Siponimod is extensively metabolized, mainly by CYP2C9 enzyme (79.3%), and subsequently by CYP3A4 enzyme (18.5%). The pharmacological activity of the main metabolites M3 and M17 is not expected to be responsible for the clinical effect and the safety of siponimod in humans [FDA label].
In large controlled trials of siponimod in patients with multiple sclerosis, serum ALT elevations were common, typically arising during the first 3 months and persisting throughout the treatment period. The elevations were generally mild and asymptomatic, and they returned to baseline values within 3 months of stopping. Aminotransferase elevations above 3 times upper limit of normal (ULN) were reported in 6% to 8% of siponimod recipients compared to less than 2% of placebo recipients. In these prelicensure clinical trials, there were no cases of acute hepatitis or clinically apparent liver injury but elevations in liver tests led to discontinuation in 1% if subjects. Thus, mild-to-moderate and transient serum enzyme elevations during therapy are not uncommon, but clinically apparent liver injury with jaundice due to siponimod has not been reported, although the clinical experience with its use has been limited.
**Carcinogenesis** Oral carcinogenicity studies of siponimod were performed in mice and rats. There was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day [FDA label]. **Mutagenesis** Siponimod was negative in several in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays [FDA label]. **Impairment of fertility** When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) before and throughout the mating period, there was a dose-related increase in the precoital interval at any dose. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were noted at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the recommended human dose [FDA label]. When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were noted up to the highest dose studied (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose studied is about 16 times that in humans at the recommended human dose [FDA label]. **Use in pregnancy and lactation** Siponimod may cause fetal harm, based on the results of animal studies. Because it takes about 10 days to eliminate this drug from the body, women of childbearing potential should use adequate contraception to avoid pregnancy during and for 10 days after the cessation of treatment [FDA label]. No data currently exist regarding the presence of siponimod in human milk [FDA label]. A study in lactating rats demonstrated excretion of the drug and/or its metabolites in milk. The benefits nursing should be considered as well as the mother’s clinical requirement for this drug and any possible adverse effects on the breastfed infant from siponimod [FDA label].
Protein binding of siponimod is higher than 99.9% in healthy patients as well as hepatic and renal impaired patients [FDA label]. Because of the high plasma protein binding of siponimod, hemodialysis is not likely to change the total and unbound siponimod concentration and no dose adjustments are expected based on this [FDA label].
The time (Tmax) to attain maximum plasma concentrations (Cmax) after oral administration of immediate-release oral doses of siponimod was found to be approximately 4 hours ( with a range 3 - 8 hours). Siponimod is heavily absorbed (at a rate greater than or equal to 70%). The absolute oral bioavailability of siponimod is about 84%. Steady-state concentrations were attained after approximately 6 days of daily administration of a single dose of siponimod [FDA label]. **Effects of food on absorption** Food ingestion leads to delayed siponimod absorption (the median Tmax increased by approximately 2-3 hours). Food intake has no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, siponimod may be taken without regard to food [FDA label].
Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine [FDA label].
Siponimod distributes to body tissues with an average volume of distribution of 124 L. Siponimod fraction mesaured in plasma is 68% in humans. Animal studies demonstrate that siponimod readily crosses the blood-brain-barrier [FDA label].
来源:DrugBank
吸收、分配和排泄
清除
在MS患者中估计出现了明显的系统清除率为3.11 L/h [FDA标签]。
Apparent systemic clearance of 3.11 L/h has been estimated in MS patients [FDA label].
[EN] PROCESS FOR PREPARATION OF SIPONIMOD, ITS SALTS AND SOLID STATE FORMS THEREOF [FR] PROCÉDÉ DE PRÉPARATION DE SIPONIMOD, DE SES SELS ET DE FORMES À L'ÉTAT SOLIDE ASSOCIÉES
[EN] AMINO PYRAZINE DERIVATIVES AS PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS<br/>[FR] DÉRIVÉS AMINÉS DE PYRAZINE UTILISABLES EN TANT QU'INHIBITEURS DE LA PHOSPHATIDYLINOSITOL 3-KINASE
申请人：NOVARTIS AG
公开号：WO2015162459A1
公开（公告）日：2015-10-29
The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.
The present invention relates to substituted indole derivatives, to processes for their production, to new stable forms, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
[EN] SUBSTITUTED INDOLE DERIVATIVES FOR THE TREATMENT OF IMMUNOLOGICAL DISORDERS<br/>[FR] DÉRIVÉS D'INDOLE SUBSTITUÉS DESTINÉS AU TRAITEMENT DE TROUBLES IMMUNOLOGIQUES
申请人：NOVARTIS AG
公开号：WO2012156936A1
公开（公告）日：2012-11-22
The present invention relates to substituted indole derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them. (I).
[EN] AMINO PYRIDINE DERIVATIVES AS PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS<br/>[FR] DÉRIVÉS AMINÉS DE PYRIDINE UTILISABLES EN TANT QU'INHIBITEURS DE LA PHOSPHATIDYLINOSITOL 3-KINASE
申请人：NOVARTIS AG
公开号：WO2015162456A1
公开（公告）日：2015-10-29
The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.
The present disclosure provides compounds that include a tetrazolone derivative of a carboxyl group of an active agent. This disclosure also relates to pharmaceutical compositions that include these compounds, methods of using these compounds in the treatment of various diseases and disorders, and processes for preparing these compounds.
