Larotrectinib is metabolized predominantly by the CYP3A4 isoenzymes [FDA Label]. Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma [FDA Label].
In early clinical trials in a total of 176 patients with various forms of solid tumors which had an NTRK gene fusion, elevations in serum aminotransferase levels occurred in 45% of patients treated with larotrectinib. Serum aminotransferase levels rose to above 5 times ULN in 6% of patients and led to early discontinuation in 2%. Serum aminotransferase elevations typically arose after 4 to 12 weeks of treatment, but usually without jaundice or alkaline phosphatase elevations. Most elevations resolved within 4 to 8 weeks and discontinuations were uncommon. Restarting larotrectinib at a reduced dose after resolution of the aminotransferase abnormalities was generally well tolerated and did not lead to recurrence of liver injury. Cases with jaundice and symptoms during larotrectinib therapy have not been reported, but the clinical experience with this kinase inhibitor has been limited and prelicensure clinical trials were carried out with careful clinical monitoring.
Although there is no available data on larotrectinib use in pregnant women, based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and the agent's mechanism of action it is believed that larotrectinib can cause embryo-fetal harm when administered to a pregnant woman [FDA Label]. Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis [FDA Label]. Furthermore, animal studies data note that lacrotrectinib can cross the placenta in animals [FDA Label]. Advise pregnant women of the potential risk to a fetus [FDA Label]. There are no data on the presence of larotrectinib or its metabolites in human milk and no data on its effects on the breastfed child or on milk production [FDA Label]. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with larotrectinib and for 1 week after the final dose [FDA Label]. Female patients of reproductive potential who are being treated with larotrectinib are advised to use effective contraception during larotrectinib treatment and for at least one week after the final dose [FDA Label]. Males with female partners of reproductive potential are also advised to use effective contraception during larotrectinib therapy and for one week after the final dose [FDA Label]. Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, larotrectinib use may reduce fertility in females [FDA Label]. The safety and effectiveness of larotrectinib in pediatric patients was established based upon data from clinical trials in adult or pediatric patients 28 days and older [FDA Label]. The pharmacokinetics of larotrectinib in the pediatric population have also been determined to be similar to those seen in adults [FDA Label]. Clinical studies of larotrectinib did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [FDA Label]. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Larotrectinib clearance was reduced in subjects with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment [FDA Label]. No dose adjustment is recommended for patients with renal impairment of any severity [FDA Label]. Carcinogenicity studies have not been conducted with larotrectinib [FDA Label]. Larotrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or in the in vitro mammalian mutagenesis assays, with or without metabolic activation [FDA Label]. In vivo, larotrectinib was negative in the mouse micronucleus test [FDA Label]. Fertility studies with larotrectinib have not been conducted. In a 3-month repeat-dose toxicity study in the rat, larotrectinib had no effects on spermatogenesis at 75 mg/kg/day (approximately 7 times the human exposure at the 100 mg twice daily dose) [FDA Label. Additionally, larotrectinib had no histological effects on the male reproductive tract in rats or monkeys at doses resulting in exposures up to 10 times the human exposure (AUC0-24hr) at the 100 mg twice daily clinical dose [FDA Label]. In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose] [FDA Label]. Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose] [FDA Label]. There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose [FDA Label]. In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose] [FDA Label]. Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose) [FDA Label]. Decreased fertility occurred in a juvenile animal study [FDA Label]. There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose [FDA Label].
Larotrectinib is approximately 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations [FDA Label]. The blood to plasma concentration ratio is 0.9 [FDA Label].
The mean absolute bioavailability of larotrectinib capsules has been recorded as 34%, from a range spanning 32% to 37% [FDA Label]. In adult patients who received larotrectinib capsules 100 mg twice daily, peak plasma levels Cmax were achieved at about one hour after dosing and steady-state was reached within the time span of three days [FDA Label]. The mean steady-state of these administered larotrectinib capsules was Cmax 788 ng/mL and the AUC(0-24hr) was 4351 ng*h/mL [FDA Label]. Concurrently, in healthy subjects, the AUC of the administered larotrectinib oral solution formulation was similar to that of the capsules and the particular Cmax was 36% greater with the oral solution [FDA Label]. The AUC of larotrectinib was similar but the Cmax was reduced by 35% after oral administration of a single 100 mg capsule of larotrectinib to healthy subjects taken with a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUC in the fasted state [FDA Label].
Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine [FDA Label].
来源:DrugBank
吸收、分配和排泄
分布容积
拉罗曲替尼的平均分布容积Vss在健康受试者中静脉给药后记录为48升[FDA标签]。
The mean volume of distribution Vss of larotrectinib has been documented as being 48L following intravenous administration in healthy subjects [FDA Label].
来源:DrugBank
吸收、分配和排泄
清除
拉罗曲替尼的平均清除率CL/F已记录为98 L/h [FDA标签]。
The mean clearance CL/F of larotrectinib has been documented as 98 L/h [FDA Label].
[EN] SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS<br/>[FR] COMPOSÉS DE PYRAZOLO[1,5-A]PYRIMIDINE SUBSTITUÉS COMME INHIBITEURS DE LA TRK KINASE
申请人：ARRAY BIOPHARMA INC
公开号：WO2010048314A1
公开（公告）日：2010-04-29
Compounds of Formula (I) in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.
A method of treating a pediatric cancer in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, or a combination thereof.
[EN] SUBSTITUTED PYRAZOLOPYRIMIDINES USEFUL AS KINASES INHIBITORS<br/>[FR] PYRAZOLOPYRIMIDINES SUBSTITUÉES POUVANT ÊTRE EMPLOYÉES EN TANT QU'INHIBITEURS DE KINASES
申请人：TELIGENE LTD
公开号：WO2019029629A1
公开（公告）日：2019-02-14
Disclosed are novel pyrzaolopyrimidines of Formula (I), their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds have protein kinases inhibitory activities and are expected to be useful for the treatment of protein kinases mediated diseases and conditions.
[EN] PREPARATION OF (S)-N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-Y L)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE<br/>[FR] PRÉPARATION DE (S)-N-(5-((R)-2-(2,5-DIFLUOROPHÉNYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE
申请人：REYNOLDS MARK
公开号：WO2017201241A1
公开（公告）日：2017-11-23
Process for preparing (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l- yl)pyrazolo[l,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide (formula I) or a salt thereof by reacting phenyl(5-((R)-2-(2,5- difluorophenyl)pyrrolidin-l-yl)-3,3a-dihydropyrazolo[l,5-a]pyrimidin-3- yl)carbamate or a similar derivative (formula 13) with (S)-pyrrolidin-3- ol (formula 14). Process for preparing phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l- yl)-3,3a-dihydropyrazolo[l,5-a]pyrimidin-3-yl)carbamate (formula 13) or a similar derivative by reduction of (R)-5-(2-(2,5-difluorophenyl) pyrrolidin-l-yl)-3-nitropyrazolo[l,5-a]pyrimidine (formula 11) to (R) -5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3- amine (formula 12). Process for preparing (R)-2-(2,5-difluorophenyl)pyrrolidine(R) -2-hydroxysuccinate (formula 10) by treating (R)-N-((R)-l-(2,5- difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2- sulfinamide (formula 19) with an acid and a reducing agent. (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-l-yl)-pyrazolo[l,5- a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide, is a tyrosin kinase (TRK) inhibitor for trearing e.g. cancer.
