FDA 标签上的原文是：“Sarecycline 通过人肝微粒体酶的代谢在体外是微不足道的（< 15%）[FDA 标签]。已经发现了由非酶促立体异构化、O-脱甲基化、N-脱甲基化、羟基化和脱饱和产生的少量代谢物 [FDA 标签]。”
Metabolism of sarecycline by enzymes in human liver microsomes is minimal (< 15%) in vitro [FDA Label]. Minor metabolites resulting from non-enzymic epimerization, O-/N-demethylation, hydroxylation, and desaturation have been found [FDA Label].
In preclinical clinical trials of sarecycline in facial acne, serum aminotransferase elevations were mild and no more frequent than with placebo or comparator arms. There were no instances of clinically apparent liver injury. Nevertheless, other tetracycline antibiotics, even when used in low doses, are well known causes of drug induced liver injury particularly when given long term. Minocycline which is also used for acne is one of the most common causes of liver injury with jaundice. The injury typically arises after months or years of therapy and frequently presents as an autoimmune-like syndrome that can mimic lupus erythematosus, rheumatoid arthritis or autoimmune hepatitis. While sarecycline has not been associated with a similar syndrome, it has been available for a short time only, and the prelicensure clinical trials were generally for 12 weeks only.
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 [FDA 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) [FDA 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 [FDA 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 [FDA Label]. Female fertility was not affected at doses up to 400 mg/kg/day (8 times the MRHD based on AUC comparison) [FDA 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) [FDA Label]. Male fertility was not affected at doses up to 150 mg/kg/day (4 times the MRHD based on AUC comparison) [FDA 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 [FDA Label]. The limited available human data are not sufficient to inform a drug- associated risk for birth defects or miscarriage [FDA Label]. Tetracyclines are known to cross the placental barrier; therefore, sarecycline may be transmitted from the mother to the developing fetus [FDA 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) [FDA 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) [FDA 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 [FDA Label]. Tetracyclines are excreted in human milk [FDA 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 [FDA Label]. Avoid using sarecycline in males who are attempting to conceive a child [FDA 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) [FDA 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 [FDA Label]. The safety and effectiveness of sarecycline in pediatric patients below the age of 9 years has not been established [FDA Label]. Use of tetracycline-class antibiotics below the age of 8 is not recommended due to the potential for tooth discoloration [FDA 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 [FDA Label]. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures [FDA Label]. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdose [FDA Label].
来源:DrugBank
毒理性
蛋白质结合
sarecycline的蛋白质结合率已记录为在体外从62.5%到74.7%之间[FDA标签]。
The protein binding of sarecycline has been recorded as ranging from 62.5% to 74.7% in vitro [FDA Label].
The median time to peak plasma concentration (Tmax) of sarecycline is 1.5 to 2.0 hours [FDA 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 [FDA Label].
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) [FDA Label].
来源:DrugBank
吸收、分配和排泄
分布容积
稳态下，沙雷环素的平均表观分布容积范围从91.4升到97.0升。[FDA标签]。
The mean apparent volume of distribution of sarecycline at steady-state ranges from 91.4 L to 97.0 L [FDA Label].
[EN] COMBINATION OF ZIDOVUDINE WITH A TETRACYCLINE ANTIBIOTIC<br/>[FR] COMBINAISON DE ZIDOVUDINE ET D'UN ANTIBIOTIQUE TÉTRACYCLINE
申请人：HELPERBY THERAPEUTICS LTD
公开号：WO2021074598A1
公开（公告）日：2021-04-22
The present invention relates to a combination comprising zidovudine or a pharmaceutically acceptable derivative thereof and a tetracycline antibiotic or a pharmaceutically acceptable derivative or prodrug thereof, for use in treating a microbial infection, particularly a bacterial infection such as a urinary tract infection.
