (25-mM sodium citrate
buffer adjusted to pH 1.5). Individual faecal samples were
collected pre-dose and for up to 9 days following dose
administration, and homogenized using approximately
three volumes by weight of pH 1.5 Sorensen’s citrate buf-
fer. Blood (two 5-mL samples for plasma radioactivity
counting, a 3-mL sample for whole blood radioactivity
counting, a 2-mL sample for apremilast analysis and a
10-mL sample for metabolite profiling) was collected
into heparinized tubes at pre-dose, 0.5, 1, 1.5, 2, 2.5, 3,
4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 h fol-
lowing dose administration. Blood samples collected
for radioactivity counting were stored at or below −20°C
until analysed. Plasma was harvested by centrifugation
from all other blood samples. The plasma samples for
apremilast analysis and metabolite profiling were mixed
with an equal volume of pH 1.5 Sorensen’s citrate buffer
containing 20-μM amastatin. All urine, faecal homoge-
nates and plasma samples were stored at or below −20°C
until analysed.
Radioanalysis
All radioactivity determinations were performed using
a Tri-Carb model 1600TR liquid scintillation counter
(PerkinElmer, Wellesley, MA). For plasma and urine analy-
sis, duplicate samples of a known volume were mixed with
Ultima Gold XR scintillation cocktail and directly analysed
by liquid scintillation counting. For faecal homogenate
and blood samples, duplicate aliquots were weighed,
allowed to dry and combusted using a PerkinElmer
model 307 sample oxidizer. The resultant [14C]CO2 was
trapped in Carbosorb (PerkinElmer) in combination with
Permafluor and assayed by liquid scintillation counting.
For all matrices, an appropriate quench curve was used to
convert cpm values to dpm values. Any sample that was
less than two times the background dpm was assigned a
value of zero. Using these criteria, the lower limit of quan-
tification in plasma, blood, urine and faeces were 2.07 ng
[14C]apremilast equivalent/mL (ngEq/mL), 2.61 ngEq/g,
1.89 ngEq/mL and 2.52 ngEq/g, respectively.
Measurement of apremilast in plasma
Plasma concentrations of apremilast were determined
using a Chiral liquid chromatography with tandem
mass spectrometry (LC/MS/MS) assay validated for
concentrations between 1.00 and 1000 ng/mL, with
Figure 1. Structure of apremilast, with the site of the 14C label
indicated (*).

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Disposition, metabolism and mass balance of apremilast 1065
© 2011 Informa UK, Ltd.
quality control (QC) samples prepared at 3.00, 50.0
and 750 ng/mL. Apremilast and (3S-cis)-(+)-tetrahydro-
3,7a-diphenylpyrrolo[2, 1-b] oxazol-5(6H)-one (internal
standard; IS) were extracted from 50 μL of plasma
(stabilized with 50-μL Sorenson’s citrate buffer) using
liquid−liquid extraction with methyl tertiary butyl ether.
The aqueous layer was frozen and the solvent layer was
transferred to a new tube. The solvent was evaporated, the
samples were reconstituted and injected for LC/MS/MS
analysis using a Chiral AGP (150 × 4.0 mm, 5 μm; Chrom
Tech, Inc., Apple Valley, MN) analytical column. Positive
ions were measured in the multiple reaction monitor-
ing (MRM) mode using a Sciex API-4000 tandem mass
spectrometer equipped with a Turbo IonSpray source
with precursor→product ion pairs of 461.0→177.9 for
apremilast and 280.1→160.3 for IS. For the QC samples,
the accuracy ranged from 87.5% to 106.7%.
Metabolite profiling by high-performance liquid
chromatography (HPLC)
Individual plasma samples collected from all subjects
at 0.5, 1, 2.5, 8, 24, 36 and 48 h post-dose were analysed
for metabolite profiling. A pooled sample (equal volume
from 0.5, 1, 2.5, 8 and 24 h) from subject 1 was also used for
metabolite profiling. Three volumes of acetonitrile were
added to each sample, followed by mixing and centrifu-
gation. The supernatant was removed and the pellet was
washed twice with acetonitrile. The combined superna-
tants were evaporated to dryness under a stream of nitro-
gen. The residues were re-suspended in acetonitrile:1%
formic acid in water (1:1), assayed for extraction recovery
and analysed for metabolite profiling.
For each subject, urine samples were pooled using an
equal percentage by volume of the 0−4, 4−8, 8−12 and
12−24-h samples. The 24−48-h urine sample from each
subject and a pool of the 0−168-h urine samples from
subject 1 were also analysed for metabolite profiling.
Samples were mixed and centrifuged prior to the super-
natants being transferred to fresh tubes for metabolite
profiling analysis.
Faecal homogenates for metabolite profiling were
pooled using an equal percentage by weight to generate
two pools (0−48 h and 48−96 h) for each subject. An addi-
tional pool (0−168 h) was prepared using the samples col-
lected from subject 1. An aliquot (approximately 6 g) of
each pool was extracted with three volumes of acetonitrile;
samples were mixed and centrifuged. The supernatant
was removed and the pellets were extracted twice with an
additional 12 mL of acetonitrile each time. The combined
supernatants were evaporated to dryness under a stream
of nitrogen and the residue was re-suspended in a small
volume (approximately 400 μL) of acetonitrile:1% formic
acid in water (1:1). Samples were assayed for extraction
recovery prior to metabolite profiling.
HPLC analysis for metabolite profiling was per-
formed using a Shimadzu LC-10ADVP (Shimadzu Corp.,
Columbia, MD) or a Waters 2695 Alliance Separation
Module (Waters Corp., Milford, MA) with the autosampler
set to an ambient temperature of approximately 22°C.
A SPD-10A VP UV-Vis Detector or a Waters 996 Photodiode
array detector set to 254 nm was used to detect UV absor-
bance. [14C]Apremilast and metabolites were separated
using a Phenomenex Luna C18(2) column (150 × 4.6 mm,
3 μm; Phenomenex, Torrance, CA) equipped with a RP-18
guard column (15 × 3.2 mm, 7 μm) or using an ACE 3 C18
column (150 × 4.6 mm, 3 μm; Advanced Chromatography
Technologies, Aberdeen, Scotland) equipped with an
ACE 3 guard column (10 × 3 mm, 3 μm). The mobile
phases used were 0.4% formic acid in water; pH 3.2 with
ammonium hydroxide (mobile phase A) and acetonitrile
(mobile phase B). The column temperature was 30°C
and the flow rate was 0.7 mL/min. The linear gradient
was delivered as follows: 0−5 min to 100% A; 5−20 min
to 85% A; 20−30 min hold at 85% A; 30−50 min to 65% A;
50−60 min to 60% A; 60−70 min to 50% A; 70−75 min to 0%
A; hold at 0% A until 80 min; return to initial conditions
over 2 min.
Radioactivity profiles for excreta were determined by
radiochromatography using liquid chromatography-ac-
curate radioisotope counting stop-flow system (LC-ARC;
AIM Research Company, Wilmington, DE). Radioactivity
was detected using a β-Ram Radioflow detector (IN/US
Systems, Brandon, FL) equipped with a 1300-μL liquid
cell. Liquid scintillation cocktail and column eluate were
mixed at a ratio of 2.5:1. Radioactive peaks were quan-
tified using LC-ARC data handling software. Plasma
radioactivity profiles were determined by collecting the
column eluate into 96-well Deepwell LumaPlates at a rate
of 0.25 min/fraction. The plates were dried and the radio-
activity in each well determined using a PerkinElmer
TopCount NXT Microplate Scintillation Counter. HPLC
radiochromatograms were reconstructed using LC-ARC
data handling software.
For some urine and faecal samples, extracts were pre-
pared by solid-phase extraction and repeatedly injected,
and fractions were collected (0.25 min/well) in order
to obtain sufficient metabolite concentrations to allow
for additional mass spectrometry characterization. The
M12 peak isolated from urine was also subjected to
β-glucuronidase hydrolysis to confirm its identity. A 2-mL
solution of M12 in 0.2-M sodium phosphate buffer (pH
6.7) was incubated with β-glucuronidase (360 units) at
37°C for 4 h, and then extracted with ethyl acetate and
analysed by LC/MS.
Metabolite characterization by mass spectrometry
Selected plasma, urine and faecal extracts, as well as iso-
lated metabolites were analysed by HPLC coupled with
a radioactivity detector and mass spectrometer. For the
mass spectrometry analysis, mobile phase B was changed
to methanol, and for some samples, acetonitrile was added
as a post-column addition at 0.2 mL/min. Minor changes
to the LC gradient were also made for some samples to
help separate radioactive peaks with similar retention
times. Metabolites were characterized using a Finnigan
LCQ mass spectrometer (Thermo Scientific, Waltham,

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1066 M. Hoffmann et al.
Xenobiotica
MA) or a SCIEX Q Trap (Applied Biosystems, Foster City,
CA), equipped with an electrospray source. The Finnigan
mass spectrometer was operated in the positive ionization
mode, while the SCIEX mass spectrometer was operated in
the positive or negative ionization mode. The instrument
settings and potentials were adjusted as necessary to pro-
vide optimal data. The Finnigan mass spectrometer was
operated with an electrospray needle potential of 4.5 kV
and a capillary temperature of 240°C. The collision-acti-
vated dissociation studies were conducted using helium
as the collision gas. For the SCIEX mass spectrometer, the
electrospray needle potential was 5.0 kV in the positive
mode and 4.5 kV in the negative mode; the turbo probe
temperature was 550°C, the curtain gas was nitrogen, the
entrance potential was 10 V, the declustering potential was
50 V and the collision energy was 8−25 eV.
PDE4 and TNF-α activity of apremilast metabolites
PDE4 enzyme was isolated from U937 human monocytic
cells and used for testing inhibition in a cAMP hydrolysis
assay as previously described (Schafer et al. 2010). For the
TNF-α production assay, human peripheral blood mono-
nuclear cells (PBMC) were isolated from buffy coat of nor-
mal donor blood units (Blood Center of New Jersey, East
Orange, NJ) by density centrifugation over Ficoll Hypaque
(Pharmacia, Piscataway, NJ). Cells were cultured in RPMI
1640 (Life Technologies, Grand Island, NY) supple-
mented with 5% AB+ human serum (Gemini Bio-products,
Woodland, CA), 2-mM L-glutamine, 100-U/mL penicillin
and 100-μg/mL streptomycin (Life Technologies). PBMC
(2 × 105 cells) were plated in 96-well flat-bottom Costar
tissue culture plates (Corning, NY) in duplicate. Cells
were stimulated with lipopolysaccharides (LPS) (from
Salmonella abortus equi; Sigma cat.no. L-1887, St.Louis,
MO) at a final concentration of 1 ng/mL in the absence or
presence of compounds. The compounds were dissolved
in DMSO (Sigma) and subsequent dilutions were done in
culture medium immediately before use. The compounds
were added to cells 1 h before LPS stimulation. The cells
were incubated for 16−18 h at 37°C in 5% CO2, and super-
natants were then collected, diluted with culture medium
and assayed for TNF-α levels by enzyme-linked immuno-
sorbent assay (ThermoFisher, Rockford, IL). Fifty percent
inhibitory concentrations (IC50) for the PDE4 enzymatic
and TNF-α assay were calculated by non-linear regres-
sion analysis using Prism 5.1 (GraphPad Software).
Regression curves were sigmoidal dose response curves
with maximum and minimum constrained to 100% and
0%, respectively.
Pharmacokinetic analysis
Pharmacokinetic data were generated by non-compart-
mental analysis of plasma or whole blood versus time
profiles using WinNonlin (version 4.1, Enterprise Edition).
For individual subjects, the peak concentration (Cmax),
time to Cmax (Tmax), area under the concentration versus
time curve from time zero to the last quantifiable concen-
tration (AUC0-t), area under the concentration versus time
curve from time zero to infinity (AUC0−∞) and the appar-
ent terminal elimination half-life (t½) were determined.
AUC0−t and AUC0−∞ were calculated using the linear trap-
ezoidal rule. AUC0−∞ was calculated as the sum of AUC0−t +
Clast/λz, where Clast is the last observed quantifiable con-
centration. The terminal elimination rate constant (λz)
and, therefore, t½ and AUC0−∞ were estimated by fitting a
linear regression of log concentration against time values
utilizing a minimum of three data points (excluding Cmax)
that appeared to be on the terminal elimination portion
of the concentration versus time curve. λz, t½ and AUC0−∞
were not estimated in cases where the terminal elimina-
tion phase did not exhibit a linear decline with a regres-
sion coefficient (r2) > 0.8, or the data points selected did
not encompass a time interval of at least one t½.
Calculations
The amount of total radioactivity (ngEq) in urine and fae-
ces was determined by multiplying the volume or weight
of the samples by the radioactivity concentration. The
dose recovered at each time point was determined by
total radioactivity in the sample, divided by the total dose
administered, multiplied by 100%. For data values below
the limit of quantification, a value of zero was assigned
for calculations of means.
Results
Excretion of radioactivity
Following a single 20 mg, 100-μCi dose of [14C]apremilast,
urine and faeces were collected from six subjects over
216 h (9 days). Excretion of radioactivity was nearly com-
plete, with a mean recovery of approximately 97% (range
94.1%−99.3%). The amount of radioactivity (expressed as
percentage of dose) excreted in urine ranged from 47.4%
to 71.2% (mean 57.9% ± 9.9%), whereas faecal excretion
ranged from 27.6% to 50.8% (mean 39.2% ± 9.7%) over
the collection period. The majority of the radioactivity
(>90%) was recovered within the first 4 days (96 h) after
dose administration (Figure 2).
Pharmacokinetic analysis
The absorption of [14C]apremilast was relatively rapid
(Tmax of 1.5 h) and the plasma half-life was moderate
(approximately 7 h), while plasma radioactivity had a
much longer half-life (approximately 50 h) (Tables 1 and 2,
Figure 3), suggesting the presence of metabolites that
are longer-lived than parent compound. Apremilast
was generally not detected in plasma beyond the 48-h
time point, whereas radioactivity was detected out to
168 h following dose administration. Modest differences
in apremilast AUC determined via LC/MS (1913 ± 339
ng*h/mL) or via radiochromatography (2455 ± 690
ngEq*h/mL) may be attributed to method and limit of
detection differences. Based on radiochromatography,
plasma exposure (AUC) of apremilast was approximately
40% relative to total radioactivity. The pharmacokinetic
parameters of some of the more abundant metabolites

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Disposition, metabolism and mass balance of apremilast 1067
© 2011 Informa UK, Ltd.
were determined using radiochromatography (Table
2, Figure 4). The peak plasma concentrations of the
metabolites generally occurred later (Tmax of 1−5 h for
metabolites vs. 1.5 h for apremilast) and the metabolites
had somewhat longer t½ values than apremilast (11−16 h
for metabolites vs 7 h for apremilast). The most abundant
circulating metabolite was M12 (O-desmethyl apremi-
last glucuronide), which represented 39% of the circulat-
ing radioactivity and had an AUC similar to apremilast.
In addition, nine other metabolites were detectable in
plasma, none representing >7% of the circulating radio-
activity. The mean blood/plasma ratios of radioactivity
were between 0.53 and 0.63 at all time points evaluated
(data not shown), indicating no noteworthy binding
of radioactivity (apremilast and its metabolites) to the
blood cell constituents.
Metabolic profiles
HPLC radiochromatograms of plasma, urine and faecal
homogenate from a representative subject are shown in
Figure 2. Cumulative elimination of radioactivity in urine and faeces after a single oral 20-mg dose of [14C]apremilast in male healthy
subjects (● urine, ○ faeces, ■ total). Values are mean ± standard deviation.
Table 1. Plasma and whole blood total radioactivity pharmacokinetic parameters following a single oral 20-mg dose of [14C]apremilast.
PK parameter Whole-blood total radioactivitya
Cmax (ngEq/mL) 303 ± 77
Tmax (h) 2.0 (1.0−3.0)
AUC0−t (ngEq*h/mL)
3489 ± 509
AUC0−∞ (ngEq*h/mL)
3664 ± 556
t½ (h)16.3 ± 5.2
NA, not applicable; ngEq, ng [14C]apremilast equivalent.
aValues are reported as mean ± standard deviation except Tmax values, which are reported as median (min-max).
Plasma total radioactivitya
527 ± 127
1.5 (1.0−3.0)
6201 ± 937
6632 ± 653
50.4 ± 8.7
Blood-to-plasma ratio
0.57
NA
0.56
0.55
NA
Table 2. Mean ± standard deviation plasma pharmacokinetic parameters for apremilast and circulating metabolites after a single oral
20-mg dose of [14C]apremilast.
TRAApremilasta
Apremilastb
Cmax (ngEq/mL)527 ± 127333 ± 76 321 ± 134
Tmax (h)1.5 (1.0−3.0) 1.5 (1.0−3.0)1.8 (1.0−2.5)
AUC0−t (ngEq*h/mL)
5483 ± 825c
1913 ± 3392455 ± 690
AUC0−∞ (ngEq*h/mL)
6632 ± 6531970 ± 343 2636 ± 705
t½ (h)50.4 ± 8.76.8 ± 2.67.1 ± 2.7
Tmax, median and range; TRA, total radioactivity.
aApremilast concentrations in plasma determined using a Chiral LC/MS/MS assay.
bApremilast and metabolite concentrations in plasma calculated using plasma radioactivity concentrations and radiochromatography.
cAUC0−48 was used for TRA for these calculations.
dNot calculated.
M11 M12
111 ± 36
M13
7.5 ± 6.8
2.5 (1.0−24)
133 ± 125
n/cd
n/c
M14
9.4 ± 4.3
2.5 (1.0−24)
269 ± 146
n/c
n/c
M16
20.2 ± 7.6
1.0 (0.5−2.5) 2.5 (1.0−2.5)
139 ± 89
232 ± 151
10.7 ± 10.2
27.6 ± 26.0
5.3 (1.0−8.0)
363 ± 54
389 ± 91
11.0 ± 2.4
2124 ± 331
2446 ± 416
15.8 ± 3.9