Durvalumab

Identification

Summary

Durvalumab is an antineoplastic monoclonal antibody used to treat urothelial carcinoma and locally advanced, unresectable non-small cell lung cancer.

Brand Names
Imfinzi
Generic Name
Durvalumab
DrugBank Accession Number
DB11714
Background

Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody and a novel immune-checkpoint inhibitor for cancer treatment.2 Produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture,7 durvalumab is a programmed death-ligand 1 (PD-L1) blocking antibody that works to promote normal immune responses that attack tumour cells.7,9

Durvalumab is marketed under the brand name Imfinzi, which is available for intravenous injections. It was granted accelerated approval by the FDA in May 2017 5 for the treatment of selected patients with locally advanced or metastatic urothelial carcinoma.7 In September 2018, durvalumab was approved by the EMA for the treatment of adult patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), only if PD-L1 is expressed in ≥ 1% of tumour cells and there was no observable disease progression following platinum-based chemoradiation therapy.2,9 On March 27, 2020, durvalumab was approved by the FDA for use in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).8

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6502H10018N1742O2024S42
Protein Average Weight
146300.0 Da
Sequences
>Durvalumab heavy chain
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYY
VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSRE
EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Durvalumab light chain
EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIP
DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. KEGG DRUG: Durvalumab [Link]
Download FASTA Format
Synonyms
  • Durvalumab
External IDs
  • MEDI 4736
  • MEDI-4736
  • MEDI4736

Pharmacology

Indication

Durvalumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.7

Durvalumab is indicated for the treatment of patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.7 It is also approved for the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) in combination with etoposide and either carboplatin or cisplatin as first-line therapy.8

Durvalumab is indicated as monotherapy used for the treatment of locally advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥ 1% of tumour cells and whose disease has not progressed following platinum-based chemoradiation therapy.9

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Durvalumab is an anticancer antibody that works to promote the antitumour responses mediated by immune cells. By blocking the action of PD-L1, durvalumab exerts its anticancer effects by increasing T-cell activation, enhancing detection and ablation of tumour cells.7 In in vitro assays, durvalumab inhibited the activity of PD-L1 in a concentration-dependent manner.5 In co-engrafted human tumor and immune cell xenograft mouse models, durvalumab was effective in decreasing tumour size. Durvalumab does not mediate antibody-dependent cell-mediated cytotoxicity (ADCC).7

Mechanism of action

Because cancer cells express antigens that are recognized and taken up by antigen-presenting cells (APCs), the immune responses prime and activate cytotoxic T cells, and allow them to travel to the site of tumour to destroy cancer cells. However, tumours often evade T cell-mediated immune responses to enhance their survival.4 Inflammatory mediators, such as IFN-gamma, induce the expression of programmed cell death ligand-1 (PD-L1), which is a type 1 transmembrane protein expressed on tumour cells and tumour-associated immune cells in the tumour microenvironment.2,7 PD-L1 acts as an immune checkpoint to regulate immune responses. PD-L1 is a ligand to PD-1, which is a cell surface receptor expressed on activated T cells in peripheral tissues following antigen exposure.2,3 Both PD-L1 and PD-1 are co-inhibitory molecules involved in blocking T cell-mediated immune responses. PD-L1 also interacts with CD-80, which is a receptor constitutively expressed by T cells and is upregulated early after T cell activation.6

The expression of PD-L1 is an adaptive immune response by tumour cells, resulting in over-expression of the molecule in some cancers.3 PD-L1 interacts with PD-1 and CD80, which leads to blocked cytotoxic T cell activation, T cell proliferation, and cytokine production.7 By binding to PD-L1 and preventing its association with PD-1 and CD80, durvalumab activates the immune responses mediated by cytotoxic T cells that attack tumour cells.7 Durvalumab displays selective and high affinity toward PD-L1 but not PD-L2, which is a regulatory ligand expressed in tumour cells to a lesser extent and involved in regulating inflammation and differentiation of T cells.2

TargetActionsOrganism
AProgrammed cell death 1 ligand 1
inhibitor
antibody
Humans
Absorption

Durvalumab exhibits a dose-proportional pharmacokinetic profile that is non-linear at doses <3 mg/kg and linear at doses ≥3 mg/kg. Following intravenous administration in patients with solid tumours, the steady-state plasma concentrations were reached at approximately 16 weeks.7

Volume of distribution

In patients receiving the dose range of ≥ 10 mg/kg every 2 weeks, the mean steady state volume of distribution (Vss) was 5.64 L.7,9

Protein binding

There is limited information on the serum protein binding profile of durvalumab.

Metabolism

Durvalumab is subject to protein catabolism via reticuloedothelial system or target-mediated disposition.9

Route of elimination

Durvalumab is primarily eliminated by protein catabolism.9

Half-life

Based on baseline clearance rate, the geometric mean terminal half-life is 18 days.7,9

Clearance

Clearance of durvalumab decreases over time, resulting in a mean steady-state clearance (CLss) of 8.2 mL/h following 365 days of initial drug administration. However, the decrease in CLss is not considered clinically relevant.7,9

Adverse Effects
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Toxicity

There is limited information about the overdose profile and LD50 of durvalumab. In case of overdose, the patient should be closely monitored for drug-related adverse events, and appropriate symptomatic treatment should be immediately initiated.9 Based on the findings of clinical studies, durvalumab had a risk of causing immune-mediated reactions, such as pneumonitis, hepatitis, and other serious infections. In animal reproductive studies, durvalumab caused fetal harm and this fetal toxicity may be possible in humans.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 Durvalumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Durvalumab.
AducanumabThe risk or severity of adverse effects can be increased when Durvalumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Durvalumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Durvalumab.
AmivantamabThe risk or severity of adverse effects can be increased when Durvalumab is combined with Amivantamab.
AnsuvimabThe risk or severity of adverse effects can be increased when Durvalumab 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 Durvalumab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Durvalumab.
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Durvalumab.
Interactions
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Food Interactions
No interactions found.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ImfinziInjection, solution, concentrate50 mg/mlIntravenousAstra Zeneca Ab2021-01-12Not applicableEU flag
ImfinziSolution50 mg / mLIntravenousAstra Zeneca2017-11-20Not applicableCanada flag
ImfinziInjection, solution500 mg/10mLIntravenousAstraZeneca Pharmaceuticals LP2017-05-01Not applicableUS flag
ImfinziInjection, solution, concentrate50 mg/mlIntravenousAstra Zeneca Ab2021-01-12Not applicableEU flag
ImfinziInjection, solution120 mg/2.4mLIntravenousAstraZeneca Pharmaceuticals LP2017-05-01Not applicableUS flag

Categories

ATC Codes
L01XC28 — Durvalumab
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
28X28X9OKV
CAS number
1428935-60-7

References

General References
  1. 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]
  2. Botticella A, Mezquita L, Le Pechoux C, Planchard D: Durvalumab for stage III non-small-cell lung cancer patients: clinical evidence and real-world experience. Ther Adv Respir Dis. 2019 Jan-Dec;13:1753466619885530. doi: 10.1177/1753466619885530. [Article]
  3. Lee HT, Lee JY, Lim H, Lee SH, Moon YJ, Pyo HJ, Ryu SE, Shin W, Heo YS: Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep. 2017 Jul 17;7(1):5532. doi: 10.1038/s41598-017-06002-8. [Article]
  4. Faiena I, Cummings AL, Crosetti AM, Pantuck AJ, Chamie K, Drakaki A: Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma. Drug Des Devel Ther. 2018 Jan 23;12:209-215. doi: 10.2147/DDDT.S141491. eCollection 2018. [Article]
  5. Syed YY: Durvalumab: First Global Approval. Drugs. 2017 Aug;77(12):1369-1376. doi: 10.1007/s40265-017-0782-5. [Article]
  6. Ni X, Song Q, Cassady K, Deng R, Jin H, Zhang M, Dong H, Forman S, Martin PJ, Chen YZ, Wang J, Zeng D: PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells. J Clin Invest. 2017 May 1;127(5):1960-1977. doi: 10.1172/JCI91138. Epub 2017 Apr 17. [Article]
  7. FDA Approved Drug Products: IMFINZI (durvalumab) injection, for intravenous use [Link]
  8. FDA.gov Resources for Information: FDA approves durvalumab for extensive-stage small cell lung cancer [Link]
  9. European Medicines Agency: IMFINZI (durvalumab) Summary of Product Characteristics [Link]
KEGG Drug
D10808
PubChem Substance
347911229
RxNav
1919503
Drugs.com
Drugs.com Drug Page
Wikipedia
Durvalumab
FDA label
Download (576 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentDurvalumab / Leptomeningeal Metastasis1
4Not Yet RecruitingTreatmentLung Cancers1
4Not Yet RecruitingTreatmentUnresectable Non-small Cell Lung Cancer (NSCLC) and Urothelial Cancer1
4RecruitingTreatmentTumors, Solid1
3Active Not RecruitingTreatmentAdvanced Solid Malignancies1
3Active Not RecruitingTreatmentLocally Advanced Cervical Cancer1
3Active Not RecruitingTreatmentLocally Advanced or Metastatic EGFR T790M+ NSCLC1
3Active Not RecruitingTreatmentNon-muscle Invasive Bladder Cancer (NMIBC)1
3Active Not RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)6
3Active Not RecruitingTreatmentSmall Cell Lung Carcinoma, Extensive Disease2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous120 mg/2.4mL
Injection, solutionIntravenous500 mg/10mL
Injection, solution, concentrateIntravenous
Injection, solution, concentrateIntravenous50 mg/ml
Injection, solution, concentrateIntravenous50 mg/1ml
Injection, solution, concentrateIntravenous; Parenteral
SolutionIntravenous50 mg / mL
Injection, solution, concentrate
Injection, solutionIntravenous
Solution, concentrateIntravenous50 mg
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
Yes
Actions
Inhibitor
Antibody
General Function
Not Available
Specific Function
Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell ...
Gene Name
CD274
Uniprot ID
Q9NZQ7
Uniprot Name
Programmed cell death 1 ligand 1
Molecular Weight
33275.095 Da
References
  1. Bellmunt J, Powles T, Vogelzang NJ: A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treat Rev. 2017 Mar;54:58-67. doi: 10.1016/j.ctrv.2017.01.007. Epub 2017 Feb 2. [Article]
  2. Faiena I, Cummings AL, Crosetti AM, Pantuck AJ, Chamie K, Drakaki A: Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma. Drug Des Devel Ther. 2018 Jan 23;12:209-215. doi: 10.2147/DDDT.S141491. eCollection 2018. [Article]
  3. Lee HT, Lee JY, Lim H, Lee SH, Moon YJ, Pyo HJ, Ryu SE, Shin W, Heo YS: Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci Rep. 2017 Jul 17;7(1):5532. doi: 10.1038/s41598-017-06002-8. [Article]

Drug created on October 20, 2016 20:41 / Updated on July 29, 2021 06:27