Identification

Summary

Mobocertinib is an oral kinase inhibitor targeted against EGFR and used in the treatment of NSCLC with EGFR exon 20 insertion mutations.

Brand Names
Exkivity
Generic Name
Mobocertinib
DrugBank Accession Number
DB16390
Background

Mobocertinib is a kinase inhibitor targeted against human epidermal growth factor receptor (EGFR). It is used specifically in the treatment of non-small cell lung cancer (NSCLC) caused by exon 20 insertion mutations in the EGFR gene,8 which are typically associated with a poorer prognosis (as compared to "classical" EGFR mutants causing NSCLC) and are associated with resistance to standard targeted EGFR inhibitors.6 Mobocertinib appears to be an effective means of treating this otherwise treatment-resistant NSCLC, exerting an inhibitory effect on EGFR exon 20 insertion mutant variants at concentrations 1.5- to 10-fold lower than those required to inhibit wild-type EGFR.7

Mobocertinib, under the brand name Exkivity (Takeda Pharmaceuticals Inc.), was granted accelerated approval by the FDA in September 2021 for the treatment of locally advanced or metastatic NSCLC in patients with EGFR exon 20 insertion mutations who have failed previous therapies.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 585.709
Monoisotopic: 585.306352764
Chemical Formula
C32H39N7O4
Synonyms
  • Mobocertinib
External IDs
  • AP-32788
  • AP32788
  • TAK-788
  • WHO 11183

Pharmacology

Indication

Mobocertinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.7

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Mobocertinib is an inhibitor of EGFR that preferentially targets exon 20 insertion mutant variants.7 It is available as an oral capsule taken with or without food once daily.

Mobocertinib can cause a concentration-dependent increase in QTc interval which may lead to life-threatening complications such as Torsades de Pointes. Patients with baseline risk factors for QTc prolongation should consider alternative medications or be monitored carefully throughout therapy. The use of concomitant QTc-prolonging medications should be avoided, as should concomitant inhibitors of CYP3A, as these may increase the concentration of mobocertinib and thus the risk of QTc-prolongation.7

Mechanism of action

The epidermal growth factor receptor (EGFR) is a transmembrane receptor that regulates signaling pathways in the control of cellular proliferation.5 Mutations in these proteins have been associated with certain types of lung cancer, including non-small cell lung cancer (NSCLC). While the majority of EGFR mutations associated with NSCLC involve the EGFR L858R point mutation or exon 19 deletions (referred to as "classical" EGFR mutations), less common EGFR exon 20 insertion mutations carry a particularly poor prognosis and are associated with resistance to standard targeted EGFR inhibitors.6

Mobocertinib is an inhibitor of EGFR that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR proteins, exerting a pharmacologic effect on mutant variants at concentrations 1.5- to 10-fold lower than on wild-type proteins.7

TargetActionsOrganism
AEpidermal growth factor receptor
inhibitor
Humans
Absorption

The mean absolute bioavailability of mobocertinib is 37% and the median Tmax is approximately 4 hours.7 Following a single oral dose of 160mg of mobocertinib to fasted patients, the mean Cmax and AUC0-inf were 45.8 ng/mL and 862 ng•h/mL, respectively.2

Volume of distribution

The mean apparent volume of distribution of mobocertinib was approximately 3,509 L at steady-state.7

Protein binding

Mobocertinib and its metabolites are extensively protein-bound in plasma, although the specific proteins to which they bind have not been elucidated. Following oral administration, mobocertinib is 99.3% protein-bound, AP32960 is 99.5% protein-bound, and AP32914 is 98.6% protein-bound.7

Metabolism

Mobocertinib is metabolized primarily by CYP3A enzymes to two active metabolites, AP32960 and AP32914, which are equipotent to mobocertinib and account for 36% and 4% of its combined molar AUC, respectively.7

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Route of elimination

Following oral administration of mobocertinib, approximately 76% of the administered dose was recovered in the feces (6% as unchanged parent drug) with only 4% recovered in the urine (1% as unchanged parent drug).7 The metabolite AP32960 comprised 12% and 1% of the recovered dose found in the feces and urine, respectively, while the metabolite AP32914 was below the detection limit in both.

Half-life

At steady-state, the mean elimination half-life of mobocertinib and its two active metabolites, AP32960 and AP32914, was 18 hours, 24 hours, and 18 hours, respectively.7

Clearance

At steady-state, the mean apparent oral clearance of mobocertinib and its two active metabolites, AP32960 and AP32914, was 138 L/hr, 149 L/hr, and 159 L/hr, respectively.7

Adverse Effects
Adverseeffects
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Toxicity

No data are available regarding overdosage with mobocertinib. Symptoms of overdosage are likely to be consistent with mobocertinib's adverse effects and may therefore include significant gastrointestinal symptoms, pain, fatigue, and rash.7

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Mobocertinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Mobocertinib can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be decreased when it is combined with Mobocertinib.
AbirateroneThe metabolism of Mobocertinib can be decreased when combined with Abiraterone.
AcalabrutinibThe serum concentration of Acalabrutinib can be decreased when it is combined with Mobocertinib.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Mobocertinib.
AcenocoumarolThe serum concentration of Acenocoumarol can be decreased when it is combined with Mobocertinib.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Mobocertinib.
AdalimumabThe metabolism of Mobocertinib can be increased when combined with Adalimumab.
AdenosineThe risk or severity of QTc prolongation can be increased when Adenosine is combined with Mobocertinib.
Interactions
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Food Interactions
  • Avoid St. John's Wort. St. John's Wort is a potent CYP3A inducer and may decrease the efficacy of mobocertinib.
  • Take with or without food. Co-administration with food does not significantly affect the disposition of mobocertinib.

Products

Products2
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Product Ingredients
IngredientUNIICASInChI Key
Mobocertinib succinate53QIA92ZEE2389149-74-8YXYAEUMTJQGKHS-UHFFFAOYSA-N
International/Other Brands
Exkivity (Takeda Pharmaceutical Company Limited)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ExkivityCapsule40 mg/1OralTakeda Pharmaceuticals America, Inc.2021-09-15Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
39HBQ4A67L
CAS number
1847461-43-1
InChI Key
AZSRSNUQCUDCGG-UHFFFAOYSA-N
InChI
InChI=1S/C32H39N7O4/c1-9-29(40)34-24-16-25(28(42-8)17-27(24)38(6)15-14-37(4)5)35-32-33-18-22(31(41)43-20(2)3)30(36-32)23-19-39(7)26-13-11-10-12-21(23)26/h9-13,16-20H,1,14-15H2,2-8H3,(H,34,40)(H,33,35,36)
IUPAC Name
propan-2-yl 2-[(4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxy-5-(prop-2-enamido)phenyl)amino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate
SMILES
COC1=C(NC2=NC=C(C(=O)OC(C)C)C(=N2)C2=CN(C)C3=C2C=CC=C3)C=C(NC(=O)C=C)C(=C1)N(C)CCN(C)C

References

General References
  1. Zhang S, Jin S, Griffin C, Feng Z, Lin J, Venkatakrishnan K, Gupta N: Effects of Itraconazole and Rifampin on the Pharmacokinetics of Mobocertinib (TAK-788), an Oral Epidermal Growth Factor Receptor Inhibitor, in Healthy Volunteers. Clin Pharmacol Drug Dev. 2021 Sep;10(9):1044-1053. doi: 10.1002/cpdd.967. Epub 2021 Jun 19. [Article]
  2. Zhang S, Jin S, Griffin C, Feng Z, Lin J, Baratta M, Brake R, Venkatakrishnan K, Gupta N: Single-Dose Pharmacokinetics and Tolerability of the Oral Epidermal Growth Factor Receptor Inhibitor Mobocertinib (TAK-788) in Healthy Volunteers: Low-Fat Meal Effect and Relative Bioavailability of 2 Capsule Products. Clin Pharmacol Drug Dev. 2021 Sep;10(9):1028-1043. doi: 10.1002/cpdd.951. Epub 2021 Jun 12. [Article]
  3. Vasconcelos PENS, Kobayashi IS, Kobayashi SS, Costa DB: Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations. JTO Clin Res Rep. 2021 Mar;2(3). doi: 10.1016/j.jtocrr.2020.100105. Epub 2020 Oct 6. [Article]
  4. Gonzalvez F, Vincent S, Baker TE, Gould AE, Li S, Wardwell SD, Nadworny S, Ning Y, Zhang S, Huang WS, Hu Y, Li F, Greenfield MT, Zech SG, Das B, Narasimhan NI, Clackson T, Dalgarno D, Shakespeare WC, Fitzgerald M, Chouitar J, Griffin RJ, Liu S, Wong KK, Zhu X, Rivera VM: Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer. Cancer Discov. 2021 Jul;11(7):1672-1687. doi: 10.1158/2159-8290.CD-20-1683. Epub 2021 Feb 25. [Article]
  5. Bethune G, Bethune D, Ridgway N, Xu Z: Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010 Mar;2(1):48-51. [Article]
  6. Vyse S, Huang PH: Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther. 2019 Mar 8;4:5. doi: 10.1038/s41392-019-0038-9. eCollection 2019. [Article]
  7. FDA Approved Drug Products: Exkivity (mobocertinib) capsules for oral use [Link]
  8. FDA News Release: FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations [Link]
ChemSpider
84455481
BindingDB
368374
RxNav
2570736
Wikipedia
Mobocertinib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentAdvanced/Metastatic Non-Small Cell Lung Cancer (NSCLC)1
2WithdrawnPreventionNon-Small Cell Lung Carcinoma (NSCLC)1
1Active Not RecruitingOtherNeoplasms, Lung / Non-Small Cell Lung Carcinoma (NSCLC)1
1Active Not RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
1CompletedOtherHealthy Subjects (HS)4
1RecruitingOtherCoronavirus Disease 2019 (COVID‑19) / Deteriorating renal function / Healthy Subjects (HS)1
1RecruitingOtherCoronavirus Disease 2019 (COVID‑19) / Healthy Subjects (HS) / Hepatic Impairment1
1, 2RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
Not AvailableApproved for MarketingNot AvailableNon-Small Cell Lung Carcinoma (NSCLC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral40 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility152 mg/mL @ pH 1.0; >17.6 mg/mL @ pH 6.8https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215310s000lbl.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0136 mg/mLALOGPS
logP4.92ALOGPS
logP5.26ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)12.78ChemAxon
pKa (Strongest Basic)8.87ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area113.85 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity171.52 m3·mol-1ChemAxon
Polarizability64.2 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
References
  1. FDA Approved Drug Products: Exkivity (mobocertinib) capsules for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Zhang S, Jin S, Griffin C, Feng Z, Lin J, Venkatakrishnan K, Gupta N: Effects of Itraconazole and Rifampin on the Pharmacokinetics of Mobocertinib (TAK-788), an Oral Epidermal Growth Factor Receptor Inhibitor, in Healthy Volunteers. Clin Pharmacol Drug Dev. 2021 Sep;10(9):1044-1053. doi: 10.1002/cpdd.967. Epub 2021 Jun 19. [Article]
  2. FDA Approved Drug Products: Exkivity (mobocertinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Zhang S, Jin S, Griffin C, Feng Z, Lin J, Venkatakrishnan K, Gupta N: Effects of Itraconazole and Rifampin on the Pharmacokinetics of Mobocertinib (TAK-788), an Oral Epidermal Growth Factor Receptor Inhibitor, in Healthy Volunteers. Clin Pharmacol Drug Dev. 2021 Sep;10(9):1044-1053. doi: 10.1002/cpdd.967. Epub 2021 Jun 19. [Article]
  2. FDA Approved Drug Products: Exkivity (mobocertinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. FDA Approved Drug Products: Exkivity (mobocertinib) capsules for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Exkivity (mobocertinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Exkivity (mobocertinib) capsules for oral use [Link]

Drug created at December 23, 2020 15:59 / Updated at October 09, 2021 02:49