Hepatic (CYP-mediated). Rotigotine is extensively and rapidly metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl-rotigotine. Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine.
CYP2C19 was found to be the major CYP isoform involved in the phase 1 metabolism of rotigotine. However, multiple CYP-isoforms appear to be capable of catalyzing the metabolism. In vitro studies suggest a low risk for drug-drug interactions with co-administered drugs which are substrates of CYP isoforms in vivo. Also, no induction of human liver CYP isoforms has been found. No potential for displacement of rotigotine by warfarin and vice versa was detected with human serum albumin in vitro. Rotigotine was found not to be a substrate for P-glycoprotein and does not modulate digoxin transport in vitro.
Following absorption rotigotine was rapidly metabolised. Three phase 1 metabolites showed pharmacological activity. However, pharmacokinetics of these metabolites were not required as their presence in plasma was too low. The major metabolite observed in animal hepatocytes, the glucuronide conjugate of rotigotine, was in vivo excreted into bile and only reached the blood system at low levels. Conjugates of the Ndealkylated metabolites were found to be the major metabolites in plasma. Following subcutaneous administration, the sulfate and the glucuronide conjugates of the SPM 9206 metabolite and the sulfate conjugates of the SPM 9257 and the sulfate of the desthienylethyl despropyl metabolite were found to be the major metabolites in plasma. In human plasma, the sulphate conjugates of rotigotine, the SPM 9206 and the SPM 9257 metabolite were found to be the major metabolites. All the human major metabolites found in plasma were also found in the plasma of the main toxicological species.
Rotigotine is extensively metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl-rotigotine. Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine.
Rotigotine is primarily excreted in urine (approximately 71%) as inactive conjugates of the parent compound and N-desalkyl metabolites. A smaller proportion is excreted in feces (approximately 23%). The major metabolites found in urine were rotigotine sulfate (16% to 22% of the absorbed dose), rotigotine glucuronide (11% to 15%), and N-despropyl-rotigotine sulfate metabolite (14% to 20%) and N-desthienylethyl-rotigotine sulfate metabolite (10% to 21%). Approximately 11% is renally eliminated as other metabolites. A small amount of unconjugated rotigotine is renally eliminated (less than 1% of the absorbed dose).
IDENTIFICATION AND USE: Rotigotine is a white to off white powder formulated into a transdermal system (patch). It is a nonergot-derivative dopamine receptor agonist used for the symptomatic management of idiopathic parkinsonian syndrome. It is also used for the symptomatic management of moderate-to-severe primary restless legs syndrome. HUMAN EXPOSURE AND TOXICITY: The most likely symptoms of overdose would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions, and other signs of excessive dopaminergic stimulation. Post-marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic behavior during rotigotine treatment or after starting or increasing the dose of rotigotine. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior may consist of one or more of the following: paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. These various manifestations of psychotic behavior were also observed during the clinical development of rotigotine for early- and advanced-stage Parkinson's disease and Restless Legs Syndrome. Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including rotigotine, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. ANIMAL STUDIES: Two-year carcinogenicity studies of rotigotine were conducted in mice at doses of 0, 3, 10, and 30 mg/kg and in rats at doses of 0, 0.3, 1, and 3 mg/kg; in both studies rotigotine was administered subcutaneously once every 48 hours. No significant increases in tumors occurred in mice at doses up to 9 times the maximum recommended human dose (MRHD) in Parkinson's disease (8 mg/24 hours). In rats, there were increases in Leydig cell tumors and in uterine tumors (adenocarcinomas, squamous cell carcinomas) at all doses. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans. Therefore, there were no tumor findings considered relevant to humans at plasma exposures (AUC) up to 4 to 6 times that in humans at the MRHD. Rotigotine administered subcutaneously (10, 30, or 90 mg/kg/day) to pregnant mice during organogenesis resulted in increased incidences of delayed skeletal ossification and decreased fetal body weights at the two highest doses and an increase in embryo-fetal death at the high dose. Rotigotine administered subcutaneously (0.5, 1.5, or 5 mg/kg/day) to pregnant rats during organogenesis resulted in increased embryo-fetal death at all doses. When rotigotine was administered subcutaneously (5, 10, or 30 mg/kg/day) to pregnant rabbits during organogenesis, an increase in embryo-fetal death occurred at the two highest doses tested. In a study in which rotigotine was administered subcutaneously (0.1, 0.3, or 1 mg/kg/day) to rats throughout pregnancy and lactation, impaired growth and development during lactation and long-term neurobehavioral abnormalities were observed in the offspring at the highest dose tested; when those offspring were mated, growth and survival of the next generation were adversely affected. When rotigotine was administered subcutaneously (1.5, 5, or 15 mg/kg/day) to female rats prior to and during mating and continuing through gestation day 7, an absence of implantation was observed at all doses. In male rats treated from 70 days prior to and during mating, there was no effect on fertility; however, a decrease in epididymal sperm motility was observed at the highest dose tested. When rotigotine was administered subcutaneously to female mice at doses of 10, 30, and 90 mg/kg/day from 2 weeks until 4 days before mating and then at a dose of 6 mg/kg/day (all groups) from 3 days before mating until gestation day 7, a markedly reduced (low dose) or complete absence of implantation (mid and high doses) was observed. The effects on implantation in rodents are thought to be due to the prolactin-lowering effect of rotigotine. In humans, chorionic gonadotropin, not prolactin, is essential for implantation. Rotigotine was negative in the in vitro bacterial reverse mutation (Ames) and in the in vivo micronucleus assays. Rotigotine was mutagenic and clastogenic in the in vivo mouse lymphoma tk assay
In multiple, controlled trials in Parkinson disease and restless leg syndrome, rotigotine transdermal patches were not associated with serum enzyme elevations, liver related severe adverse events or instances of clinically apparent liver injury. Since the approval and more wide scale use of rotigotine, there have been no published case reports of liver injury associated with its use and hepatotoxicity is not mentioned in the product label.
◉ Summary of Use during Lactation:No information is available on the use of rotigotine during breastfeeding, but it suppresses serum prolactin and may interfere with breastfeeding. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information in nursing mothers was not found as of the revision date. Rotigotine lowers serum prolactin. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Concurrent oral administration of levodopa/carbidopa (100/25 mg twice daily) and transdermal rotigotine (4 mg/24 hours) in patients with restless legs syndrome had no effect on the steady-state pharmacokinetics of any of the drugs. Transdermal rotigotine may potentiate the therapeutic effects of levodopa as well as its adverse dopaminergic effects (including dyskinesia).
Concurrent administration of transdermal rotigotine (3 mg/24 hours) did not substantially affect the pharmacodynamics or pharmacokinetics of an oral estrogen-progestin combination contraceptive (ethinyl estradiol 0.03 mg with 0.15 mg levonorgestrel) in healthy females. Possible interactions with rotigotine and other forms of hormonal contraceptives have not been evaluated to date.
Bioavailability varies depending on the application site. Differences in bioavailability were very small between the abdomen and hip (<1%). In contrast, the shoulder and thigh had a very large different in measured bioavailability (46%), with the shoulder showing the higher value. Tmax, 8 mg dose = 15 - 18 hours (it take approximately 3 hours until rotigotine reaches detectable levels in the plasma). The peak concentration cannot be observered. Steady state is reached in 2-3 days.
Results obtained with the patch administration in animals showed that the silicone based patch was superior to the acrylic based patch with respect to substance release. Following repeated dosing, 81 and 93 % substance was released from the silicone patch on the rat and monkey, respectively. The corresponding % release from the acrylic based patch was 28 and 22 %, respectively.
The weight normalized apparent volume of distribution (Vd/F) in humans is approximately 84 L/kg after repeated dose administration. The binding of rotigotine to human plasma proteins is approximately 92% in vitro and 89.5% in vivo.
[EN] POLYOXAZOLINE ANTIBODY DRUG CONJUGATES<br/>[FR] CONJUGUÉS ANTICORPS-MÉDICAMENT DE POLYOXAZOLINE
申请人：SERINA THERAPEUTICS INC
公开号：WO2016019340A1
公开（公告）日：2016-02-04
In the present disclosure, polymer conjugates, including polymer-antibody-drug conjugates (polymer ADCs) are described, as well as the use of such conjugates to treat human disease. The polymer conjugates can contain a large number of polymer-bound agents, thus effectively increasing the drug antibody ration (DAR) of the antibody significantly beyond the currently available technology. This may be of particular importance when antibodies to low density antigens are used as target antibodies. The described polymer-ADCs have improved pharmacokinetics and solubility relative to traditional ADCs. The linker between agent and the polymer can be tailored to provide release of toxin at the desired site and under the desired conditions within the tumor. An additional feature of the polymer-ADCs of the current disclosure is that a purification moiety can be attached to the polymer backbone to provide ease of purification of the polymer-ADCs.
SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization
作者：Zilei Liu、Jie Li、Suhua Li、Gencheng Li、K. Barry Sharpless、Peng Wu
DOI：10.1021/jacs.7b12788
日期：2018.2.28
Sulfur(VI) Fluoride Exchange (SuFEx) is a new family of clickchemistry transformations which relies on readily available materials to produce compounds bearing the SVI-F motif. The potential of SuFEx in drug discovery has just started to be explored. We report the first method of SuFExchemistry for the conversion of phenolic compounds to their respective arylfluorosulfate derivatives in situ in 96-well
Novel Process for the Preparation of Nitrogen Substituted Aminotetralins Derivatives
申请人：Ates Celal
公开号：US20130102794A1
公开（公告）日：2013-04-25
The present invention provides an alternative synthesis of N-substituted aminotetralines comprising resolution of N-substituted aminotetralins of formula (II), wherein R
1
, R
2
and R
3
are as defined for compound of formula (I).
S-5-SUBSTITUENT-N-2'-(THIOPHENE-2-YL)ETHYL-TETRALIN-2-AMINE OR CHIRAL ACID SALTS THEREOF AND USE FOR PREPARING ROTIGOTINE
申请人：He Xungui
公开号：US20130046100A1
公开（公告）日：2013-02-21
The chiral compound S-5-substituted-N-2′-(thienyl-2-yl-)ethyl-tetralin-2-amine or its chiral acid salts and preparation method thereof are disclosed, and the method for preparing Rotigotine by using the chiral compound is also disclosed. Racemic 5-substituted-N-2′-(thien-2-yl-)ethyl-tetralin-2-amine (compound 1) is resolved by using a conventional chiral acid to obtain an optically pure chiral acid salt of S-5-substituted-N-2′-(thien-2-yl-)ethyl-tetralin-2-amine, which is then dissociated to obtain S-5-substituted-N-2′-(thien-2-yl-)ethyl-tetralin-2-amine (compound 2). The compound 2 or chiral acid salt thereof is alkylated and deprotected to produce rotigotine (compound 5).
[EN] A PROCESS FOR THE PREPARATION OF ROTIGOTINE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE LA ROTIGOTINE
申请人：FIDIA FARMACEUTICI
公开号：WO2010035111A1
公开（公告）日：2010-04-01
A process for the preparation of Rotigotine (I) and of pharmaceutically acceptable salts thereof, which comprises the reductive amination of an amine of formula 6 with the 2-thienylacetic acid- sodium boron hydride complex and which makes use of hydrobromide 5 as an intermediate (II) The process is advantageous from the industrial point of view in that it allows to obtain Rotigotine with high enantiomeric purity starting from optically active 5,6,7,8-tetrahydro-6-(S)-N-propylamino-l-methoxy- naphthalene (2), avoiding the use of dangerous reactives, the need for difficult chromatographic separation or the formation of by-products. Furthermore, two novel crystalline forms are disclosed.
