Apremilast (CC-10004) has an IC50 of 104 nM (pIC50=6.98±0.2) that inhibits TNF-α release by lipopolysaccharide (LPS). This is similar to the potency of Apremilast for PDE4 enzymatic inhibition (IC50=74 nM) and nearly exactly replicates the TNF-α inhibition that Apremilast has previously been shown to inhibit on peripheral blood mononuclear cells (PBMCs) (IC50=110 nM). With increased intracellular cAMP levels, apremilast suppresses TNF-α, and these results convincingly support this theory. Apremilast-induced IL-10 activation and TNF-α suppression were not observed in the presence of PKA, Epac1, or Epac2 knockdowns].

When taken orally at a dose of 5 mg/kg, apremilast (CC-10004) dramatically reduces the amount of TNF-α produced in the air pouch by 39% (61±6% of the vehicle, P <0.001) and decreases the number of leukocytes by 28% (72±12% of the vehicle, P <0.05). Immunohistologic investigation confirms that Apremilast significantly reduces neutrophil accumulation in the air pouch membrane. Both methotrexate (MTX) and apremilast considerably decrease leukocyte infiltration in the murine air pouch model, however only apremilast significantly inhibits TNF-α release. There is no greater suppression of leukocyte infiltration or TNF-α release when MTX (1 mg/kg) is added to Apremilast (5 mg/kg) than when Apremilast is used alone[1]. It has been demonstrated that the new oral PDE4 inhibitor apremilast controls inflammatory mediators. The mean maximum plasma concentration (Cmax) following oral administration of Apremilast is determined to be 67.00±14.87 ng/mL. Apremilast's plasma concentration drops quickly, and it eventually disappears from plasma with a terminal half-life of 0.92±0.46 h[2].

Absorption, Distribution and Excretion
An oral dose of apremilast is well-absorbed and the absolute bioavailability is approximately 73%. Tmax is approximately 2.5 hours and Cmax has been reported to be approximately 584 ng/mL in one pharmacokinetic study. Food intake does not appear to affect apremilast absorption.
Only 3% and 7% of an apremilast dose are detected in the urine and feces as unchanged drug, respectively, indicating extensive metabolism and high absorption.
The average apparent volume of distribution (Vd) is about 87 L, suggesting that apremilast is distributed in the extravascular compartment.
In healthy patients, the plasma clearance of apremilast is about 10 L/hour.
Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L.
The lacteal excretion of apremilast was evaluated following oral administration of apremilast to lactating CD-1 mice. In this study, female mice approximately 13 days postpartum received a single oral dose of apremilast at 10 mg/kg, administered by oral gavage in a volume of 10 mL/kg. Milk and blood samples from 5 animals per time point were obtained at 1, 6, and 24 hr postdose and apremilast concentrations determined in plasma and milk using LC-MS/MS analysis. The mean apremilast plasma concentrations at 1 and 6 hr post-dose were 984 and 138 ng/mL, while concentrations in milk were 1441 and 186 ng/mL, respectively. The resulting mean milk-to-plasma ratios ranged from 1.46 to 1.62, indicating transfer of apremilast into milk in mice. Plasma and milk concentrations were below the detection limit of 3 ng/mL in the 24-hr samples.
In monkeys, pregnant animals were administered daily oral doses of apremilast beginning on gestation day 20 through gestation day 50, and a single oral dose on gestation day 100 at dosages of 20, 50, 200, and 1000 mg/kg/day (n = 16/group at the beginning of the study). Maternal and fetal blood was collected at 5 hr postdose on gestation Day 100. In all dosage groups, the fetal-to-maternal plasma concentration ratios were between 0.3 and 0.4, indicating apremilast crossed the placenta in monkeys.
As part of fertility and developmental toxicity study in female CD-1 mice and an embryo-fetal development study in cynomolgus monkeys, the transport of apremilast across the placenta was assessed. In mice, following daily oral administration of apremilast beginning 15 days prior to cohabitation and continuing through Day 15 of presumed gestation at doses of 10, 20, 40, and 80 mg/kg/day, blood was collected from pregnant mice (n = 3/time point) at 0.5, 2, 4, 8, and 24 hr postdose on gestation Day 15. Blood was collected from fetuses) at the time of sacrifice in the 24 hr postdose mice. Maternal plasma apremilast concentrations increased in a less than dose proportional manner. The fetal plasma concentrations at 24 hr were highly variable, with six of the ten litters evaluated being below the limit of quantification (1 ng/mL). In fetal plasma from four of the ten litters evaluated, apremilast was quantified, with concentrations ranging from 14.5 to 2813 ng/mL. The mean fetal-to-maternal plasma concentration ratios ranged from 0.3 to 1.07, indicating apremilast crossed the placenta in mice.
For more Absorption, Distribution and Excretion (Complete) data for Apremilast (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
Apremilast is heavily metabolized by various pathways, which include oxidation, hydrolysis, in addition to conjugation. About 23 metabolites are produced from its metabolism. The CYP3A4 primarily mediates the oxidative metabolism of this drug, with smaller contributions from CYP1A2 and CYP2A6 enzymes. The main metabolite of apremilast, M12, is an inactive glucuronide conjugate form of the O-demethylated drug. Some other major metabolites, M14 and M16, are significantly less active in the inhibition of PDE4 and inflammatory mediators than their parent drug, apremilast. After an oral dose, unchanged apremilast (45%) and the inactive metabolite, O-desmethyl apremilast glucuronide (39%) are found in the plasma. Minor metabolites M7 and M17 are active, but are only present in about 2% or less of apremilast concentrations, and likely not significant contributors to the actions of apremilast.
The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively.
Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.
In /an/ oral study, concentrations of both total radioactivity (e.g., parent compound plus any metabolites) and of parent compound in plasma were greater in females than in males. In males, the total radioactivity AUC values were 25 to 96 times greater than those for parent compound, whereas in females the difference was only 2- to 3-fold, suggesting that metabolism was more extensive in male than in female rats. In the same study following six daily doses, accumulation was indicated by Cmax and AUC values in females, but not in males.
In a bile-duct cannulated male mouse study following a single 10 mg/kg oral dose of (14)C-apremilast, 54% and 16% of the radioactive dose was excreted via the biliary and urinary routes, suggesting that at least 70% of the radioactive dose was absorbed in mice, indicating apremilast is subject to moderate first pass metabolism. Toxicokinetic evaluation in mice suggests exposure increases dose-proportionally and less than dose-proportionally at doses over 100 mg/kg/day. The studies do not indicate sex-related differences or inversion of apremilast to its R enantiomer in mice.
For more Metabolism/Metabolites (Complete) data for Apremilast (6 total), please visit the HSDB record page.

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Biological Half-Life
The average elimination half-life of this drug ranges from 6-9 hours.
terminal elimination half-life of approximately 6-9 hours

Toxicity Summary
IDENTIFICATION AND USE: Apremilast is a white to pale-yellow powder. Apremilast is used for the treatment of adult patients with active psoriatic arthritis. It is also used for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. HUMAN EXPOSURE AND TOXICITY: The most common adverse reactions are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache. Apremilast did not induce chromosome aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. ANIMAL STUDIES: Apremilast has low potential for acute toxicity. Apremilast was evaluated in a series of repeat-dose oral toxicity studies of up to 6 months duration in mice (dose levels of 10, 100 and 1000 mg/kg/day), 12 months duration in monkeys (dose levels of 60, 180 and 600 mg/kg/day) and 90 days duration in rats. Apremilast-related mortality was observed in mice and rats and was primarily attributed to vascular and/or perivascular inflammation. Dose-related inflammatory responses were predominantly observed in mice and rats and included neutrophilia, lymphopenia, and changes in serum proteins (decreased albumin, increased globulin, and increased hapotoglobin, C-reactive protein (CRP), and/or fibrinogen). These inflammatory responses were associated with arteritis and perivascular inflammation in various tissues and organs (e.g. mesentery, heart, lungs, thymus, liver, skeletal muscle, mammary gland, skin and pancreas) in mice and rats, but not in monkeys, even at higher systemic exposures than those achieved in mice and rats. Complete or partial reversibility of the inflammatory findings in mice and rats was observed. Other target organs of apremilast toxicity include non-adverse centrilobular hepatocellular hypertrophy in the liver (mouse) and variable lymphoid depletion in lymphoid tissues (mouse and rat). Long-term studies were conducted in mice and rats with apremilast to evaluate its carcinogenic potential. No evidence of apremilast-induced tumors was observed in mice at oral doses up to 8.8-times the Maximum Recommended Human Dose (MRHD) on an AUC basis (1000 mg/kg/day) or in rats at oral doses up to approximately 0.08- and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in females, respectively). In a male mouse fertility study, apremilast at oral dosages of 1, 10, 25, and 50 mg/kg/day produced no effects on male fertility. In a combined female mouse fertility and embryo-fetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, altered estrous cycling and increased time to mating was observed from 20 mg/kg/day. Nevertheless, all mice mated and pregnancy rates were unaffected. Apremilast did not induce mutations in an Ames assay. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg/day.

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Interactions
Otezla has not been evaluated and is not indicated to be used in combination with biological therapeutics for psoriasis such as TNF antagonists and anti-IL-12/23 p40 antibodies. Otezla is not recommended in combination with these biological therapeutics.
Otezla has not been evaluated and is not indicated in combination with potent immunosuppressive drugs (e.g. cyclosporine, tacrolimus). Otezla is not recommended in combination with potent immunosuppressive drugs.
Apremilast exposure (AUC) and maximal concentrations (Cmax) were decreased by 72% and 43% when co-administered with CYP3A4 inducer rifampin, and may result in reduced clinical efficacy of apremilast. Hence coadministration of rifampin or other CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin) along with Otezla is not recommended.
St John's Wort is a CYP3A4 inducer, and co-administration with Otezla may result in loss of efficacy or reduced clinical response, and is not recommended.

[1]. Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors. Arthritis Res Ther. 2015 Sep 15;17:249.

[2]. Determination of Apremilast in Rat Plasma by UPLC-MS-MS and Its Application to a Pharmacokinetic Study. J Chromatogr Sci. 2016 Sep;54(8):1336-40.

Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal; Phosphodiesterase Inhibitors
Otezla is indicated for the treatment of adult patients with active psoriatic arthritis. /Included in US product label/
Otezla is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. /Included in US product label/
EXPL THER /The purpose of this study is/ to evaluate the efficacy and safety of an oral phosphodiesterase 4 inhibitor, apremilast, in treatment of ankylosing spondylitis (AS) by monitoring symptoms and signs in a pilot study including exploratory investigation of effects of PDE4 inhibition on blood biomarkers of bone biology. In this double-blind, placebo-controlled, single-centre, Phase II study, patients with symptomatic AS with active disease on MRI were randomized to apremilast 30 mg BID or placebo over 12 weeks. Bath Indices were monitored serially. Patients were followed for 4 weeks after stopping medication. Bone biomarkers were assessed at baseline and day 85. 38 subjects were randomised and 36 subjects completed the study. Although the primary end-point (change in BASDAI at week 12) was not met, apremilast was associated with numerically greater improvement from baseline for all clinical assessments compared with placebo with mean change in BASDAI (-1.59 + or - 1.48 vs -0.77 + or - 1.47), BASFI (-1.74 + or - 1.91 vs -0.28 + or - 1.61) and BASMI (-0.51 + or - 1.02 vs -0.21 + or - 0.67); however, differences did not achieve statistical significance. The clinical indices returned to baseline values by 4 weeks after cessation of apremilast. Six apremilast patients (35.3%) vs 3 placebo (15.8%) achieved ASAS20 responses (p=0.25). There were statistically significant decreases in serum RANKL and RANKL:osteoprotegrin ratio and plasma sclerostin but no significant changes in serum DKK-1, bone alkaline phosphatase, TRAP5b, MMP3, osteoprotegrin, or osteocalcin. Although a small pilot study, these results suggest that apremilast may be effective and well tolerated in AS and modulates biomarkers of bone biology. These data support further research of apremilast in axial inflammation.
EXPL THER Discoid lupus erythematosus (DLE) is a chronic inflammatory disorder mediated by Th1 cells. Apremilast is a novel oral PDE4 enzyme inhibitor capable of blocking leukocyte production of IL-12, IL-23, TNF-a, INF- with subsequent suppression of Th1 and Th17-mediated immune responses, and proven clinical efficacy for psoriasis as well as rheumatoid and psoriatic arthritis. Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) showed a significant (P<0.05) decrease after 85 days of treatment with apremilast 20 mg twice daily in 8 patients with active discoid lupus. The adverse events related to the drug were mild and transient. This is the first open label study to use apremilast as a treatment modality for discoid lupus. Our observations indicate that apremilast may constitute a safe and effective therapeutic option for DLE.

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Drug Warnings
Treatment with Otezla is associated with an increase in adverse reactions of depression. Before using Otezla in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with Otezla in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Otezla if such events occur.
The safety and effectiveness of Otezla in pediatric patients less than 18 years of age have not been established.
It is not known whether Otezla or its metabolites are present in human milk; however apremilast was detected in milk of lactating mice. Because many drugs are present in human milk, caution should be exercised when Otezla is administered to a nursing woman.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
For more Drug Warnings (Complete) data for Apremilast (11 total), please visit the HSDB record page.

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Pharmacodynamics
Apremilast reduces but does not completely inhibit various inflammatory cytokines such as IL-1α, IL-6, IL-8, IL-10 MCP-1, MIP-1β, MMP-3, and TNF-α, relieving the symptoms of psoriasis and Behcet's disease, which are caused by an increase in these inflammatory mediators. This drug has also been proven to be effective in relieving the pain associated with oral ulcers in Behcet's disease. Apremilast may cause unwanted weight loss and worsen depression, leading to suicidal thoughts or actions. It is advisable to monitor for symptoms of depression and seek medical attention if they occur, especially in patients with pre-existing depression. The need for apremilast should be carefully assessed along with the risk of worsening depression and suicide. If weight loss occurs, the degree of weight loss should be evaluated, and consideration should be made for the possible discontinuation of apremilast.

C22H24N2O7S

460.50

460.13

608141-41-9

Apremilast-d5;1258597-47-5;(R)-Apremilast;608141-44-2;(Rac)-Apremilast-d5;1258597-61-3

11561674

White to light yellow solid powder

1.4±0.1 g/cm3

741.3±60.0 °C at 760 mmHg

402.1±32.9 °C

0.0±2.5 mmHg at 25°C

1.612

1.75

1

7

8

32

825

1

CCOC1=C(C=CC(=C1)[C@@H](CS(=O)(=O)C)N2C(=O)C3=C(C2=O)C(=CC=C3)NC(=O)C)OC

IMOZEMNVLZVGJZ-QGZVFWFLSA-N

InChI=1S/C22H24N2O7S/c1-5-31-19-11-14(9-10-18(19)30-3)17(12-32(4,28)29)24-21(26)15-7-6-8-16(23-13(2)25)20(15)22(24)27/h6-11,17H,5,12H2,1-4H3,(H,23,25)/t17-/m1/s1

(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide

CC-10004; CC10004; Apremilast; CC 10004; Otezla (Trade name)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (5.43 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 5 mg/mL (10.86 mM) in 0.5% CMC-Na 0.5% Tween-80 (add these co-solvents sequentially from left to right, and one by one), Suspened solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)