Details of the Drug

General Information of Drug (ID: DMTWS9E)

Drug Name

Apremilast

Synonyms

Apremilast (USAN); CC-10004; N-[2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethyl]-1,3-dioxo-isoindol-4-yl]acetamide

Indication

Disease Entry	ICD 11	Status	REF
Psoriasis vulgaris	EA90	Approved	[1], [2]

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

460.5

Topological Polar Surface Area (xlogp)

1.8

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 584 mcg/L [3]
Absorption Tmax: The time to maximum plasma concentration (Tmax) is 2.5 h [3]
Bioavailability: The bioavailability of drug is 73% [3]
Clearance: The clearance of drug is 10 L/h [4]
Elimination: Only 3% and 7% of an apremilast dose are detected in the urine and feces as unchanged drug, respectively [4]
Half-life: The concentration or amount of drug in body reduced by one-half in 6 - 9 hours [5]
Metabolism: The drug is metabolized via oxidation, hydrolysis, in addition to conjugation [6]
Unbound Fraction: The unbound fraction of drug in plasma is 0.32% [7]
Vd: The volume of distribution (Vd) of drug is 87 L [4]

Chemical Identifiers

Formula: C22H24N2O7S
IUPAC Name: N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindol-4-yl]acetamide
Canonical SMILES: CCOC1=C(C=CC(=C1)[C@@H](CS(=O)(=O)C)N2C(=O)C3=C(C2=O)C(=CC=C3)NC(=O)C)OC
InChI: 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
InChIKey: IMOZEMNVLZVGJZ-QGZVFWFLSA-N

Cross-matching ID

PubChem CID: 11561674
ChEBI ID: CHEBI:78540
CAS Number: 608141-41-9
DrugBank ID: DB05676
TTD ID: D07ESC
VARIDT ID: DR01264
INTEDE ID: DR0124
ACDINA ID: D00041

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Cyclin-dependent kinase 4 (CDK4)	TT0PG8F	CDK4_HUMAN	Inhibitor	[8]
Cyclin-dependent kinase 6 (CDK6)	TTO0FDJ	CDK6_HUMAN	Inhibitor	[8]
Phosphodiesterase 4 (PDE4)	TTV5CGO	NOUNIPROTAC	Inhibitor	[9], [10], [2]

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Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)_{Main DME}	DE4LYSA	CP3A4_HUMAN	Substrate	[12]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Substrate	[13]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Substrate	[13]

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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

The Studied Disease

Psoriasis vulgaris

ICD Disease Classification

EA90

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Cyclin-dependent kinase 4 (CDK4)	DTT	CDK4	3.30E-72	0.65	2.39
P-glycoprotein 1 (ABCB1)	DTP	P-GP	3.12E-33	-8.30E-01	-1.04E+00
Cytochrome P450 2A6 (CYP2A6)	DME	CYP2A6	5.48E-01	-5.89E-02	-1.77E-01
Cytochrome P450 1A2 (CYP1A2)	DME	CYP1A2	5.52E-19	-2.25E-01	-5.53E-01
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	5.59E-39	-3.76E-01	-1.64E+00

Molecular Expression Atlas (MEA)

MEA Detail

Jump to Detail Molecular Expression Atlas of This Drug

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Apremilast (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Ivosidenib	DM8S6T7	Moderate	Increased metabolism of Apremilast caused by Ivosidenib mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[64]
Arn-509	DMT81LZ	Major	Increased metabolism of Apremilast caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[64]
Gilteritinib	DMWQ4MZ	Moderate	Decreased clearance of Apremilast due to the transporter inhibition by Gilteritinib.	Acute myeloid leukaemia [2A60]	[65]
Erdafitinib	DMI782S	Moderate	Decreased clearance of Apremilast due to the transporter inhibition by Erdafitinib.	Bladder cancer [2C94]	[66]
Pexidartinib	DMS2J0Z	Moderate	Increased metabolism of Apremilast caused by Pexidartinib mediated induction of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[64]
Tucatinib	DMBESUA	Moderate	Decreased clearance of Apremilast due to the transporter inhibition by Tucatinib.	Breast cancer [2C60-2C6Y]	[67]
PF-04449913	DMSB068	Moderate	Decreased clearance of Apremilast due to the transporter inhibition by PF-04449913.	Chronic myelomonocytic leukaemia [2A40]	[68]
Lumacaftor	DMCLWDJ	Major	Increased metabolism of Apremilast caused by Lumacaftor mediated induction of CYP450 enzyme.	Cystic fibrosis [CA25]	[69]
Cenobamate	DMGOVHA	Moderate	Increased metabolism of Apremilast caused by Cenobamate mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[64]
Rufinamide	DMWE60C	Moderate	Increased metabolism of Apremilast caused by Rufinamide mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[64]
Eslicarbazepine	DMZREFQ	Moderate	Increased metabolism of Apremilast caused by Eslicarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[64]
Tazemetostat	DMWP1BH	Moderate	Increased metabolism of Apremilast caused by Tazemetostat mediated induction of CYP450 enzyme.	Follicular lymphoma [2A80]	[64]
Ripretinib	DM958QB	Moderate	Decreased clearance of Apremilast due to the transporter inhibition by Ripretinib.	Gastrointestinal stromal tumour [2B5B]	[65]
GS-5885	DMSL3DX	Moderate	Decreased clearance of Apremilast due to the transporter inhibition by GS-5885.	Hepatitis virus infection [1E50-1E51]	[70]
Etravirine	DMGV8QU	Moderate	Increased metabolism of Apremilast caused by Etravirine mediated induction of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[64]
Lesinurad	DMUR64T	Moderate	Increased metabolism of Apremilast caused by Lesinurad mediated induction of CYP450 enzyme.	Inborn purine/pyrimidine/nucleotide metabolism error [5C55]	[64]
Brigatinib	DM7W94S	Moderate	Increased metabolism of Apremilast caused by Brigatinib mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[64]
PF-06463922	DMKM7EW	Moderate	Increased metabolism of Apremilast caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[64]
Vemurafenib	DM62UG5	Moderate	Increased metabolism of Apremilast caused by Vemurafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[64]
Dabrafenib	DMX6OE3	Moderate	Increased metabolism of Apremilast caused by Dabrafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[64]
Lasmiditan	DMXLVDT	Moderate	Decreased clearance of Apremilast due to the transporter inhibition by Lasmiditan.	Migraine [8A80]	[71]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Apremilast caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[72]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Apremilast caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[73]
Enzalutamide	DMGL19D	Major	Increased metabolism of Apremilast caused by Enzalutamide mediated induction of CYP450 enzyme.	Prostate cancer [2C82]	[64]
Telotristat ethyl	DMDIYFZ	Moderate	Increased metabolism of Apremilast caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[68]
Armodafinil	DMGB035	Minor	Increased metabolism of Apremilast caused by Armodafinil mediated induction of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[74]
Fostamatinib	DM6AUHV	Moderate	Decreased metabolism of Apremilast caused by Fostamatinib mediated inhibition of CYP450 enzyme.	Thrombocytopenia [3B64]	[75]
Elagolix	DMB2C0E	Moderate	Increased metabolism of Apremilast caused by Elagolix mediated induction of CYP450 enzyme.	Uterine fibroid [2E86]	[64]
Betrixaban	DM2C4RF	Moderate	Decreased clearance of Apremilast due to the transporter inhibition by Betrixaban.	Venous thromboembolism [BD72]	[76]
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⏷ Show the Full List of 29 DDI Information of This Drug

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Carmellose sodium	E00625	Not Available	Disintegrant
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
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Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Apremilast 30 mg tablet	30 mg	Oral Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7372).
2	Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
3	FDA Approved Drug Products: Otezla (apremilast) tablets for oral use
4	Otezla product information
5	Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor: A novel treatment option for nurse practitioners treating patients with psoriatic disease. J Am Assoc Nurse Pract. 2016 Dec;28(12):683-695. doi: 10.1002/2327-6924.12428. Epub 2016 Nov 21.
6	Chavan BB, Kalariya PD, Tiwari S, Nimbalkar RD, Garg P, Srinivas R, Talluri MVNK: Identification and characterization of vilazodone metabolites in rats and microsomes by ultrahigh-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry. Rapid Commun Mass Spectrom. 2017 Dec 15;31(23):1974-1984. doi: 10.1002/rcm.7982.
7	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
8	Agreement signed with Prostagenics to develop prostate cancer treatment. Innovate Oncology, Inc. 2005.
9	Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26.
10	CC-10004 . Curr Opin Investig Drugs. 2005 May;6(5):518-25.
11	Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
12	Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor: a novel treatment option for nurse practitioners treating patients with psoriatic disease. J Am Assoc Nurse Pract. 2016 Dec;28(12):683-695.
13	Apremilast (Otezla): a new oral treatment for adults with psoriasis and psoriatic arthritis. P T. 2015 Aug;40(8):495-500.
14	Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
15	Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
16	Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
17	Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
18	Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
19	Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
20	Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
21	The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
22	Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
23	Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
24	Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
25	Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
26	Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
27	PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
28	The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
29	The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
30	Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
31	Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.
32	Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
33	Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
34	Psychotropic drug interactions with valproate. Clin Neuropharmacol. 2005 Mar-Apr;28(2):96-101.
35	The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
36	Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
37	CYP2A6- and CYP2A13-catalyzed metabolism of the nicotine delta-5'(1')iminium ion. J Pharmacol Exp Ther. 2012 Nov;343(2):307-15.
38	Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
39	MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
40	Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
41	Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
42	Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
43	Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
44	Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit. 2011 Apr;33(2):244-50.
45	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
46	2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
47	Therapeutic targeting of 3',5'-cyclic nucleotide phosphodiesterases: inhibition and beyond. Nat Rev Drug Discov. 2019 Oct;18(10):770-796.
48	2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76.
49	Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
50	Trial of Roflumilast Cream for Chronic Plaque Psoriasis. N Engl J Med. 2020 Jul 16;383(3):229-239.
51	Ocular hypotension induced by topical dopaminergic drugs and phosphodiesterase inhibitors. Eur J Pharmacol. 1994 Jun 2;258(1-2):85-94.
52	Antipruritic effect of the topical phosphodiesterase 4 inhibitor E6005 ameliorates skin lesions in a mouse atopic dermatitis model. J Pharmacol Exp Ther. 2013 Jul;346(1):105-12.
53	Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
54	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2017
55	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
56	Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82.
57	A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
58	Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
59	Liposarcoma: molecular genetics and therapeutics. Sarcoma. 2011;2011:483154.
60	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
61	Clinical pipeline report, company report or official report of Gan & Lee Pharmaceuticals.
62	Clinical pipeline report, company report or official report of Fochon Pharmaceuticals.
63	Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. J Med Chem. 2018 Feb 22;61(4):1499-1518.
64	Product Information. Otezla (apremilast). Celgene Corporation, Summit, NJ.
65	Cerner Multum, Inc. "Australian Product Information.".
66	Product Information. Balversa (erdafitinib). Janssen Products, LP, Horsham, PA.
67	Product Information. Tukysa (tucatinib). Seattle Genetics Inc, Bothell, WA.
68	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
69	Product Information. Kalydeco (ivacaftor). Vertex Pharmaceuticals, Cambridge, MA.
70	Product Information. Harvoni (ledipasvir-sofosbuvir). Gilead Sciences, Foster City, CA.
71	Product Information. Reyvow (lasmiditan). Lilly, Eli and Company, Indianapolis, IN.
72	Product Information. Xeglyze (abametapir topical). Dr. Reddy's Laboratories Inc, Upper Saddle River, NJ.
73	Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
74	Doherty MM, Charman WN "The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism?" Clin Pharmacokinet 41 (2002): 235-53. [PMID: 11978143]
75	Product Information. Tavalisse (fostamatinib). Rigel Pharmaceuticals, South San Francisco, CA.
76	Product Information. Bevyxxa (betrixaban). Portola Pharmaceuticals, South San Francisco, CA.