Dornase alfa

Identification

Name
Dornase alfa
Accession Number
DB00003  (BTD00001, BIOD00001)
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Description

Dornase alfa is a biosynthetic form of human deoxyribunuclease I (DNase I) enzyme. It is produced in genetically modified Chinese hamster ovary (CHO) cells using recombinant DNA technology. The 260-amino acid sequence of dornase alfa is identical to the endogenous human enzyme. Dornase alfa cleaves extracellular DNA to 5´-phosphodinucleotide and 5´-phosphooligonucleotide end products without affecting intracellular DNA. In individuals with cystic fibrosis, extracellular DNA, which is an extremely viscous anion, is released by degenerating leukocytes that accumulate during inflammatory responses to infections. Enzymatic breakdown of this extracellular DNA appears to reduce sputum viscosity and viscoelasticity.

Protein structure
Db00003
Protein chemical formula
C1321H1999N339O396S9
Protein average weight
29253.9 Da
Sequences
>Dornase alfa sequence
LKIAAFNIQTFGETKMSNATLVSYIVQILSRYDIALVQEVRDSHLTAVGKLLDNLNQDAP
DTYHYVVSEPLGRNSYKERYLFVYRPDQVSAVDSYYYDDGCEPCGNDTFNREPAIVRFFS
RFTEVREFAIVPLHAAPGDAVAEIDALYDVYLDVQEKWGLEDVMLMGDFNAGCSYVRPSQ
WSSIRLWTSPTFQWLIPDSADTTATPTHCAYDRIVVAGMLLRGAVVPDSALPFNFQAAYG
LSDQLAQAISDHYPVEVMLK
Download FASTA Format
Synonyms
  • Deoxyribonuclease (human clone 18-1 protein moiety)
  • Dornase alfa, recombinant
  • Dornase alpha
  • Recombinant deoxyribonuclease (DNAse)
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PulmozymeSolution1 mg/mLRespiratory (inhalation)Genentech, Inc.1993-12-30Not applicableUs
Pulmozyme 1mg/mlSolution1 mgRespiratory (inhalation)Hoffmann La Roche1994-12-31Not applicableCanada
International/Other Brands
Viscozyme (Roche (Chile))
Categories
UNII
953A26OA1Y
CAS number
143831-71-4

Pharmacology

Indication

Used as adjunct therapy in the treatment of cystic fibrosis.

Structured Indications
Pharmacodynamics

Cystic fibrosis (CF) is a disease characterized by the retention of viscous purulent secretions in the airways. These thick secretions contribute both to reduced pulmonary function and to frequent pulmonary infection. Purulent pulmonary secretions of individuals with cystic fibrosis contain very high concentrations of extracellular DNA released by degenerating leukocytes that accumulate in response to these infections. Dornase alfa hydrolyzes the DNA in sputum of CF patients and reduces sputum viscosity and viscoelasticity. The enzyme does not appear to affect sputum in the absence of an inflammatory response to infection, nor does it affect the sputum of healthy individuals.

Mechanism of action

Dornase alfa is a biosynthetic form of human DNase I. The enzyme is involved in endonucleolytic cleavage of extracellular DNA to 5´-phosphodinucleotide and 5´-phosphooligonucleotide end products. It has no effect on intracellular DNA. Optimal activity is dependent on the presence of divalent cations such as calcium and magnesium. Extracellular DNA is a viscous anionic polymer and its breakdown appears to improve the viscosity and viscoelasticity of purulent sputum of individuals with CF, thus reducing airflow obstruction. Dornase alfa does not seem to have any effect on non-purulent sputum.

TargetActionsOrganism
ADNANot AvailableHuman
Absorption

Studies in rats and monkeys after inhalation of dornase alfa shows very little systemic absorption (less than 15% for rats and less than 2% for monkeys). The results were also witnessed in patients. Dornase alfa is also associated with very low accumulation with no serum concentration greater than 10ng/mL observed no matter the dose administered. Bioavailability: mean sputum concentrations of dornase alfa can be measured after 15 minutes. Onset is achieved within 3 to 7 days. Peak concentrations are achieved after 9 days.

Volume of distribution

In studies in rats and monkeys, the initial volume of distribution is similar to the serum volume. Concentrations in sputum decline rapidly after inhalation.

Protein binding
Not Available
Metabolism

While no conclusive studies have yet been published, dornase alfa is expected to be metabolized by proteases in biofluids.

Route of elimination
Not Available
Half life
Not Available
Clearance

Studies in rats indicate that, following aerosol administration, the disappearance half-life of dornase alfa from the lungs is 11 hours. In humans, sputum DNase levels declined below half of those detected immediately post-administration within 2 hours but effects on sputum rheology persisted beyond 12 hours.

Toxicity

Adverse reactions occur at a frequency of < 1/1000 and are usually mild and transient in nature. Reported adverse effects include chest pain (pleuritic/non-cardiac), fever, dyspepsia, voice alteration (hoarseness), pharyngitis, dyspnea, laryngitis, rhinitis, decreased lung function, rash, urticaria, and conjunctivitis. There is no evidence of carcinogenic or mutagenic properties. The safety of dornase alfa has not been studied in pregnant women, nursing women and children under the age of 5 years old.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
No interactions found.
Food Interactions
Not Available

References

General References
  1. Cramer GW, Bosso JA: The role of dornase alfa in the treatment of cystic fibrosis. Ann Pharmacother. 1996 Jun;30(6):656-61. [PubMed:8792953]
  2. Jones AP, Wallis C: Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD001127. doi: 10.1002/14651858.CD001127.pub2. [PubMed:20238314]
  3. Riethmueller J, Kumpf M, Borth-Bruhns T, Brehm W, Wiskirchen J, Sieverding L, Ankele C, Hofbeck M, Baden W: Clinical and in vitro effect of dornase alfa in mechanically ventilated pediatric non-cystic fibrosis patients with atelectases. Cell Physiol Biochem. 2009;23(1-3):205-10. doi: 10.1159/000204109. Epub 2009 Feb 18. [PubMed:19255515]
External Links
UniProt
P24855
Genbank
M55983
ChEMBL
CHEMBL1201431
Therapeutic Targets Database
DAP000981
PharmGKB
PA10318
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dornase_alfa
ATC Codes
R05CB13 — Dornase alfa (desoxyribonuclease)
AHFS Codes
  • 44:00.00 — Enzymes
FDA label
Download (131 KB)
MSDS
Download (10.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Unknown StatusSupportive CareHead and Neck Carcinoma1
1Active Not RecruitingTreatmentPeritoneal dialysis therapy / Peritoneal Dialysis, Continuous Ambulatory1
1WithdrawnSupportive CareCoughing / Sjögren's Syndrome1
1, 2RecruitingTreatmentEye Dryness1
1, 2RecruitingTreatmentEye Dryness / Graft versus host disease in eye1
2CompletedTreatmentAsthma Bronchial1
2CompletedTreatmentCystic Fibrosis (CF)1
2CompletedTreatmentCystic Fibrosis (CF) / Sinusitis1
2RecruitingTreatmentLower Respiratory Tract Infection (LRTI) / Lung Transplant Infection1
2Unknown StatusTreatmentCystic Fibrosis (CF)1
2, 3Unknown StatusPreventionLong Term Ventilation1
2, 3Unknown StatusTreatmentPleural Empyema1
3CompletedTreatmentAcute maxillary sinusitis caused by M. catarrhalis / Cystic Fibrosis (CF)1
3CompletedTreatmentChronic Rhinosinusitis / Cystic Fibrosis (CF)1
3RecruitingTreatmentPleural Empyema1
3WithdrawnTreatmentCystic Fibrosis (CF) / Sinusitis1
4Active Not RecruitingTreatmentPulmonary Infections1
4CompletedBasic ScienceCystic Fibrosis (CF)1
4CompletedTreatmentAtelectasis1
4CompletedTreatmentCystic Fibrosis (CF)1
4CompletedTreatmentOtitis Media (OM)1
4RecruitingTreatmentPleural Diseases1
4TerminatedTreatmentCystic Fibrosis (CF)2
Not AvailableCompletedTreatmentAtelectasis1
Not AvailableCompletedTreatmentAtelectasis / Ventilations, Mechanical1

Pharmacoeconomics

Manufacturers
  • Genentech, Inc
Packagers
Dosage forms
FormRouteStrength
SolutionRespiratory (inhalation)1 mg/mL
SolutionRespiratory (inhalation)1 mg
Prices
Unit descriptionCostUnit
Pulmozyme 1 mg/ml Solution 2.5ml Plastic Container77.06USD plastic
Pulmozyme 1 mg/ml ampul37.05USD ml
Lufyllin 400 mg tablet4.81USD tablet
Lufyllin-400 tablet4.62USD tablet
Lufyllin-GG 200-200 mg tablet3.99USD tablet
Lufyllin-gg tablet3.84USD tablet
Lufyllin 200 mg tablet3.21USD tablet
Lufyllin-GG 100-100 mg/15ml Elixir0.6USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2184581No2005-02-222015-02-28Canada
CA2137237No2004-10-262013-05-28Canada

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)67 °CChan, H.K. et al., Pharm Res. 13:756-761 (1996)
hydrophobicity-0.083Not Available
isoelectric point4.58Not Available

Taxonomy

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

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Yes
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Cramer GW, Bosso JA: The role of dornase alfa in the treatment of cystic fibrosis. Ann Pharmacother. 1996 Jun;30(6):656-61. [PubMed:8792953]

Drug created on June 13, 2005 07:24 / Updated on October 23, 2017 14:13