At least 64% of a ponatinib dose undergoes phase I and phase II metabolism. CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the phase I metabolism of ponatinib in vitro. Ponatinib is also metabolized by esterases and/or amidases.
In vivo, ponatinib was hydrolysed by non-specific esterases or amidases at the amide bond to an acid and aniline. AP24600 was the major metabolite in rat and human plasma but was a trace level metabolite in monkey plasma. In rat, monkey and human plasma, the amide hydrolysis metabolite AP24600 was 263%, < 1% and 58.4% of the ponatinib levels. In rats, the metabolism of ponatinib was mainly to the N-desmethyl metabolite AP24567, which was excreted in feces, and AP24600 (and its downstream metabolites) which was excreted in urine. In monkey feces drug-related radioactivity was present mostly as the parent compound or as N-desmethyl ponatinib (M42), hydroxy ponatinib (M31), a double lactam at piperazine moiety (M35) and N-oxide ponatinib (M36). In human feces, ponatinib accounted for 23.7% of the radioactivity and there was extensive metabolism of ponatinib. Other metabolites identified in human feces were hydroxy ponatinib, N-desmethyl ponatinib, and several minor metabolites resulting from two or more modifications.
At least 64% of a ponatinib dose undergoes phase I and phase II metabolism. CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the phase I metabolism of ponatinib in vitro. Ponatinib is also metabolized by esterases and/or amidases.
In large clinical trials, elevations in serum aminotransferase levels during ponatinib therapy occurred in up to 56% of patients and were above 5 times upper limit of normal (ULN) in 8% of patients. While these abnormalities were reversible in most patients, they were prolonged or severe in some. Instances of clinically apparent liver disease and progressive hepatic failure and death were reported in clinical trials of ponatinib, although the clinical features of the liver injury have not been well described. The latency until onset can be rapid and most cases have had a hepatocellular pattern of serum enzyme elevations. Because of the potential for serious hepatotoxicity, routine monitoring of liver tests is recommended during ponatinib therapy and dose modification or discontinuation recommended for ALT or AST elevations above 3 times ULN. Thus, ponatinib therapy is associated with a high rate of transient serum aminotransferase elevations and is reported to cause rare instances of severe hepatic injury, but there have been no cases described in the literature.
Reactivation of hepatitis B has been reported with imatinib and nilotinib therapy of CML, but not with ponatinib. Reactivation typically occurs in an HBsAg positive person treated with the tyrosine kinase inhibitor for 3 to 6 months, presenting with jaundice, marked serum aminotransferase elevations and an increase in HBV DNA levels. Reactivation of hepatitis B can be severe, and fatal instances have been reported after imatinib and nilotinib therapy. Screening of patients for HBsAg and anti-HBc is sometimes recommended before starting cancer chemotherapy and those with HBsAg offered prophylaxis with oral antiviral agents, such as lamivudine, tenofovir or entecavir. Whether reactivation occurs with ponatinib therapy is unknown.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia in patients resistant or intolerant to prior TKIs. In vitro studies suggested that metabolism of ponatinib is partially mediated by CYP3A4. The effects of CYP3A4 inhibition on the pharmacokinetics of ponatinib and its CYP3A4-mediated metabolite, AP24567, were evaluated in a single-center, randomized, two-period, two-sequence crossover study in healthy volunteers. Subjects (N = 22) received two single doses (orally) of ponatinib 15 mg, once given alone and once coadministered with daily (5 days) ketoconazole 400 mg, a CYP3A4 inhibitor. Ponatinib plus ketoconazole increased ponatinib maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC) compared with ponatinib alone. The estimated mean ratios for AUC0-8, AUC0-t, and C(max) indicated increased exposures to ponatinib of 78%, 70%, and 47%, respectively; exposure to AP24567 decreased by 71%. Exposure to AP24567 was marginal after ponatinib alone (no more than 4% of the exposure to ponatinib). These results suggest that caution should be exercised with the concurrent use of ponatinib and strong CYP3A4 inhibitors and that a ponatinib dose decrease to 30 mg daily, from the 45 mg daily starting dose, could be considered.
... Ponatinib at pharmacologically relevant concentrations produced synergistic cytotoxicity with ABCB1 and ABCG2 substrate chemotherapy drugs and enhanced apoptosis induced by these drugs, including daunorubicin, mitoxantrone, topotecan, and flavopiridol, in cells overexpressing these transport proteins. ...
The most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.
/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/
The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are observed within 6 hours after Iclusig oral administration. Food does not affect absorption of food. The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility. When 45 mg of ponatinib is given to cancer patients, the pharmacokinetic parameters are as follows: Cmax = 73 ng/mL; AUC = 1253 ng•hr/mL;
Ponatinib is mainly eliminated via feces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine.
After oral administration of 45 mg ponatinib once daily for 28 days in cancer patients, the steady state volume of distribution is 1223 L. Ponatinib is a weak substrate for P-gp and ABCG2.
Ponatinib is greater than 99% bound to plasma proteins in vitro. The geometric mean (CV%) apparent steady state volume of distribution is 1223 liters (102%) following oral administration of Iclusig 45 mg once daily for 28 days in patients with cancer. Ponatinib is a weak substrate for both P-gp and ABCG2 [also known as BCRP] in vitro. Ponatinib is not a substrate for organic anion transporting polypeptides (OATP1B1, OATP1B3) and organic cation transporter 1 (OCT1) in vitro.
Exposure increased by approximately 90% (median) (range: 20% to 440%) between the first dose and presumed steady state. Ponatinib is mainly eliminated via feces. Following a single oral dose of (14)C-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine.
[EN] NOVEL SALTS OF 3-(2-IMIDAZO[1,2-b]PYRIDAZIN-3-YLETHYNYL)-4-METHYL-N-[4-[(4-METHYL- 1-PIPERAZINYL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL] BENZAMIDE [FR] NOUVEAUX SELS DE 3-(2-IMIDAZO[1,2-B]PYRIDAZIN-3-YL-ÉTHYNYL)-4-MÉTHYL-N-[4-[(4-MÉTHYL-1-PIPÉRAZINYL)MÉTHYL]-3-(TRIFLUOROMÉTHYL)PHÉNYL]BENZAMIDE
[EN] BCR-ABL TYROSINE-KINASE LIGANDS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME<br/>[FR] LIGANDS DE TYROSINE-KINASE BCR-ABL CAPABLES DE SE DIMÉRISER DANS UNE SOLUTION AQUEUSE, ET PROCÉDÉS D'UTILISATION DE CEUX-CI
申请人：COFERON INC
公开号：WO2015106292A1
公开（公告）日：2015-07-16
Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. invivo) to form a multimer (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding sites on a Bcr-Abl tyrosine kinase.
[EN] METHODS AND COMPOSITIONS FOR RAF KINASE MEDIATED DISEASES<br/>[FR] PROCÉDÉS ET COMPOSITIONS POUR LE TRAITEMENT DE MALADIES MÉDIÉES PAR LA KINASE RAF
申请人：ARIAD PHARMA INC
公开号：WO2013162727A1
公开（公告）日：2013-10-31
The invention discloses methods and compositions for treating or preventing RAF kinase mediated diseases or conditions by administering a compound of Formula 1: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the variables are defined as herein.
[EN] CRYSTALLINE FORMS<br/>[FR] FORMES CRISTALLINES
申请人：METCALF ANDREW T
公开号：WO2019075108A1
公开（公告）日：2019-04-18
Provided herein are compound of Formula I-IV and pharmaceutically acceptable salts thereof which exhibit rearranged during transfection (RET) kinase inhibition. In particular, provided herein are novel crystalline forms of 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV), and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, processes for making the compounds, and the use of the compounds in therapy. More particularly, the application relates to novel crystalline forms of Formula I-IV and pharmaceutically acceptable salts thereof useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.
[EN] SUBSTITUTED PYRAZOLYL[4,3-C]PYRIDINECOMPOUNDS AS RET KINASE INHIBITORS<br/>[FR] COMPOSÉS DE PYRAZOLYL[4,3-C]PYRIDINE SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA KINASE RET
申请人：ARRAY BIOPHARMA INC
公开号：WO2019143994A1
公开（公告）日：2019-07-25
Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2 and R3 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.
[EN] NEW COMPOUNDS AND METHODS<br/>[FR] NOUVEAUX COMPOSÉS ET PROCÉDÉS
申请人：BENEVOLENTAI BIO LTD
公开号：WO2020260871A1
公开（公告）日：2020-12-30
The present invention relates to compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and/or prodrug thereof. The present invention also relates to pharmaceutical compositions comprising the compounds of the invention, and to their use in the treatment or prevention of medical conditions in which inhibition of c-ABL is beneficial. (I)
