Identification

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Name
Sarecycline
Accession Number
DB12035
Type
Small Molecule
Groups
Approved, Investigational
Description

Sarecycline is a semi-synthetic derivative of tetracycline that was initially discovered by Paratek Pharmaceuticals from Boston, MA but then licensed to Warner Chilcott of Rockaway, NJ in July of 2007 4. After completing various phase-II and phase-III trials demonstrating its effectiveness in treating moderate to severe facial acne vulgaris 2,3 the US Food and Drug Administration approved Barcelona based Almirall, S.A.'s Seysara (sarecylcine) as a new first in class narrow spectrum tetracycline derived oral antibiotic for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients nine years of age and older 5. Seysara (sarecycline) was originally part of Allergan's US Medical Dermatology portfolio, before Almirall acquired the portfolio in the second half of 2018 as a means of consolidating and reinforcing the dermatology-focused pharmaceutical company's presence in the United States 6.

Acne vulgaris itself is a common chronic skin condition associated with the blockage and/or inflammation of hair follicles and their accompanying sebaceous glands 5. The acne often presents physically as a mixture of non-inflammatory and inflammatory lesions mainly on the face but on the back and chest as well 5. Based upon data from Global Burden of Disease studies, the acne vulgaris condition affects up to 85% of young adults aged 12 to 25 years globally - with the possibility of permanent physical and mental scarring resulting from cases of severe acne 5.

Subsequently, while a number of first line tetracycline therapies like doxycycline and minocycline do exist for treating acne vulgaris, sarecycline presents a new and innovative therapy choice because it exhibits the necessary antibacterial activity against relevant pathogens that cause acne vulgaris but also possesses a low propensity for resistance development in such pathogens and a narrower, more specific spectrum of antibacterial activity, resulting in fewer off-target antibacterial effects on endogenous intestinal flora and consequently fewer resultant adverse effects associated with diarrhea, fungal overgrowth, etc.

Structure
Thumb
Synonyms
  • Sarecycline
External IDs
P-005672
Product Ingredients
IngredientUNIICASInChI Key
Sarecycline hydrochloride36718856JR1035979-44-2APPRLAGZQKOUFL-FIPJBXKNSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SeysaraTablet100 mg/1OralAllergan, Inc.2018-08-01Not applicableUs
SeysaraTablet, coated150 mg/1OralAlmirall, LLC2019-01-04Not applicableUs
SeysaraTablet60 mg/1OralAllergan, Inc.2018-08-01Not applicableUs
SeysaraTablet, coated100 mg/1OralAlmirall, LLC2019-01-04Not applicableUs
SeysaraTablet, coated60 mg/1OralAlmirall, LLC2019-01-04Not applicableUs
SeysaraTablet150 mg/1OralAllergan, Inc.2018-08-01Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
94O110CX2E
CAS number
1035654-66-0
Weight
Average: 487.509
Monoisotopic: 487.195464906
Chemical Formula
C24H29N3O8
InChI Key
PQJQFLNBMSCUSH-SBAJWEJLSA-N
InChI
InChI=1S/C24H29N3O8/c1-26(2)18-13-8-11-7-12-10(9-27(3)35-4)5-6-14(28)16(12)19(29)15(11)21(31)24(13,34)22(32)17(20(18)30)23(25)33/h5-6,11,13,18,28,30-31,34H,7-9H2,1-4H3,(H2,25,33)/t11-,13-,18-,24-/m0/s1
IUPAC Name
(4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-{[methoxy(methyl)amino]methyl}-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide
SMILES
[H][C@@]12CC3=C(C(O)=CC=C3CN(C)OC)C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@]([H])(N(C)C)[C@]1([H])C2

Pharmacology

Indication

Sarecycline is a tetracycline-class drug indicated for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older Label.

Associated Conditions
Pharmacodynamics

Compared to various examples of first-line tetracycline therapies for moderate to severe acne like doxycycline and minocycline, studies have shown that sarecycline can be sixteen to thirty-two fold less active against aerobic Gram-negative bacilli present within the normal human intestinal microbiome 1. Furthermore, it has also been demonstrated that sarecycline may be four to eight fold less active against various anaerobic bacteria that also comprise the normal human intestinal microbiome 1. Subsequently, while doxycycline and minocycline typically elicit broad-spectrum antimicrobial activity that can often cause adverse effects like diarrhea, fungal overgrowth, vaginal candidiasis, etc. due to undesirable off-target antibacterial effects on endogenous intestinal flora, sarecycline demonstrates a noticeably more target specific narrow spectrum activity with lower incidence of such side effects 1,2,3,Label.

Moreover, sarecycline also shares a relatively low propensity for resistance development in Cutibacterium acnes - one of the principal anaerobic organisms associated with acne lesions - with doxycycline and minocycline treatments 1.

Mechanism of action

It has been demonstrated that tetracyclines like sarecycline elicit their antimicrobial action by targeting and inhibiting protein synthesis in microbial agents like Cutibacterium acnes present in acne lesions 1,2,3. In particular, it is believed that sarecycline's mechanism of action revolves around the inhibition of various macromolecular biosynthesis activities like the macromolecular biosynthesis of microbial DNA, RNA, proteins, lipids, and cell wall 1. Specifically, it has been observed that while sarecycline demonstrates appreciable inhibition of microbial macromolecular DNA and protein synthesis, the compound has little to no effect on lipid biosynthesis, cell wall synthesis, and RNA synthesis 1. In addition, because Cutibacterium acnes also generates proteins and enzymes that are capable of causing inflammation, it is also believed that tetracyclines like sarecyclines can also affect an anti-inflammatory effect via the inhibition of such microbial protein synthesis 1.

Additional Data Available
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Contraindications

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Absorption

The median time to peak plasma concentration (Tmax) of sarecycline is 1.5 to 2.0 hours Label. When the medication is taken with a meal consisting of high fat (about 50% of total caloric content of the meal), high caloric (about 800 to 1000 Kcal), and milk content the Tmax can be delayed by approximately 0.53 hours and the Cmax and AUC can be decreased by 31% and 27%, respectively Label.

Volume of distribution

The mean apparent volume of distribution of sarecycline at steady-state ranges from 91.4 L to 97.0 L Label.

Protein binding

The protein binding of sarecycline has been recorded as ranging from 62.5% to 74.7% in vitro Label.

Metabolism

Metabolism of sarecycline by enzymes in human liver microsomes is minimal (< 15%) in vitro Label. Minor metabolites resulting from non-enzymic epimerization, O-/N-demethylation, hydroxylation, and desaturation have been found Label.

Route of elimination

After a single 100 mg oral dose of radiolabeled sarecycline, 42.6% of the dose was recovered in feces (14.9% as unchanged) and 44.1% in urine (24.7% as unchanged) Label.

Half life

The mean elimination half-life of sarecycline is 21 to 22 hours Label.

Clearance

The mean apparent oral clearance (CL/F) of sarecycline at steady state is about 3 L/h Label.

Toxicity

No clinically significant differences in the pharmacokinetics of sarecycline were observed based on age (11 to 73 years), weight (42 to 133 kg), sex, renal impairment, or mild to moderate hepatic impairment (Child Pugh A to B). The effect of end-stage renal disease (ESRD) or severe hepatic impairment (Child-Pugh C) on sarecycline pharmacokinetics has not been assessed Label.

In a 2-year oral mouse carcinogenicity study and a 2-year oral rat carcinogenicity study, no drug-related neoplasms were observed in male mice at oral doses of sarecycline up to 100 mg/kg/day (approximately equal to the MRHD based on AUC comparison) or in female mice at doses up to 60 mg/kg/day (approximately equal to the MRHD based on AUC comparison), or in rats at doses up to 200/100 mg/kg/day (dose reduced from 200 to 100 mg/kg/day due to increased mortality; 8 times the MRHD based on AUC comparison) Label.

Sarecycline was not mutagenic or clastogenic in a series of in vitro and in vivo genotoxicity studies, including a bacteria reverse mutation (Ames) assay, an in vitro chromosomal aberration assay in CHO cells, the L5178Y/TK+/- Mouse Lymphoma Assay, and an in vivo micronucleus assay in rats Label.

In a fertility and early embryonic development study in rats, sarecycline was administered to both male and female rats at oral doses up to 400 mg/kg/day prior to pairing and through the mating and postmating period Label. Female fertility was not affected at doses up to 400 mg/kg/day (8 times the MRHD based on AUC comparison) Label. In sperm evaluation, decreased sperm motility, decreased sperm count and concentration, and an increase in percent abnormal sperm occurred at 400 mg/kg/day (8 times the MRHD based on AUC comparison) Label. Male fertility was not affected at doses up to 150 mg/kg/day (4 times the MRHD based on AUC comparison) Label.

Sarecycline, like other tetracycline class drugs, may cause fetal harm, permanent discoloration of teeth, and reversible inhibition of bone growth when administered during pregnancy Label. The limited available human data are not sufficient to inform a drug- associated risk for birth defects or miscarriage Label. Tetracyclines are known to cross the placental barrier; therefore, sarecycline may be transmitted from the mother to the developing fetus Label. In animal reproduction studies, sarecycline induced skeletal malformations in fetuses when orally administered to pregnant rats during the period of organogenesis at a dose 1.4 times the maximum recommended human dose (MRHD) of 150 mg/day (based on AUC comparison) Label. When dosing with sarecycline continued through the period of lactation, decreases in offspring survival, offspring body weight, and implantation sites and viable embryos in offspring females occurred at a dose 3 times the MRHD (based on AUC comparison) Label. The potential risk to the fetus outweighs the potential benefit to the mother from sarecycline use during pregnancy; therefore, pregnant patients should discontinue sarecyclin as soon as pregnancy is recognized Label.

Tetracyclines are excreted in human milk Label. Because of the potential for serious adverse reactions on bone and tooth development in nursing infants from tetracycline-class antibiotics, advise a woman that breastfeeding is not recommended with sarecycline therapy Label.

Avoid using sarecycline in males who are attempting to conceive a child Label. In a fertility study in rats, sarecycline adversely affected spermatogenesis when orally administered to male rats at a dose 8 times the MRHD (based on AUC comparison) Label.

The safety and effectiveness of sarecycline have been established in pediatric patients 9 years of age and older for the treatment of moderate to severe inflammatory lesions of non-nodular acne vulgaris Label. The safety and effectiveness of sarecycline in pediatric patients below the age of 9 years has not been established Label. Use of tetracycline-class antibiotics below the age of 8 is not recommended due to the potential for tooth discoloration Label.

Clinical studies of sarecycline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects Label.

In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures Label. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdose Label.

Affected organisms
  • Humans and other mammals
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
(R)-warfarinThe risk or severity of bleeding can be increased when Sarecycline is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Sarecycline is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Sarecycline is combined with 4-hydroxycoumarin.
4-OxoretinolThe risk or severity of pseudotumor cerebri and elevated intracranial pressure can be increased when 4-Oxoretinol is combined with Sarecycline.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Sarecycline.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Sarecycline.
AcenocoumarolThe risk or severity of bleeding can be increased when Sarecycline is combined with Acenocoumarol.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Sarecycline.
Acetylcysteine zincAcetylcysteine zinc can cause a decrease in the absorption of Sarecycline resulting in a reduced serum concentration and potentially a decrease in efficacy.
AcetyldigoxinSarecycline may decrease the excretion rate of Acetyldigoxin which could result in a higher serum level.
Additional Data Available
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Food Interactions
Not Available

References

General References
  1. Zhanel G, Critchley I, Lin LY, Alvandi N: Microbiological Profile of Sarecycline: A Novel Targeted Spectrum Tetracycline for the Treatment of Acne Vulgaris. Antimicrob Agents Chemother. 2018 Nov 5. pii: AAC.01297-18. doi: 10.1128/AAC.01297-18. [PubMed:30397052]
  2. Moore A, Green LJ, Bruce S, Sadick N, Tschen E, Werschler P, Cook-Bolden FE, Dhawan SS, Forsha D, Gold MH, Guenthner S, Kempers SE, Kircik LH, Parish JL, Rendon MI, Rich P, Stein-Gold L, Tyring SK, Weiss RA, Nasir A, Schmitz C, Boodhoo TI, Kaoukhov A, Berk DR: Once-Daily Oral Sarecycline 1.5 mg/kg/day Is Effective for Moderate to Severe Acne Vulgaris: Results from Two Identically Designed, Phase 3, Randomized, Double-Blind Clinical Trials. J Drugs Dermatol. 2018 Sep 1;17(9):987-996. [PubMed:30235387]
  3. Leyden JJ, Sniukiene V, Berk DR, Kaoukhov A: Efficacy and Safety of Sarecycline, a Novel, Once-Daily, Narrow Spectrum Antibiotic for the Treatment of Moderate to Severe Facial Acne Vulgaris: Results of a Phase 2, Dose-Ranging Study. J Drugs Dermatol. 2018 Mar 1;17(3):333-338. [PubMed:29537451]
  4. Butler MS, Blaskovich MA, Cooper MA: Antibiotics in the clinical pipeline in 2013. J Antibiot (Tokyo). 2013 Oct;66(10):571-91. doi: 10.1038/ja.2013.86. Epub 2013 Sep 4. [PubMed:24002361]
  5. FDA Approval of Seysara (sarecycline) by Almirall Press Release [Link]
  6. Acquisition of Allergan US Medical Dermatology Department by Almirall, S.A. Press Release [Link]
External Links
PubChem Compound
54681908
PubChem Substance
347828347
ChemSpider
28540486
ChEMBL
CHEMBL2364632
Wikipedia
Sarecycline
ATC Codes
J01AA20 — Combinations of tetracyclines
FDA label
Download (155 KB)
MSDS
Download (17.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAcne Vulgaris1
3CompletedTreatmentAcne Vulgaris3
3WithdrawnTreatmentAcne Vulgaris1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral100 mg/1
TabletOral150 mg/1
TabletOral60 mg/1
Tablet, coatedOral100 mg/1
Tablet, coatedOral150 mg/1
Tablet, coatedOral60 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8513223No2013-08-202029-12-07Us
US9255068No2016-02-092033-02-09Us
US8318706No2012-11-272031-05-01Us
US9481639No2016-11-012028-08-10Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.01 mg/mLALOGPS
logP-0.17ALOGPS
logP-3ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)2.95ChemAxon
pKa (Strongest Basic)8.26ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area173.86 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity127.61 m3·mol-1ChemAxon
Polarizability49.56 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
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 tetracyclines. These are polyketides having an octahydrotetracene-2-carboxamide skeleton, substituted with many hydroxy and other groups.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Tetracyclines
Sub Class
Not Available
Direct Parent
Tetracyclines
Alternative Parents
Naphthacenes / Anthracenecarboxylic acids and derivatives / Tetralins / Aryl ketones / 1-hydroxy-2-unsubstituted benzenoids / Aralkylamines / Cyclohexenones / Vinylogous acids / Tertiary alcohols / Trialkylamines
show 7 more
Substituents
Tetracycline / Naphthacene / Tetracene / Anthracene carboxylic acid or derivatives / Tetralin / Aryl ketone / 1-hydroxy-2-unsubstituted benzenoid / Cyclohexenone / Phenol / Aralkylamine
show 23 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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. Sarecycline FDA Label [File]

Drug created on October 20, 2016 15:13 / Updated on December 02, 2019 09:16