Sarecycline

Identification

Summary

Sarecycline is a tetracycline antibiotic used to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris.

Generic Name

Sarecycline

DrugBank Accession Number

DB12035

Background

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.

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Sarecycline (DB12035)

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Weight

Average: 487.509
Monoisotopic: 487.195464906

Chemical Formula

C₂₄H₂₉N₃O₈

Synonyms

• Sareciclina
• Sarecycline
• Sarécycline
• Sarecyclinum

External IDs

• P-005672
• P005672

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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.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Moderate, severe non-nodular acne vulgaris		••••••••••••			••••••• •••••• ••••••••••••••

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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.

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.

Adverse Effects

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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.

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Sarecycline.
Acenocoumarol	Sarecycline may increase the anticoagulant activities of Acenocoumarol.
Acitretin	The risk or severity of pseudotumor cerebri can be increased when Acitretin is combined with Sarecycline.
Afatinib	The serum concentration of Afatinib can be increased when it is combined with Sarecycline.
Alitretinoin	The risk or severity of pseudotumor cerebri can be increased when Alitretinoin is combined with Sarecycline.

Food Interactions

• Take separate from antacids.
• Take with fluids. This may reduce irritation of the esophagus.
• Take with or without food.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Sarecycline hydrochloride	36718856JR	1035979-44-2	APPRLAGZQKOUFL-FIPJBXKNSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Seysara	Tablet	100 mg/1	Oral	Allergan, Inc.	2018-08-01	2018-08-01
Seysara	Tablet, coated	100 mg/1	Oral	Almirall, LLC	2019-01-04	Not applicable
Seysara	Tablet	60 mg/1	Oral	Allergan, Inc.	2018-08-01	2018-08-01
Seysara	Tablet, coated	60 mg/1	Oral	Almirall, LLC	2019-01-04	Not applicable
Seysara	Tablet	150 mg/1	Oral	Allergan, Inc.	2018-08-01	2018-08-01

Categories

ATC Codes

J01AA14 — Sarecycline

• J01AA — Tetracyclines
• J01A — TETRACYCLINES
• J01 — ANTIBACTERIALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

J01AA20 — Combinations of tetracyclines

• J01AA — Tetracyclines
• J01A — TETRACYCLINES
• J01 — ANTIBACTERIALS FOR SYSTEMIC USE
• J — ANTIINFECTIVES FOR SYSTEMIC USE

Drug Categories

• Anti-Acne Preparations
• Anti-Acne Preparations for Systemic Use
• Anti-Bacterial Agents
• Anti-Infective Agents
• Antibacterials for Systemic Use
• Antiinfectives for Systemic Use
• Dermatologicals
• Naphthacenes
• P-glycoprotein inhibitors
• Tetracyclines

Chemical TaxonomyProvided by Classyfire

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 / Amino acids and derivatives / Primary carboxylic acid amides / Polyols / N-organohydroxylamines / Enols / Organic oxides / Hydrocarbon derivatives

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Substituents

1-hydroxy-2-unsubstituted benzenoid / Alcohol / Amine / Amino acid or derivatives / Anthracene carboxylic acid or derivatives / Aralkylamine / Aromatic homopolycyclic compound / Aryl ketone / Benzenoid / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Cyclohexenone / Enol / Hydrocarbon derivative / Ketone / N-organohydroxylamine / Naphthacene / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organonitrogen compound / Organooxygen compound / Phenol / Polyol / Primary carboxylic acid amide / Tertiary alcohol / Tertiary aliphatic amine / Tertiary amine / Tetracene / Tetracycline / Tetralin / Vinylogous acid

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Molecular Framework

Aromatic homopolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

94O110CX2E

CAS number

1035654-66-0

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(CN(C)OC)C=CC(O)=C3C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@]1([H])C2

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. [Article]
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. [Article]
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. [Article]
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. [Article]
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

RxNav

2059018

ChEMBL

CHEMBL2364632

ZINC

ZINC000072319783

PDBe Ligand

V7A

Wikipedia

Sarecycline

PDB Entries

6xqd / 6xqe / 8crx / 8cvm / 8cvo

FDA label

Download (155 KB)

MSDS

Download (17.4 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Rosacea	1
3	Completed	Treatment	Acne Vulgaris	3
3	Withdrawn	Treatment	Acne Vulgaris	1
2	Completed	Treatment	Acne Vulgaris	1
2	Recruiting	Treatment	Acute Ischemic Stroke	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	100 mg/1
Tablet	Oral	150 mg/1
Tablet	Oral	60 mg/1
Tablet, coated	Oral	100 mg/1
Tablet, coated	Oral	150 mg/1
Tablet, coated	Oral	60 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8513223	No	2013-08-20	2029-12-07
US9255068	No	2016-02-09	2033-02-09
US8318706	No	2012-11-27	2031-05-01
US9481639	No	2016-11-01	2028-08-10

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	2.01 mg/mL	ALOGPS
logP	-0.17	ALOGPS
logP	-3.1	Chemaxon
logS	-2.4	ALOGPS
pKa (Strongest Acidic)	3.31	Chemaxon
pKa (Strongest Basic)	8.69	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	10	Chemaxon
Hydrogen Donor Count	5	Chemaxon
Polar Surface Area	173.86 Å2	Chemaxon
Rotatable Bond Count	5	Chemaxon
Refractivity	127.61 m3·mol-1	Chemaxon
Polarizability	49.31 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-000i-0000900000-813d7453234f7e757729
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-000l-0000900000-80544b198db233113d54
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0ly9-0000900000-0c1543ea5ef4090fd256
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01pa-2688900000-1e10b308e75142c9d7c3
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-06ri-2000900000-6dc60fdd29d4d96a021f
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-01p6-2023900000-bb40f5489238d64ad9b2
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	206.67245	predicted	DeepCCS 1.0 (2019)
[M+H]+	208.49734	predicted	DeepCCS 1.0 (2019)
[M+Na]+	214.10316	predicted	DeepCCS 1.0 (2019)

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Drug created at October 20, 2016 21:13 / Updated at February 21, 2021 18:53