Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.
IDENTIFICATION AND USE: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) kinase, is an antineoplastic agent and macrolide immunosuppressive agent. Everolimus (brand name Afinitor) is used in the treatment of certain types of breast cancers, neuroendocrine tumors of pancreatic origin, renal cell carcinoma, renal angiomyolipoma with tuberous sclerosis complex, and subependymal giant cell astrocytoma with tuberous sclerosis complex. Everolimus (brand name Zortress) is used for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. It is also used for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. HUMAN EXPOSURE AND TOXICITY: Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2-year-old child where no adverse reactions were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability. Single doses up to 70 mg (without cyclosporine) have been given with acceptable acute tolerability. Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including opportunistic infections. Some of these infections have been severe (e.g., resulting in respiratory or hepatic failure) or fatal. Fatal noninfectious pneumonitis also has been reported with everolimus. Increases in serum creatinine concentrations and proteinuria have been reported in clinical trials with everolimus (Afinitor). Cases of renal failure (including acute renal failure), some with a fatal outcome, also have been observed in everolimus-treated patients. ANIMAL STUDIES: Everolimus was not carcinogenic in mice or rats when administered daily by oral gavage for 2 years at doses of 0.9 mg/kg. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses greater than or equal to 0.1 mg/kg (0.6 mg/sq m). In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/sq m. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/sq m), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (approximately 5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. In a 13-week male fertility oral gavage study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count and plasma testosterone concentrations were diminished at 5 mg/kg which caused a decrease in male fertility. There was evidence of reversibility of these findings in animals examined after 13 weeks post-dosing. The 0.5 mg/kg dose in male rats resulted in AUCs in the range of clinical exposures, and the 5 mg/kg dose resulted in AUCs approximately 5 times the AUCs in humans receiving 0.75 mg twice daily. Everolimus did not affect female fertility in nonclinical studies, but everolimus crossed the placenta and was toxic to the conceptus. Everolimus was not mutagenic in the bacterial reverse mutation, the mouse lymphoma thymidine kinase assay, or the chromosome aberration assay using V79 Chinese hamster cells, or in vivo following two daily doses of 500 mg/kg in the mouse micronucleus assay.
Use of HMG-CoA reductase inhibitors such as lovastatin or simvastatin was strongly discouraged in clinical trials of everolimus with cyclosporine in renal transplant patients because of an interaction between HMG-CoA reductase inhibitors and cyclosporine. The manufacturer of Zortress recommends that patients receiving everolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative be monitored for the possible development of rhabdomyolysis and other adverse effects, which are described in the prescribing information for these antilipemic agents.
Studies in healthy individuals indicate that there are no clinically important pharmacokinetic interactions between single-dose everolimus and atorvastatin (a CYP3A4 substrate) or pravastatin (a non-CYP3A4 substrate and P-gp substrate); HMG-CoA reductase bioactivity in plasma also was not substantially affected. Therefore, dosage adjustments are not necessary when everolimus and atorvastatin or pravastatin are used concurrently. In a population pharmacokinetic analysis, simvastatin (a CYP3A4 substrate) did not affect clearance of everolimus. The manufacturer of Zortress cautions that these results cannot be extrapolated to other HMG-CoA reductase inhibitors.
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors with everolimus may increase the risk of angioedema. The use of alternative antihypertensive agents should be considered in everolimus-treated patients, if necessary.
If coadministration of a P-gp inhibitor is required in patients with SEGA, everolimus dosage should be reduced by approximately 50% to maintain trough everolimus concentrations of 5-10 ng/mL. If dosage reduction is required in patients receiving 2.5 mg daily, alternate-day dosing should be considered. Subsequent dosing should be individualized based on therapeutic drug monitoring. Trough everolimus concentrations should be assessed approximately 2 weeks after the addition of the P-gp inhibitor. If the P-gp inhibitor is discontinued, the everolimus dosage should be returned to the dosage used prior to initiation of the P-gp inhibitor and the trough everolimus concentration should be reassessed approximately 2 weeks later.
The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range 128 to 589 L).
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Afinitor 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
After administration of Afinitor tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.
No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.
来源:Hazardous Substances Data Bank (HSDB)
文献信息
HISTONE H2AX (HH2AX) BIOMARKER FOR FTI SENSITIVITY
申请人:Basso-Porcaro Andrea Dawn
公开号:US20110009387A1
公开(公告)日:2011-01-13
The present invention relates e.g., to methods for predicting cellular sensitivity to farnesyl protein transferase inhibitors, such as lonafarnib; manumycin A; FTI-276; L-744832; BMS-214662; tipifarnib; BMS-316810K. The methods involve determining if malignant cells exhibit increased expression. of phosphorylated histone H2Ax following contact of one or more of said cells with said inhibitor.
The present invention relates in part to anti-IGF1R antibodies and antigen-binding compositions thereof along with methods of use thereof. For example, methods of treating medical disorders such as cancer are covered.
ANTI-MET IN COMBINATION WITH ANTI-VEGFR2 ANTIBODIES THERAPY FOR CANCER
申请人:Eli Lilly and Company
公开号:US20160369004A1
公开(公告)日:2016-12-22
The present invention provides preparation of medicaments for use in treating and methods of treating cancer selected from the group consisting of gastric cancer, HCC, and RCC comprising a C8-H241 Ab, preferably, C8-H241-IgG4, more preferably, emibetuzumab, in combination, as described herein, with an anti-VEGFR2 Ab, preferably, ramucirumab.
DYE-STABILIZED NANOPARTICLES AND METHODS OF THEIR MANUFACTURE AND THERAPEUTIC USE
申请人:Memorial Sloan Kettering Cancer Center
公开号:US20180021259A1
公开(公告)日:2018-01-25
Described herein are nanoparticles which are largely made of (e.g., 90 wt. %) hydrophobic drugs and are stabilized by water soluble dyes. The nanoparticles can range in size from 30 nm to 150 nm and have highly negative surface charge (e.g., −55 mV). These nanoparticles are highly soluble in water, stable for days in PBS buffer and can be easily lyophilzed and reconstituted in water. Using quantitative self-assembly prediction calculations, topochemical molecular descriptors were identified and validated as highly predictive indicators of nano-assembly, nanoparticle size, and drug loading. The resulting nanoparticles selectively targeted kinase inhibitors to caveolin-1-expressing human colon cancer and autochthonous liver cancer models to yield striking therapeutic effects while avoiding pERK inhibition in healthy skin. The nanoparticles exhibited remarkable anti-tumor efficacy in vitro and in vivo in models of hepatocellular carcinoma.