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
- Weight
- Average: 487.509
Monoisotopic: 487.195464906 - Chemical Formula
- C24H29N3O8
- Synonyms
- Sareciclina
- Sarecycline
- Sarécycline
- Sarecyclinum
- External IDs
- P-005672
- P005672
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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- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib 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. Almasilate Almasilate can cause a decrease in the absorption of Sarecycline resulting in a reduced serum concentration and potentially a decrease in efficacy. Aluminium Aluminium can cause a decrease in the absorption of Sarecycline resulting in a reduced serum concentration and potentially a decrease in efficacy. Aluminium phosphate Aluminium phosphate can cause a decrease in the absorption of Sarecycline resulting in a reduced serum concentration and potentially a decrease in efficacy. Aluminum hydroxide Aluminum hydroxide can cause a decrease in the absorption of Sarecycline resulting in a reduced serum concentration and potentially a decrease in efficacy. Ambrisentan The serum concentration of Ambrisentan can be increased when it is combined with Sarecycline. Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - Food Interactions
- Take separate from antacids.
- Take with fluids. This may reduce irritation of the esophagus.
- Take with or without food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- 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 US Seysara Tablet, coated 100 mg/1 Oral Almirall, LLC 2019-01-04 Not applicable US Seysara Tablet 60 mg/1 Oral Allergan, Inc. 2018-08-01 2018-08-01 US Seysara Tablet, coated 60 mg/1 Oral Almirall, LLC 2019-01-04 Not applicable US Seysara Tablet 150 mg/1 Oral Allergan, Inc. 2018-08-01 2018-08-01 US Seysara Tablet, coated 150 mg/1 Oral Almirall, LLC 2019-01-04 Not applicable US
Categories
- ATC Codes
- J01AA14 — Sarecycline
- J01AA — Tetracyclines
- J01A — TETRACYCLINES
- J01 — ANTIBACTERIALS FOR SYSTEMIC USE
- J — ANTIINFECTIVES FOR SYSTEMIC USE
- Drug Categories
- 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 show 7 more
- 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 show 23 more
- 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
- 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]
- 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]
- 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]
- 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]
- FDA Approval of Seysara (sarecycline) by Almirall Press Release [Link]
- Acquisition of Allergan US Medical Dermatology Department by Almirall, S.A. Press Release [Link]
- External Links
- PubChem Compound
- 54681908
- PubChem Substance
- 347828347
- ChemSpider
- 28540486
- 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 Not Available Completed Not Available Acne Vulgaris 2
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 US US9255068 No 2016-02-09 2033-02-09 US US8318706 No 2012-11-27 2031-05-01 US US9481639 No 2016-11-01 2028-08-10 US
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 Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS 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
Drug created at October 20, 2016 21:13 / Updated at February 21, 2021 18:53