Details of the Drug

General Information of Drug (ID: DMSB068)

Drug Name
PF-04449913
Synonyms
Glasdegib; 1095173-27-5; PF 04449913; UNII-K673DMO5H9; K673DMO5H9; CHEMBL2043437; Glasdegib (PF-04449913); Glasdegib [USAN:INN]; Glasdegib (USAN/INN); PF-04449913;Glasdegib; GTPL8201; Glasdegib(PF-04449913); EX-A858; MolPort-035-789-706; SFNSLLSYNZWZQG-VQIMIIECSA-N; ZINC68251434; PF-913; BDBM50385635; 2640AH; AKOS027324121; CS-2
Indication
Disease Entry ICD 11 Status REF
Chronic myelomonocytic leukaemia 2A40 Approved [1]
Solid tumour/cancer 2A00-2F9Z Approved [2]
Drug Type
Small molecular drug
Structure
3D MOL is unavailable 2D MOL
#Ro5 Violations (Lipinski): 0 Molecular Weight (mw) 374.4
Logarithm of the Partition Coefficient (xlogp) 2.4
Rotatable Bond Count (rotbonds) 3
Hydrogen Bond Donor Count (hbonddonor) 3
Hydrogen Bond Acceptor Count (hbondacc) 4
ADMET Property
Absorption AUC
The area under the plot of plasma concentration (AUC) of drug is 9587 mcgh/L [3]
Absorption Cmax
The maximum plasma concentration (Cmax) of drug is 321 mcg/L [3]
Absorption Tmax
The time to maximum plasma concentration (Tmax) is 4 h [3]
Bioavailability
The bioavailability of drug is 55% [3]
Clearance
The clearance of drug is 5.22 L/h [3]
Elimination
49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form [4]
Half-life
The concentration or amount of drug in body reduced by one-half in 17.4 hours [5]
Metabolism
The drug is metabolized via the CYP3A4 [4]
Vd
The volume of distribution (Vd) of drug is 225 L [3]
Chemical Identifiers
Formula
C21H22N6O
IUPAC Name
1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea
Canonical SMILES
CN1CC[C@H](C[C@@H]1C2=NC3=CC=CC=C3N2)NC(=O)NC4=CC=C(C=C4)C#N
InChI
InChI=1S/C21H22N6O/c1-27-11-10-16(24-21(28)23-15-8-6-14(13-22)7-9-15)12-19(27)20-25-17-4-2-3-5-18(17)26-20/h2-9,16,19H,10-12H2,1H3,(H,25,26)(H2,23,24,28)/t16-,19-/m1/s1
InChIKey
SFNSLLSYNZWZQG-VQIMIIECSA-N
Cross-matching ID
PubChem CID
25166913
ChEBI ID
CHEBI:145428
CAS Number
1095173-27-5
DrugBank ID
DB11978
TTD ID
D0S5LO
INTEDE ID
DR0774
ACDINA ID
D01126
Combinatorial Drugs (CBD) Click to Jump to the Detailed CBD Information of This Drug
Repurposed Drugs (RPD) Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug


Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
Hedgehog signaling pathway (HS pathway) TT4LXBC NOUNIPROTAC Inhibitor [1]
Serine/threonine-protein kinase mTOR (mTOR) TTCJG29 MTOR_HUMAN Inhibitor [6]
Smoothened homolog (SMO) TT8J1S3 SMO_HUMAN Modulator [7]

Drug-Metabolizing Enzyme (DME)
DME Name DME ID UniProt ID MOA REF
Cytochrome P450 3A4 (CYP3A4)
Main DME 		DE4LYSA CP3A4_HUMAN Substrate []
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Substrate [8]
UDP-glucuronosyltransferase 1A9 (UGT1A9) DE85D2P UD19_HUMAN Substrate [8]
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

The Studied Disease Chronic myelomonocytic leukaemia
ICD Disease Classification 2A40
Molecule Name Molecule Type Gene Name p-value Fold-Change Z-score
Serine/threonine-protein kinase mTOR (mTOR) DTT MTOR 2.16E-05 -0.44 -2.3
Cytochrome P450 2C8 (CYP2C8) DME CYP2C8 1.73E-04 1.53E-01 7.44E-01
Molecular Expression Atlas (MEA) 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 PF-04449913 (Comorbidity)
DDI Drug Name DDI Drug ID Severity Mechanism Comorbidity REF
Ivosidenib DM8S6T7 Major Increased risk of prolong QT interval by the combination of PF-04449913 and Ivosidenib. Acute myeloid leukaemia [2A60] [9]
Gilteritinib DMTI0ZO Moderate Increased risk of prolong QT interval by the combination of PF-04449913 and Gilteritinib. Acute myeloid leukaemia [2A60] [10]
Oliceridine DM6MDCF Moderate Increased risk of prolong QT interval by the combination of PF-04449913 and Oliceridine. Acute pain [MG31] [10]
Levalbuterol DM5YBO1 Moderate Increased risk of ventricular arrhythmias by the combination of PF-04449913 and Levalbuterol. Asthma [CA23] [11]
Troleandomycin DMUZNIG Major Decreased metabolism of PF-04449913 caused by Troleandomycin mediated inhibition of CYP450 enzyme. Bacterial infection [1A00-1C4Z] [10]
Pexidartinib DMS2J0Z Major Increased metabolism of PF-04449913 caused by Pexidartinib mediated induction of CYP450 enzyme. Bone/articular cartilage neoplasm [2F7B] [12]
MK-8228 DMOB58Q Moderate Decreased metabolism of PF-04449913 caused by MK-8228 mediated inhibition of CYP450 enzyme. Cytomegaloviral disease [1D82] [10]
Eslicarbazepine DMZREFQ Major Increased metabolism of PF-04449913 caused by Eslicarbazepine mediated induction of CYP450 enzyme. Epilepsy/seizure [8A61-8A6Z] [10]
Ripretinib DM958QB Moderate Decreased clearance of PF-04449913 due to the transporter inhibition by Ripretinib. Gastrointestinal stromal tumour [2B5B] [13]
Berotralstat DMWA2DZ Moderate Decreased metabolism of PF-04449913 caused by Berotralstat mediated inhibition of CYP450 enzyme. Innate/adaptive immunodeficiency [4A00] [10]
Brigatinib DM7W94S Moderate Increased metabolism of PF-04449913 caused by Brigatinib mediated induction of CYP450 enzyme. Lung cancer [2C25] [10]
PF-06463922 DMKM7EW Major Increased metabolism of PF-04449913 caused by PF-06463922 mediated induction of CYP450 enzyme. Lung cancer [2C25] [10]
Pralsetinib DMWU0I2 Moderate Decreased clearance of PF-04449913 due to the transporter inhibition by Pralsetinib. Lung cancer [2C25] [14]
Selpercatinib DMZR15V Major Increased risk of prolong QT interval by the combination of PF-04449913 and Selpercatinib. Lung cancer [2C25] [15]
Ubrogepant DM749I3 Moderate Decreased clearance of PF-04449913 due to the transporter inhibition by Ubrogepant. Migraine [8A80] [14]
Rimegepant DMHOAUG Moderate Decreased clearance of PF-04449913 due to the transporter inhibition by Rimegepant. Migraine [8A80] [16]
Siponimod DM2R86O Major Increased risk of ventricular arrhythmias by the combination of PF-04449913 and Siponimod. Multiple sclerosis [8A40] [13]
Ozanimod DMT6AM2 Major Increased risk of ventricular arrhythmias by the combination of PF-04449913 and Ozanimod. Multiple sclerosis [8A40] [14]
Fedratinib DM4ZBK6 Moderate Decreased metabolism of PF-04449913 caused by Fedratinib mediated inhibition of CYP450 enzyme. Myeloproliferative neoplasm [2A20] [10]
Entrectinib DMMPTLH Moderate Increased risk of prolong QT interval by the combination of PF-04449913 and Entrectinib. Non-small cell lung cancer [2C25] [10]
Rucaparib DM9PVX8 Moderate Increased risk of prolong QT interval by the combination of PF-04449913 and Rucaparib. Ovarian cancer [2C73] [10]
Macimorelin DMQYJIR Major Increased risk of prolong QT interval by the combination of PF-04449913 and Macimorelin. Pituitary gland disorder [5A60-5A61] [17]
Lefamulin DME6G97 Major Increased risk of prolong QT interval by the combination of PF-04449913 and Lefamulin. Pneumonia [CA40] [18]
Darolutamide DMV7YFT Minor Decreased clearance of PF-04449913 due to the transporter inhibition by Darolutamide. Prostate cancer [2C82] [19]
Voxelotor DMCS6M5 Moderate Decreased metabolism of PF-04449913 caused by Voxelotor mediated inhibition of CYP450 enzyme. Sickle-cell disorder [3A51] [10]
Telotristat ethyl DMDIYFZ Major Increased metabolism of PF-04449913 caused by Telotristat ethyl mediated induction of CYP450 enzyme. Small intestine developmental anomaly [DA90] [12]
Larotrectinib DM26CQR Moderate Decreased metabolism of PF-04449913 caused by Larotrectinib mediated inhibition of CYP450 enzyme. Solid tumour/cancer [2A00-2F9Z] [10]
Lusutrombopag DMH6IKO Moderate Decreased clearance of PF-04449913 due to the transporter inhibition by Lusutrombopag. Thrombocytopenia [3B64] [20]
Elagolix DMB2C0E Moderate Increased metabolism of PF-04449913 caused by Elagolix mediated induction of CYP450 enzyme. Uterine fibroid [2E86] [10]
Betrixaban DM2C4RF Moderate Decreased clearance of PF-04449913 due to the transporter inhibition by Betrixaban. Venous thromboembolism [BD72] [21]
⏷ Show the Full List of 30 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
Calcium hydrogenphosphate E00294 24441 Diluent
Ferric hydroxide oxide yellow E00539 23320441 Colorant
Hypromellose E00634 Not Available Coating agent
Lactose monohydrate E00393 104938 Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate E00208 11177 lubricant
Polyethylene glycol 4000 E00654 Not Available Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Titanium dioxide E00322 26042 Coating agent; Colorant; Opacifying agent
Triacetin E00080 5541 Humectant; Plasticizing agent; Solvent
Haematite red E00236 14833 Colorant
Cellulose microcrystalline E00698 Not Available Adsorbent; Suspending agent; Diluent
⏷ Show the Full List of 10 Pharmaceutical Excipients of This Drug
Pharmaceutical Formulation
Formulation Name Drug Dosage Dosage Form Route
Glasdegib 100 mg tablet 100 mg Tablet Oral
Glasdegib 25 mg tablet 25 mg Tablet Oral
Jump to Detail Pharmaceutical Formulation Page of This Drug

References

1 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
2 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
3 Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, Onishi Y, Kobayashi M, Ikuta M, Chan G, Woolfson A, Ono C, Shaik MN, Fujii Y, Zheng X, Naoe T: Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci. 2017 Aug;108(8):1628-1633. doi: 10.1111/cas.13285. Epub 2017 Jun 19.
4 Imondi AR, Alam AS, Brennan JJ, Hagerman LM: Metabolism of sulpiride in man and rhesus monkeys. Arch Int Pharmacodyn Ther. 1978 Mar;232(1):79-91.
5 Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
6 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
7 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
8 Metabolism, excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration. Xenobiotica. 2017 Dec;47(12):1064-1076.
9 Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
10 Product Information. Daurismo (glasdegib). Pfizer U.S. Pharmaceuticals Group, New York, NY.
11 Product Information. Arcapta Neohaler (indacaterol). Novartis Pharmaceuticals, East Hanover, NJ.
12 Cronk GA, Wheatley WB, Fellers GF, Albright H "The relationship of food intake to the absorption of potassium alpha-phenoxyethyl penicillin and potassium phenoxymethyl penicillin from the gastrointestinal tract." Am J Med Sci 240 (1960): 219-25. [PMID: 13812969]
13 Cerner Multum, Inc. "Australian Product Information.".
14 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
15 Product Information. Retevmo (selpercatinib). Lilly, Eli and Company, Indianapolis, IN.
16 Product Information. Nurtec ODT (rimegepant). Biohaven Pharmaceuticals, New Haven, CT.
17 Product Information. Macrilen (macimorelin). Aeterna Zentaris, Charleston, SC.
18 Product Information. Fareston (toremifene). Schering Laboratories, Kenilworth, NJ.
19 Product Information. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.
20 EMA. European Medicines Agency. European Union "EMA - List of medicines under additional monitoring.".
21 Product Information. Bevyxxa (betrixaban). Portola Pharmaceuticals, South San Francisco, CA.