Avanafil

Identification

Summary

Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used to treat erectile dysfunction.

Brand Names
Spedra, Stendra
Generic Name
Avanafil
DrugBank Accession Number
DB06237
Background

Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used in the treatment of erectile dysfunction. In comparison with other drugs of the same class, it shows greater selectivity for PDE5 over PDE6 than both sildenafil and vardenafil but less selectivity than tadalafil, suggesting a relatively lower risk of visual disturbances associated with off-target PDE6 inhibition.5

It first received FDA approval on April 27, 2012,4 with subsequent EMA approval in June 2013.5

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 483.951
Monoisotopic: 483.17856544
Chemical Formula
C23H26ClN7O3
Synonyms
  • (S)-4-(3-Chloro-4-methoxybenzylamino)-2-(2-hydroxymethylpyrrolidin-1-yl)-N-pyrimidin-2-ylmethyl-5-pyrimidinecarboxamide
  • Avanafil
  • Avanafilo
External IDs
  • TA-1790

Pharmacology

Indication

Avanafil is indicated for the treatment of erectile dysfunction.4

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated in vitro IC50 of 5.2 nM.5 Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes,4 meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as sildenafil and vardenafil.5 It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity.4

PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol).4 PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention.4 In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil therapy.8

Mechanism of action

Avanafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Sexual arousal results in the local release of nitric oxide, which in turn stimulates the enzyme guanylate cyclase to produce cGMP. Elevated levels of cGMP result in local smooth muscle relaxation and increased blood flow to the penis (i.e. an erection).4,5

As PDE5 inhibitors like avanafil require the endogenous release of nitric oxide in order to exert their pharmacologic effect, they have no effect on the user in the absence of sexual stimulation/arousal.4,5

TargetActionsOrganism
AcGMP-specific 3',5'-cyclic phosphodiesterase
inhibitor
Humans
Absorption

Avanafil is rapidly absorbed following oral administration (Tmax of 30-45 minutes)4 and appears to have low to moderate oral bioavailability, though formal studies have not been conducted.5 Administration with a meal results in a mean delay in Tmax of 1.12 to 1.25 hours, a 39% mean reduction in Cmax, and a negligible effect on AUC.4,5

Volume of distribution

The apparent volume of distribution of avanafil is 47 to 83 L.5

Protein binding

Avanafil and its two major metabolites, M4 and M16, are highly protein-bound in plasma at approximately 99%, 97%, and 81%, respectively. Binding occurs primarily to albumin (99%), with smaller contributions from γ-globulin (43%) and α1-acid glycoprotein (66%).5

Metabolism

Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9.4,8 There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil.4

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Route of elimination

Following oral administration, avanafil is extensively metabolized. Approximately 62% of a given dose is excreted as metabolites in the feces and approximately 21% as metabolites in the urine.4

Half-life

Studies have demonstrated variability in the terminal elimination half-life of avanafil, with estimates ranging between 5 - 17 hours.5

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Experience with avanafil overdose is limited. Single doses of up to 800mg and repeat doses of up to 300mg have been administered - these patients experienced adverse effects similar to those seen at therapeutic doses but with increased incidence and severity.8 Patients experiencing an overdosage of avanafil should be treated with standard symptomatic and supportive measures. Dialysis is unlikely to be of benefit in cases of overdose as avanafil is highly protein-bound in plasma.4

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 Avanafil can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Avanafil can be increased when combined with Abatacept.
AbemaciclibAvanafil may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AbirateroneThe metabolism of Avanafil can be decreased when combined with Abiraterone.
AcebutololAvanafil may increase the antihypertensive activities of Acebutolol.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Avanafil.
AcetohexamideThe metabolism of Avanafil can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Avanafil can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe metabolism of Avanafil can be decreased when combined with Acetylsalicylic acid.
AdalimumabThe metabolism of Avanafil can be increased when combined with Adalimumab.
Interactions
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Food Interactions
  • Avoid excessive or chronic alcohol consumption. Substantial alcohol consumption (e.g. >3 units) in combination with avanafil may increase the risk of hypotension.
  • Take with or without food. High-fat meals slow absorption, but not to a clinically significant extent.

Products

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Product Images
International/Other Brands
Spedra (A. Menarini Farmaceutica Internazionale SRL)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SpedraTablet50 mgOralMenarini International Operations Luxembourg S.A.2016-09-08Not applicableEU flag
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2021-02-11Not applicableEU flag
SpedraTablet50 mgOralMenarini International Operations Luxembourg S.A.2021-02-11Not applicableEU flag
SpedraTablet200 mgOralMenarini International Operations Luxembourg S.A.2016-09-08Not applicableEU flag
SpedraTablet200 mgOralMenarini International Operations Luxembourg S.A.2021-02-11Not applicableEU flag
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2016-09-08Not applicableEU flag
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2021-02-11Not applicableEU flag
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2021-02-11Not applicableEU flag
SpedraTablet100 mgOralMenarini International Operations Luxembourg S.A.2016-09-08Not applicableEU flag
SpedraTablet50 mgOralMenarini International Operations Luxembourg S.A.2016-09-08Not applicableEU flag

Categories

ATC Codes
G04BE10 — Avanafil
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyrimidinecarboxamides. These are compounds containing a pyrimidine ring which bears a carboxamide.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Pyrimidinecarboxamides
Alternative Parents
Anisoles / Benzylamines / Phenoxy compounds / Dialkylarylamines / Methoxybenzenes / Alkyl aryl ethers / Aminopyrimidines and derivatives / Secondary alkylarylamines / Chlorobenzenes / Aryl chlorides
show 12 more
Substituents
Alcohol / Alkyl aryl ether / Amine / Amino acid or derivatives / Aminopyrimidine / Anisole / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle
show 30 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
monocarboxylic acid amide, organochlorine compound, pyrimidines, aromatic amide, prolinols (CHEBI:66876)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
DR5S136IVO
CAS number
330784-47-9
InChI Key
WEAJZXNPAWBCOA-INIZCTEOSA-N
InChI
InChI=1S/C23H26ClN7O3/c1-34-19-6-5-15(10-18(19)24)11-27-21-17(22(33)28-13-20-25-7-3-8-26-20)12-29-23(30-21)31-9-2-4-16(31)14-32/h3,5-8,10,12,16,32H,2,4,9,11,13-14H2,1H3,(H,28,33)(H,27,29,30)/t16-/m0/s1
IUPAC Name
4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-[(pyrimidin-2-yl)methyl]pyrimidine-5-carboxamide
SMILES
COC1=C(Cl)C=C(CNC2=C(C=NC(=N2)N2CCC[C@H]2CO)C(=O)NCC2=NC=CC=N2)C=C1

References

General References
  1. Gur S, Sikka SC, Hellstrom WJ: Novel phosphodiesterase-5 (PDE5) inhibitors in the alleviation of erectile dysfunction due to diabetes and ageing-induced oxidative stress. Expert Opin Investig Drugs. 2008 Jun;17(6):855-64. doi: 10.1517/13543784.17.6.855 . [Article]
  2. Bruzziches R, Francomano D, Gareri P, Lenzi A, Aversa A: An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. Expert Opin Pharmacother. 2013 Jul;14(10):1333-44. doi: 10.1517/14656566.2013.799665. Epub 2013 May 16. [Article]
  3. Kedia GT, Uckert S, Assadi-Pour F, Kuczyk MA, Albrecht K: Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013 Feb;5(1):35-41. doi: 10.1177/1756287212466282. [Article]
  4. FDA Approved Drug Products: Stendra (avanafil) tablets for oral use [Link]
  5. EMA CHMP Assessment Report: Avanafil (INN) [Link]
  6. CaymanChem: Avanafil M4 metabolite [Link]
  7. CaymanChem: Avanafil M16 metabolite [Link]
  8. EMA Summary of Product Characteristics: Spedra (avanafil) oral tablets [Link]
KEGG Drug
D03217
PubChem Compound
9869929
PubChem Substance
175427065
ChemSpider
8045620
BindingDB
235766
RxNav
1291301
ChEBI
66876
ChEMBL
CHEMBL1963681
ZINC
ZINC000011677857
PDBe Ligand
E6L
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Avanafil
PDB Entries
6l6e
FDA label
Download (465 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentErectile Dysfunction3
4CompletedTreatmentVision1
4Unknown StatusTreatmentErectile Dysfunction1
3CompletedTreatmentErectile Dysfunction6
3CompletedTreatmentSexual Function and Fertility Disorders NEC-Erectile Dysfunction1
2CompletedTreatmentErectile Dysfunction1
1CompletedBasic ScienceAvanfil ADME / Semen Exposure / Sperm Function1
1CompletedPreventionHealthy Subjects (HS)1
1CompletedTreatmentErectile Dysfunction8
1CompletedTreatmentRenal1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, coatedOral100 mg
TabletOral100 MG
TabletOral200 MG
TabletOral50 MG
TabletOral100 mg/1
TabletOral200 mg/1
TabletOral50 mg/1
TabletOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6656935No2003-12-022020-09-13US flag
US7501409No2009-03-102023-05-05US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPractically insolublehttps://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202276s018lbl.pdf
Predicted Properties
PropertyValueSource
logP2.78ChemAxon
pKa (Strongest Acidic)12.35ChemAxon
pKa (Strongest Basic)5.55ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area125.39 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity131.75 m3·mol-1ChemAxon
Polarizability50.87 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9958
Blood Brain Barrier-0.7165
Caco-2 permeable-0.61
P-glycoprotein substrateSubstrate0.672
P-glycoprotein inhibitor INon-inhibitor0.6724
P-glycoprotein inhibitor IIInhibitor0.9038
Renal organic cation transporterNon-inhibitor0.5282
CYP450 2C9 substrateNon-substrate0.7215
CYP450 2D6 substrateNon-substrate0.795
CYP450 3A4 substrateSubstrate0.6184
CYP450 1A2 substrateNon-inhibitor0.5
CYP450 2C9 inhibitorNon-inhibitor0.5841
CYP450 2D6 inhibitorNon-inhibitor0.7495
CYP450 2C19 inhibitorNon-inhibitor0.5892
CYP450 3A4 inhibitorNon-inhibitor0.549
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5277
Ames testNon AMES toxic0.6096
CarcinogenicityNon-carcinogens0.8809
BiodegradationNot ready biodegradable0.9929
Rat acute toxicity2.5077 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6671
hERG inhibition (predictor II)Inhibitor0.8671
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (PubMed:9714779, ...
Gene Name
PDE5A
Uniprot ID
O76074
Uniprot Name
cGMP-specific 3',5'-cyclic phosphodiesterase
Molecular Weight
99984.14 Da
References
  1. Kedia GT, Uckert S, Assadi-Pour F, Kuczyk MA, Albrecht K: Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013 Feb;5(1):35-41. doi: 10.1177/1756287212466282. [Article]

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. Bruzziches R, Francomano D, Gareri P, Lenzi A, Aversa A: An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. Expert Opin Pharmacother. 2013 Jul;14(10):1333-44. doi: 10.1517/14656566.2013.799665. Epub 2013 May 16. [Article]
  2. FDA Approved Drug Products: Stendra (avanafil) tablets for oral use [Link]
  3. EMA CHMP Assessment Report: Avanafil (INN) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. EMA Summary of Product Characteristics: Spedra (avanafil) oral tablets [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. EMA CHMP Assessment Report: Avanafil (INN) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. EMA CHMP Assessment Report: Avanafil (INN) [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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. EMA CHMP Assessment Report: Avanafil (INN) [Link]
  2. EMA Summary of Product Characteristics: Spedra (avanafil) oral tablets [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. EMA Summary of Product Characteristics: Spedra (avanafil) oral tablets [Link]

Drug created on March 19, 2008 16:18 / Updated on April 16, 2021 04:47