Identification

Name
Latanoprostene Bunod
Accession Number
DB11660
Type
Small Molecule
Groups
Approved, Investigational
Description

Latanoprostene Bunod has been used in trials studying the treatment of Glaucoma, Ocular Hypertension, Open-Angle Glaucoma, Open Angle Glaucoma, and Intraocular Pressure.

As of November 2, 2017 the FDA approved Bausch + Lomb's Vyzulta (latanoprostene bunod opthalmic solution), 0.024% for the indication of reducing intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Latanoprostene bunod is the first prostaglandin analog with one of its metabolites being nitric oxide (NO). The novelty of this agent subsequently lies in the proposed dual mechanism of action that stems from both its prostaglandin F2-alpha analog latanoprost acid metabolite and its ability to donate NO for proposed tissue/cell relaxation effects.

In comparison, both latanoprost and latanoprostene bunod contain a latanoprost acid backbone. Conversely however, latanoprostene bunod integrates an NO-donating moiety in lieu of the isopropyl ester typically found in latanoprost.

Structure
Thumb
Synonyms
Not Available
External IDs
BOL-303259-X / NCX 116 / NCX-116 / PF-3187207
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VyzultaSolution / drops0.24 mg/1mLOphthalmicBauch & Lomb Incorporated2017-11-02Not applicableUs
Categories
UNII
I6393O0922
CAS number
860005-21-6
Weight
Average: 507.624
Monoisotopic: 507.283217284
Chemical Formula
C27H41NO8
InChI Key
LOVMMUBRQUFEAH-UIEAZXIASA-N
InChI
InChI=1S/C27H41NO8/c29-22(15-14-21-10-4-3-5-11-21)16-17-24-23(25(30)20-26(24)31)12-6-1-2-7-13-27(32)35-18-8-9-19-36-28(33)34/h1,3-6,10-11,22-26,29-31H,2,7-9,12-20H2/b6-1-/t22-,23+,24+,25-,26+/m0/s1
IUPAC Name
4-(nitrooxy)butyl (5Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hept-5-enoate
SMILES
O[C@H](CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OCCCCO[N+]([O-])=O)CCC1=CC=CC=C1

Pharmacology

Indication

Latanoprostene bunod opthalmic solution is indicated for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension [Label].

Associated Conditions
Pharmacodynamics

Upon applying an appropriate dose of latanoprost bunod, reduction in intraocular pressure begins approximately 1 to 3 hours later with a maximum intraocular pressure reduction effect demonstrated after 11 to 13 hours [Label].

Mechanism of action

Open-angle glaucoma (OAG) is a medical condition that is associated with progressive visual field damage and the loss of vision [1].

Occular hypertension (OHT) is considered a key risk factor for OAG and reducing intraocular pressure (IOP) and being able to maintain unique and appropriate target IOPs for various different patients having OHT can delay or prevent the onset of primary OAG or slow the disease progression of established glaucoma [1].

Ordinary physiological IOP results from aqueous humor produced by the ocular ciliary body and its outflow through a) the trabecular meshwork (TM) and Schlemm's canal (SC) in what is called the conventional pathway, and b) the uveoscleral pathway via the ciliary muscle/choroid/sclera in what is refered to as the unconventional pathway [4].

In patients with OHT or OAG there is increased resistance to aqueous humor outflow by way of the TM/SC pathway, which causes increased IOP. This increase in IOP is believed to be the cause of mechanical stress on the posterior structures of the eye which can result in the dysfunction of optic nerve fibers and the destruction of retinal ganglion cells - all of which ultimately contributes to vision loss [4].

As there is no cure for glaucoma, therapeutic management is predominantly focused on minimizing disease progression and clinical sequelae via the reduction and maintainenance of appropriate target IOPs [4, 1].

Subsequently, latanoprostene bunod is thought to lower intraocular pressure via a dual mechanism of action since the medication is metabolized into two relevant moieties upon administration: (1) latanoprost acid, and (2) butanediol mononitrate [4, 1, 5].

As a prostaglandin F2-alpha analog [4], the latanoprost acid moiety operates as a selective PGF2-alpha (FP) receptor agonist [5]. Since FP receptors occur in the ciliary muscle, ciliary epithelium, and sclera the latanoprost acid moiety primarily acts in the uveoscleral pathway where it increases the expression of matrix metalloproteinases (MMPs) like MMP-1, -3, and -9 which promote the degradation of collagen types I, III, and IV in the longitudinal bundles of the ciliary musicle and surrounding sclera [5]. The resultant extracellular matrix remodeling of the ciliary muscle consequently produces reduced outflow resistance via increased permeability and increased aqueous humor outflow through the uveoscleral route [5].

Conversely, the butanediol mononitrate undergoes further metabolism to NO and an inactive 1,4-butanediol moiety. As a gas that can freely diffuse across plasma membranes, it is proposed that the relaxing effect of NO to induce reductions in the cell volume and contractility of vascular smooth muscle like cells is dependant upon activation of the sGC/cGMP/PKG cascade pathway. NO released from butanediol mononitrate consequently enters the cells of the TM and inner wall of SC, causing decreases in myosin light chain-2 phosphorylation, increased phosphorylation of large-conductance calcium-activated potassium (BKCa) channels, and a subsequent efflux of potassium ions through such BKCa channels. All of these changes serve to decrease the cell contractility and volume, as well as to rearrange the actin cytoskeleton of the TM and SC cells. These biomechanical changes ultimately allow for enhanced conventional outflow of aqueous humor [5].

TargetActionsOrganism
AProstaglandin F2-alpha receptor
agonist
Human
Absorption

In a study with 22 healthy subjects monitored for 28 days, there were no quantifiable plasma concentrations of latanoprostene bunod (Lower Limit Of Quantitation, LLOQ, of 10.0 pg/mL) or butanediol mononitrate (LLOQ of 200 pg/mL) post daily dose of one drop bilaterally in the morning on Day 1 and 28 [Label].

The mean time of maximum plasma concentration (Tmax) for latanoprost acid was about 5 minutes post dosage on both Day 1 and 28 of therapy [Label].

The mean maximum plasma concentrations (Cmax) of latanoprost acid (LLOQ of 30 pg/mL) were 59.1 pg/mL on Day 1 and 28, respectively [Label].

Volume of distribution

Unfortunately there have been no formal ocular distribution studies performed in humans at this time [Label].

Protein binding
Not Available
Metabolism

Upon topical administration at the ocular surface, latanoprostene bunod undergoes rapid carboxyl ester hydrolysis by endogenous corneal esterases into latanoprost acid and butanediol mononitrate [Label].

After the latanoprost acid reaches the systemic circulation, it is largely metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites by way of fatty acid beta-oxidation [Label].

The butanediol monohidrate undergoes further metabolism (reduction) to 1,4-butanediol and nitric oxide (NO). Furthermore, this 1,4-butanediol metabolite is further oxidized to succinic acid that is subsequently then primarily taken up as a component in the tricarboxylic acid (TCA) cycle in cellular aerobic respiration [Label].

Route of elimination

The latanoprost acid component of latanoprostene bunod is predominantly metabolized by the liver and excreted primarily in the urine [Label].

Half life

The half-life after application of latanoprostene bunod in rabbits was 1.8 hours in cornea, 2.1 hours in aqueous humor, and 4.6 hours in the iris/ciliary body [5].

Clearance

Since latanoprost acid plasma concentration dropped below the LLOQ (Lower Limit Of Quantitation) of 30 pg/mL in the majority of study subjects by 15 minutes following ordinary ocular administration, the elimination of latanoprost acid from human plasma is considered rapid [Label].

Toxicity

There are no available human data for the use of latanoprost bunod during pregnancy to inform any drug associated risks. Use during pregnancy must consider whether any potential benefit to the patient will justify the risk presented to the fetus [Label].

There are no data on the presence of latanoprost bunod in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding must be considered along with the mother's potential clinical need for latanoprost bunod and any possible risk to the breastfed infant [Label].

Prolonged, continued use of latanoprost bunod 0.024% opthalmic solution is expected to cause increased pigmentation of the iris and eyelid. Such pigmentation is expected to increase for as long as the medication is used. Upon discontinuing the medication, although pigmentation changes of the eyelid tissue may likely reverse, pigmentation changes to the iris is likely permanent. Such pigmentation changes typically present as brown pigmentation spreading and increasing concentrically outward from the pupil. These changes may not be noticeable for several months to years. The long-term effects of increased pigmentation are not known and any prospective patients should be informed of this effect. While usage of the medication can continue in patients who do develop such pigmentation changes they should also be examined regularly [Label].

Prolonged, continued use of this medication is also expected to cause changes involving the increased length, thickness, and number of eyelash hairs. These changes are usually reversible upon discontinuation of the medication.

Latanoprost bunod can cause or exacerbate existing intraocular inflammation (iritis or uveitis). Use with caution in patients with a history of or active intraocular inflammation.

As a prostaglanding analog, latanoprost bunod has the potential to cuase macular edema, including cystoid macular edema. Use with caution in aphakic patients, in pseudoaphakic patients with a torn posterior lens capsule, or in patients with with known risk factors for macular edema.

Bacterial keratitis or other eye infections are commonly associated with the use of opthalmic solution containers that have been inadvertently contaminated by patients who have a concurrent corneal disease or a disruption of the ocular epithelial surfaced.

Contact lenses should be removed prior to the use of latanoprost bunod because its benzalkonium chloride preservative can affect or alter contact lenses [Label].

The most common adverse reactions obseved in patients treated with latanoprostene bunod during clinical trials were conjuctival hyperemica, eye irritation, eye pain, and installation site pain [FDA Lable].

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

Interactions

Drug Interactions
DrugInteraction
(4R)-limoneneThe therapeutic efficacy of Latanoprostene Bunod can be decreased when used in combination with (4R)-limonene.
AceclofenacThe therapeutic efficacy of Latanoprostene Bunod can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Latanoprostene Bunod can be decreased when used in combination with Acemetacin.
AcetaminophenAcetaminophen may decrease the excretion rate of Latanoprostene Bunod which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Latanoprostene Bunod which could result in a higher serum level.
AlclofenacThe therapeutic efficacy of Latanoprostene Bunod can be decreased when used in combination with Alclofenac.
AlminoprofenThe therapeutic efficacy of Latanoprostene Bunod can be decreased when used in combination with Alminoprofen.
AlprazolamAlprazolam may decrease the excretion rate of Latanoprostene Bunod which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Latanoprostene Bunod which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineLatanoprostene Bunod may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Kawase K, Vittitow JL, Weinreb RN, Araie M: Long-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER Study. Adv Ther. 2016 Sep;33(9):1612-27. doi: 10.1007/s12325-016-0385-7. Epub 2016 Jul 25. [PubMed:27457469]
  2. Medeiros FA, Martin KR, Peace J, Scassellati Sforzolini B, Vittitow JL, Weinreb RN: Comparison of Latanoprostene Bunod 0.024% and Timolol Maleate 0.5% in Open-Angle Glaucoma or Ocular Hypertension: The LUNAR Study. Am J Ophthalmol. 2016 Aug;168:250-259. doi: 10.1016/j.ajo.2016.05.012. Epub 2016 May 20. [PubMed:27210275]
  3. Weinreb RN, Scassellati Sforzolini B, Vittitow J, Liebmann J: Latanoprostene Bunod 0.024% versus Timolol Maleate 0.5% in Subjects with Open-Angle Glaucoma or Ocular Hypertension: The APOLLO Study. Ophthalmology. 2016 May;123(5):965-73. doi: 10.1016/j.ophtha.2016.01.019. Epub 2016 Feb 11. [PubMed:26875002]
  4. Kaufman PL: Latanoprostene bunod ophthalmic solution 0.024% for IOP lowering in glaucoma and ocular hypertension. Expert Opin Pharmacother. 2017 Mar;18(4):433-444. doi: 10.1080/14656566.2017.1293654. Epub 2017 Feb 20. [PubMed:28234563]
  5. Garcia GA, Ngai P, Mosaed S, Lin KY: Critical evaluation of latanoprostene bunod in the treatment of glaucoma. Clin Ophthalmol. 2016 Oct 18;10:2035-2050. eCollection 2016. [PubMed:27799730]
External Links
PubChem Compound
11156438
PubChem Substance
347828030
ChemSpider
9331546
ChEMBL
CHEMBL2364612
FDA label
Download (182 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentIntraocular Pressure1
2CompletedScreeningIntraocular Pressure1
2CompletedTreatmentOcular Hypertension / Open Angle Glaucoma (OAG)1
3CompletedTreatmentGlaucoma / Ocular Hypertension1
3CompletedTreatmentOcular Hypertension / Open-angle Glaucoma (OAG)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Solution / dropsOphthalmic0.24 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8058467No2005-01-052025-01-05Us
US7910767No2005-01-052025-01-05Us
US7273946No2005-10-032025-10-03Us
US7629345No2005-01-052025-01-05Us
US6211233No1998-06-172018-06-17Us

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0032 mg/mLALOGPS
logP3.94ALOGPS
logP3.79ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)14.47ChemAxon
pKa (Strongest Basic)-2.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area139.36 Å2ChemAxon
Rotatable Bond Count19ChemAxon
Refractivity136.66 m3·mol-1ChemAxon
Polarizability56.95 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as prostaglandins and related compounds. These are unsaturated carboxylic acids consisting of a 20 carbon skeleton that also contains a five member ring, and are based upon the fatty acid arachidonic acid.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Fatty Acyls
Sub Class
Eicosanoids
Direct Parent
Prostaglandins and related compounds
Alternative Parents
Fatty acid esters / Cyclopentanols / Benzene and substituted derivatives / Alkyl nitrates / Organic nitro compounds / Organic nitric acids and derivatives / Cyclic alcohols and derivatives / Carboxylic acid esters / Monocarboxylic acids and derivatives / Organic zwitterions
show 4 more
Substituents
Prostaglandin skeleton / Fatty acid ester / Monocyclic benzene moiety / Cyclopentanol / Benzenoid / Cyclic alcohol / Alkyl nitrate / Organic nitrate / Carboxylic acid ester / Organic nitro compound
show 15 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Prostaglandin f receptor activity
Specific Function
Receptor for prostaglandin F2-alpha (PGF2-alpha). The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. Initiates luteolysis...
Gene Name
PTGFR
Uniprot ID
P43088
Uniprot Name
Prostaglandin F2-alpha receptor
Molecular Weight
40054.1 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da
References
  1. Kraft ME, Glaeser H, Mandery K, Konig J, Auge D, Fromm MF, Schlotzer-Schrehardt U, Welge-Lussen U, Kruse FE, Zolk O: The prostaglandin transporter OATP2A1 is expressed in human ocular tissues and transports the antiglaucoma prostanoid latanoprost. Invest Ophthalmol Vis Sci. 2010 May;51(5):2504-11. doi: 10.1167/iovs.09-4290. Epub 2009 Dec 17. [PubMed:20019365]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. Kimura H, Takeda M, Narikawa S, Enomoto A, Ichida K, Endou H: Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther. 2002 Apr;301(1):293-8. [PubMed:11907186]

Drug created on October 20, 2016 14:38 / Updated on August 02, 2018 06:27