Daratumumab

Identification

Summary

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

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

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db09331
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

Pharmacology

Indication

Daratumumab is indicated as an intravenous injection alone or in combination with other medications for the treatment of multiple myeloma.6 Subcutaneous daratumumab with hyaluronidase is also indicated alone or in combination for the treatment of multiple myeloma.7

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
UADP-ribosyl cyclase 1
antibody
Humans
Absorption

Subcutaneous daratumumab reaches a Cmax of 592µg/mL compared to intravenous daratumumab, which reaches a Cmax 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
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
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Daratumumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Daratumumab.
AducanumabThe risk or severity of adverse effects can be increased when Daratumumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Daratumumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Daratumumab.
AmivantamabThe risk or severity of adverse effects can be increased when Daratumumab is combined with Amivantamab.
AnsuvimabThe risk or severity of adverse effects can be increased when Daratumumab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Daratumumab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Daratumumab.
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Daratumumab.
Interactions
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Food Interactions
No interactions found.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DarzalexSolution100 mg / 5 mLIntravenousJanssen Pharmaceuticals2016-07-12Not applicableCanada flag
DarzalexInjection, solution, concentrate20 mg/mlIntravenousJanssen Cilag International Nv2016-09-08Not applicableEU flag
DarzalexInjection, solution1800 mgSubcutaneousJanssen Cilag International Nv2020-12-16Not applicableEU flag
DarzalexInjection, solution, concentrate20 mg/mlIntravenousJanssen Cilag International Nv2016-09-08Not applicableEU flag
DarzalexSolution400 mg / 20 mLIntravenousJanssen Pharmaceuticals2016-07-12Not applicableCanada flag
DarzalexInjection, solution, concentrate20 mg/mlIntravenousJanssen Cilag International Nv2020-12-16Not applicableEU flag
DarzalexInjection, solution, concentrate100 mg/5mLIntravenousJanssen Biotech, Inc.2015-11-16Not applicableUS flag
Darzalex ScSolution1800 mg / 15 mLSubcutaneousJanssen Pharmaceuticals2020-08-12Not applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Darzalex FasproDaratumumab (1800 mg/15mL) + Hyaluronidase (human recombinant) (30000 U/15mL)InjectionSubcutaneousJanssen Biotech, Inc.2020-05-01Not applicableUS flag

Categories

ATC Codes
L01XC24 — Daratumumab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
4Z63YK6E0E
CAS number
945721-28-8

References

General References
  1. McKeage K: Daratumumab: First Global Approval. Drugs. 2016 Feb;76(2):275-81. doi: 10.1007/s40265-015-0536-1. [Article]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. FDA Approved Drug Products: Darzalex Daratumumab Intravenous Injection [Link]
  7. FDA Approved Drug Products: Darzalex Faspro Daratumumab and Hyaluronidase-fihj Subcutaneous Injection [Link]
PubChem Substance
347910441
RxNav
1721947
ChEMBL
CHEMBL1743007
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Daratumumab
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (417 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentMultiple Myeloma (MM)1
3Active Not RecruitingTreatmentAmyloidosis1
3Active Not RecruitingTreatmentMultiple Myeloma (MM)11
3Active Not RecruitingTreatmentRefractory Multiple Myeloma / Relapsed Multiple Myeloma1
3Active Not RecruitingTreatmentSmoldering Multiple Myeloma (SMM)1
3RecruitingTreatmentMultiple Myeloma (MM)7
3RecruitingTreatmentMultiple Myeloma (MM) / Relapse Multiple Myeloma1
3RecruitingTreatmentMultiple Myeloma in Relapse1
3RecruitingTreatmentMultiple Myeloma Stage I1
3RecruitingTreatmentNewly Diagnosed Multiple Myeloma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous
Injection, solutionSubcutaneous1800 mg
Injection, solution, concentrateIntravenous
Injection, solution, concentrateIntravenous100 mg/5mL
Injection, solution, concentrateIntravenous20 mg/ml
Injection, solution, concentrateIntravenous20 mg/1ml
Injection, solution, concentrateIntravenous; Parenteral
SolutionIntravenous100 mg / 5 mL
SolutionIntravenous400 mg / 20 mL
Injection, solution, concentrate
Solution, concentrateIntravenous20 mg
Injection, solutionIntravenous
InjectionSubcutaneous
SolutionSubcutaneous1800 mg / 15 mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets
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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
  1. 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 on November 18, 2015 17:34 / Updated on June 22, 2021 09:25