Metabolism of telavancin does not involve the cytochrome P450 enzyme system. Primary metabolite is called THRX-651540, but the metabolite pathway has not been identified.
In a mass balance study in male subjects using radiolabeled telavancin, 3 hydroxylated metabolites were identified with the predominant metabolite (THRX-651540) accounting for <10% of the radioactivity in urine and <2% of the radioactivity in plasma. The metabolic pathway for telavancin has not been identified.
No metabolites of telavancin were detected in in vitro studies using human liver microsomes, liver slices, hepatocytes, and kidney S9 fraction. None of the following recombinant CYP 450 isoforms were shown to metabolize telavancin in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, 3A4, 3A5, 4A11.
Telavancin was not extensively metabolized in rats, dogs and monkeys after IV administration. Unchanged telavancin was the predominant component in the serum (99, 89 and 94 % of total AUC for rats, dogs and monkeys, respectively) while 7-OH-telavancin (AMI-11352), telavancin des-phosphonate (AMI-999) and other OH-metabolites were identified. Telavancin accounted for more than 60% (dogs) and 86% (monkeys) of the urinary recoveries. AMI-11352 represented about 17% (dogs) and 5% (monkeys) of total urinary recovery while AMI-999 represented about 1.2% (dogs) and 1.8% (monkeys) and other OH-metabolites represented about 17% (dogs) and 6% (monkey). There was no significant gender-related difference observed for metabolism profiles. Of the three OH-metabolites of the 2-(decylamino) ethyl side chain of telavancin identified in human urine 7-OH-telavancin (AMI-11352) was the most abundant. The plasma AUC of 7-OH-telavancin (which is much less active against bacteria than telavancin) was about 2-3% of the AUC of telavancin and accounted for 50% of total peak areas of the three hydroxylated metabolites. AMI-11355 (8-OH metabolite) and AMI-11353 (9-OH metabolite) accounted for 24.2% and 25.3% of the total peak areas of the three hydroxylated metabolites, respectively. Plasma concentrations of AMI-11352 were low in the rat and increases in Cmax and AUC0-24 were less than dose-proportional. Systemic exposure to AMI-11352 was larger in dogs compared to rats. According to the applicant, saturation of the metabolic pathway at higher doses may be anticipated as the AUC0-t metabolite/telavancin ratio decreased at high doses in both rats and dogs. Systemic exposures to telavancin, AMI-999 and AMI-11352 in rats and/or dogs at steady state exceeded human systemic exposure at the proposed clinical dose of 10 mg/kg/day.
The main metabolite of telavancin, 7-OH-Telavancin (AMI-11352), has antibacterial activity but is 10-fold less potent than telavancin. Due to the low antibacterial activity of AMI-11352 and the low human exposure, this metabolite is not considered to have a relevant contribution to the overall activity of telavancin in vivo.
IDENTIFICATION AND USE: Telavancin is off-white to slightly colored amorphous powder that is formulated into a solution for IV injection. Telavancin, a lipoglycopeptide antibacterial, is a synthetic derivative of vancomycin. It is used for the treatment of complicated skin and skin structure infections. Telavancin is also used for the treatment of adult patients with hospital-acquired and ventilator associated bacterial pneumonia. The US Food and Drug Administration approved a Risk Evaluation and Mitigation Strategy (REMS) for telavancin to prevent unintended telavancin exposure in pregnant women. HUMAN EXPOSURE AND TOXICITY: Women should avoid the use of telavancin during pregnancy unless the potential benefit outweighs the potential risk to the fetus. Furthermore, women of childbearing potential should have a serum pregnancy test prior to administration of telavancin. Also, patients with pre-existing moderate to severe renal impairment had increased mortality observed versus vancomycin in clinical trials. Therefore, use of telavancin in such patients should be considered only when the anticipated benefit to the patient outweighs the potential risk. Prolongation of the corrected QT interval (QTc) has also been reported in individuals receiving telavancin. Telavancin should therefore be avoided in individuals with congenital long QT syndrome, known prolongation of the QTc interval, uncompensated heart failure, or severe left ventricular hypertrophy. Finally, serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have occurred in patients following the first or subsequent doses of telavancin. ANIMAL STUDIES: The toxicity of repeated infusion of telavancin was investigated for up to three months in dogs and up to six months in rats at doses of up to 25 mg/kg/day. In the liver, treatment for 13 weeks or longer resulted in reversible degeneration/necrosis of hepatocytes accompanied by elevations in serum liver enzymes in both rats and dogs. Effects on the kidney of rats and dogs occurred after a minimum of 4 weeks of dosing and were a combination of renal tubular injury and tubular epithelial vacuolization. The tubular injury was characterized by degeneration and necrosis of proximal tubular cells, and was associated with increases in creatinine that reach a maximum of 2 times the control values at the highest doses. The tubular injury was reversible, but not all animals had reached full recovery 4 weeks after the end of treatment. In embryo-fetal development studies in rats, rabbits, and minipigs, telavancin demonstrated the potential to cause limb and skeletal malformations when given intravenously during the period of organogenesis at doses up to 150, 45, or 75 mg/kg/day, respectively. Malformations observed at <1% (but absent or at lower rates in historical or concurrent controls), included brachymelia (rats and rabbits), syndactyly (rats, minipigs), adactyly (rabbits), and polydactyly (minipigs). Additional findings included flexed front paw and absent ulna in rabbits, and misshapen digits and deformed front leg in the minipigs. Fetal body weights were decreased in rats. In a prenatal/perinatal development study, pregnant rats received intravenous telavancin at up to 150 mg/kg/day from the start of organogenesis through lactation. Offspring showed decreases in fetal body weight and an increase in the number of stillborn pups. Brachymelia was also observed. Neither mutagenic nor clastogenic potential of telavancin was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion), an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.
◉ Summary of Use during Lactation:Telavancin is 93% plasma protein bound and is poorly absorbed orally, so it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. If telavancin is required by the mother, it is not a reason to discontinue breastfeeding. Monitor the infant for possible effects on the gastrointestinal tract, such as diarrhea, vomiting, and candidiasis (e.g., thrush, diaper rash).
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Adverse renal effects are more likely to occur in patients ... receiving concomitant therapy with an agent that affects renal function (eg, nonsteroidal anti-inflammatory agents (NSAIAs), certain diuretics, angiotensin-converting enzyme (ACE) inhibitors).
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Telavancin demonstrates linear pharmacokinetics at doses between 1 and 12.5 mg/kg. Furthermore, 24 hours post-infusion of a dose of 7.5 to 15 mg/kg, activity against MRSA and penicillin-resistant Streptococcus pneumonia can still be observed. The trough concentration at this point of time is approximately 10 μg/mL. Telavancin also has poor bioavailability and must be administered over 30-120 minutes IV. Cmax, healthy subjects, 10 mg/kg = 93.6 ± 14.2 μg/mL; AUC (0- ∞), healthy subjects, 10 mg/kg = 747 ± 129 μg · h/mL; AUC (0-24h), healthy subjects, 10 mg/kg = 666± 107 μg · h/mL; Time to steady state = 3 days;
来源:DrugBank
吸收、分配和排泄
消除途径
尿液中有超过80%的未改变药物和小于20%的羟基代谢物（剂量为10mg/kg）；粪便（小于1%）。
Urine with >80% as unchanged drug and <20% as hydroxylated metabolites (with dose of 10mg/kg); Feces (<1%)
Telavancin is primarily eliminated by the kidney. In a mass balance study, approximately 76% of the administered dose was recovered from urine and <1% of the dose was recovered from feces (collected up to 216 hours) based on total radioactivity.
Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections
Lipophilic substitution on vancomycin is an effective strategy for the development of novel vancomycin analogues against drug-resistant bacteria by enhancing bacterial cell wall interactions. However, hydrophobic structures usually lead to long elimination half-life and accumulative toxicity; therefore, hydrophilic fragments were also introduced to the lipo-vancomycin to regulate their pharmacokin
Hydrochloride salts of a glycopeptide phosphonate derivative
申请人：Liu Jyanwei
公开号：US20090069534A1
公开（公告）日：2009-03-12
Disclosed are hydrochloride salts of telavancin having a chloride ion content of from about 2.4 wt. % to about 4.8 wt. %. The disclosed salts have improved stability during storage at ambient temperatures compared to other hydrochloride salts. Also disclosed are processes for preparing such salts.
MACROCYCLIZATION OF PEPTIDOMIMETICS
申请人：UNIVERSITY OF WARWICK
公开号：US20210024579A1
公开（公告）日：2021-01-28
The invention provides an improved method of macrocyclization of peptidomimetics, as measured by isolated yields and product distribution, which comprises substitution of one or more of the backbone amide C═O bonds with a turn-inducing motif. The method is general with enhancements seen across a range of ring sizes (e.g. tri-, tetra-, penta- and hexapeptides). Specifically, the invention provides a peptidomimetic macrocycle comprising a carbonylbioisosteric turn-inducing element having the structure: (I) wherein X is a heteroatom; and wherein R
1
to R
6
are each independently selected from alkyl, aryl, heteroaryl and H.
