Daratumumab

Identification

Summary

Daratumumab is a CD38-directed cytolytic antibody used alone or as an adjunct drug in the treatment of multiple myeloma and light chain amyloidosis.

Brand Names

Darzalex, Darzalex Faspro

Generic Name

Daratumumab

DrugBank Accession Number

DB09331

Background

Daratumumab is an immunoglobulin G1 kappa monoclonal antibody developed by Janssen and Genmab.¹ It was first described in the literature in 2010 as a monoclonal antibody that targets CD38+ multiple myeloma cells; the first of its kind.⁵

Daratumumab was granted FDA approval on 16 November 2015.⁶ It is approved for the treatment of multiple myeloma as monotherapy or combination therapy and light chain (AL) amyloidosis in combination with other drugs.^6,7

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

Protein Chemical Formula: C₆₄₆₆H₉₉₉₆N₁₇₂₄O₂₀₁₀S₄₂
Protein Average Weight: 145391.67 Da

Sequences

>Daratumumab heavy chain
EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

>Daratumumab light chain
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA
RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Download FASTA Format

Synonyms

Daratumumab

External IDs

HuMax-CD 38
HuMax-CD38
JNJ-54767414

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Pharmacology

Indication

Daratumumab is indicated as an intravenous injection alone or in combination with other medications for the treatment of multiple myeloma.⁶ It is available as a combination product with hyaluronidase for the treatment of adults with multiple myeloma as monotherapy or combination therapy and light chain amyloidosis in combination with other drugs.⁷

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Used in combination to treat	Light-chain amyloidosis	Regimen in combination with: Hyaluronidase (human recombinant) (DB06205), Cyclophosphamide (DB00531), Bortezomib (DB00188), Dexamethasone (DB01234)	••••••••••••	•••••	••••• •••••••••
Used in combination to treat	Multiple myeloma (mm)	Combination Product in combination with: Hyaluronidase (human recombinant) (DB06205)	••••••••••••	•••••	••••••••••••••••• •• • •••••••••• ••••••••• ••• •• •••••••••••••••• •••••
Used in combination to treat	Multiple myeloma (mm)	Combination Product in combination with: Hyaluronidase (human recombinant) (DB06205)	••••••••••••	•••••	•••••••• •••••••••• ••••••••• •••••••••• •••••••• •••••••••••••••• ••••• •••••••••• •••••••• •• ••••• ••••• ••••• ••••• •• •••••••• •••••••
Used in combination to treat	Multiple myeloma (mm)	Regimen in combination with: Dexamethasone (DB01234), Lenalidomide (DB00480), Hyaluronidase (human recombinant) (DB06205)	••••••••••••	•••••	••••• •••••••••• •••••••••• ••• •••••••••• •••• •••• ••••••••••
Treatment of	Multiple myeloma (mm)		••••••••••••	•••••	••••••••••••••••• •• • •••••••••• ••••••••• ••• •• •••••••••••••••• •••••	•••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Daratumumab is a monoclonal antibody that targets and induces apoptosis in cells that highly express CD38, including multiple myeloma cells.^6,7 It has a long duration of action as it is given every 1-4 weeks.^6,7 Patients should be counselled regarding the risk of hypersensitivity, neutropenia, thrombocytopenia, embryo-fetal toxicity, and interferences with cross-matching and red blood cell antibody screening.^6,7

Mechanism of action

CD38 is a glycoprotein present on the surface of hematopoietic cells and is responsible for a number of cell signalling functions.^1,2,3,6,7 Daratumumab is an immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that targets CD38.³ Cancers like multiple myeloma overexpress CD38, allowing daratumumab to have higher affinity for these cells.³ This binding allows daratumumab to induce apoptosis, antibody dependent cellular phagocytosis, and antibody and complement-dependent cytotoxicity.^2,3,6,7 Antibody dependent cellular phagocytosis is mediated by the FC region of the antibody inducing phagocytes such as macrophages, antibody dependent cellular cytotoxicity is mediated by the FC region of the antibody inducing effector cells such as natural killer cells, and complement dependent cytotoxicity is mediated by the FC region of the antibody binding to and inducing complement protein activity.^1,2,3

Target	Actions	Organism
UADP-ribosyl cyclase 1	antibody	Humans

Absorption

Subcutaneous daratumumab reaches a C_max of 592µg/mL compared to intravenous daratumumab, which reaches a C_max of 688µg/mL.⁷ The AUC of subcutaneous daratumumab is 4017µg/mL*day compared to intravenous daratumumab, which has an AUC of 4019µg/mL*day.⁷

Volume of distribution

Daratumumab intravenous monotherapy has a volume of distribution of 4.7 ± 1.3L and the combination therapy has a volume of distribution of 4.4 ± 1.5L.⁶ Subcutaneous daratumumab has a volume of distribution of the central compartment of 5.2L and a volume of distribution of the peripheral compartment of 3.8L.⁷

Protein binding

Data regarding protein binding of daratumumab in serum is not readily available.^6,7

Metabolism

Monoclonal antibodies are expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes.⁴

Route of elimination

Monoclonal antibodies are metabolized to amino acids used for synthesis of new proteins or are eliminated by the kidneys.⁴

Half-life

Intravenous daratumumab has a terminal half life of 18 ± 9 days.⁶ Subcutaneous daratumumab has a half life of 20 days.⁷

Clearance

Intravenous daratumumab has a clearance of 171.4 ± 95.3mL/day.⁶ Subcutaneous daratumumab has a clearance of 119mL/day.⁷

Adverse Effects

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Toxicity

Data regarding overdoses of daratumumab are not readily available.^6,7 Patients should be treated with symptomatic and supportive measures.^6,7

Pathways

Not Available

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Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

Drug	Interaction
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Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Daratumumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Daratumumab.
Aducanumab	The risk or severity of adverse effects can be increased when Daratumumab is combined with Aducanumab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Daratumumab.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Daratumumab.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Darzalex	Solution	400 mg / 20 mL	Intravenous	Janssen Pharmaceuticals	2016-07-12	Not applicable
Darzalex	Injection, solution, concentrate	100 mg/5mL	Intravenous	Janssen Biotech, Inc.	2015-11-16	Not applicable
Darzalex	Injection, solution	1800 mg	Subcutaneous	Janssen Cilag International Nv	2020-12-16	Not applicable
Darzalex	Injection, solution, concentrate	20 mg/ml	Intravenous	Janssen Cilag International Nv	2016-09-08	Not applicable
Darzalex	Solution	100 mg / 5 mL	Intravenous	Janssen Pharmaceuticals	2016-07-12	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Darzalex Faspro	Daratumumab (1800 mg/15mL) + Hyaluronidase (human recombinant) (30000 U/15mL)	Injection	Subcutaneous	Janssen Biotech, Inc.	2020-05-01	Not applicable

Chemical Identifiers

UNII: 4Z63YK6E0E
CAS number: 945721-28-8

References

General References

McKeage K: Daratumumab: First Global Approval. Drugs. 2016 Feb;76(2):275-81. doi: 10.1007/s40265-015-0536-1. [Article]
Phipps C, Chen Y, Gopalakrishnan S, Tan D: Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development. Ther Adv Hematol. 2015 Jun;6(3):120-7. doi: 10.1177/2040620715572295. [Article]
de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW, Mutis T, Bleeker WK, Anderson KC, Lokhorst HM, van de Winkel JG, Parren PW: Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011 Feb 1;186(3):1840-8. doi: 10.4049/jimmunol.1003032. Epub 2010 Dec 27. [Article]
Keizer RJ, Huitema AD, Schellens JH, Beijnen JH: Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010 Aug;49(8):493-507. doi: 10.2165/11531280-000000000-00000. [Article]
van der Veer MS, de Weers M, van Kessel B, Bakker JM, Wittebol S, Parren PW, Lokhorst HM, Mutis T: Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica. 2011 Feb;96(2):284-90. doi: 10.3324/haematol.2010.030759. Epub 2010 Nov 25. [Article]
FDA Approved Drug Products: DARZALEX (daratumumab) injection, for intravenous use [Link]
FDA Approved Drug Products: DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) injection, for subcutaneous use [Link]

External Links

PubChem Substance: 347910441
RxNav: 1721947
ChEMBL: CHEMBL1743007
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Daratumumab

FDA label

Download (417 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Multiple Myeloma (MM)	1
4	Recruiting	Treatment	Acquired Haemophilia	1
4	Recruiting	Treatment	Hemophilia A With Inhibitors	1
4	Recruiting	Treatment	Multiple Myeloma (MM)	1
3	Active Not Recruiting	Treatment	Amyloidosis	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Subcutaneous	1800 MG
Injection, solution, concentrate	Intravenous
Injection, solution, concentrate	Intravenous	100 mg/5mL
Injection, solution, concentrate	Intravenous	20 mg/ml
Injection, solution, concentrate	Intravenous	20 mg/1ml
Injection, solution, concentrate	Intravenous; Parenteral	20 MG/ML
Solution	Intravenous	100 mg / 5 mL
Solution	Intravenous	400 mg / 20 mL
Injection, solution, concentrate		100 mg/5ml
Solution, concentrate	Intravenous	20 mg
Injection, solution	Intravenous
Injection, solution, concentrate		400 mg/20ml
Solution	Intravenous	20 mg/mL
Injection	Subcutaneous
Solution	Subcutaneous	1800 mg / 15 mL
Injection, solution	Subcutaneous	1800 mg/15mL
Solution	Subcutaneous	120 mg

Prices

Not Available

Patents

Not Available

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. ADP-ribosyl cyclase 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Antibody

General Function: Transferase activity
Specific Function: Synthesizes the second messagers cyclic ADP-ribose and nicotinate-adenine dinucleotide phosphate, the former a second messenger for glucose-induced insulin secretion. Also has cADPr hydrolase activ...
Gene Name: CD38
Uniprot ID: P28907
Uniprot Name: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
Molecular Weight: 34328.145 Da

References

de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW, Mutis T, Bleeker WK, Anderson KC, Lokhorst HM, van de Winkel JG, Parren PW: Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011 Feb 1;186(3):1840-8. doi: 10.4049/jimmunol.1003032. Epub 2010 Dec 27. [Article]

Drug created at November 18, 2015 17:34 / Updated at June 03, 2022 07:24

Daratumumab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References