Peringatan Keamanan

The maximum tolerated dose of crizotinib is the same as the recommended dosing regimen (250 mg twice daily). This was defined based on a phase 1 dose-escalation study in patients with advanced solid tumors. The treatment of crizotinib overdoses should consist of symptomatic treatment and other supportive measures. There is no antidote for crizotinib.L42485 In vitro and in vivo studies have shown that crizotinib is genotoxic, and the Ames test showed that crizotinib was not mutagenic. Carcinogenicity studies with crizotinib have not been performed.L42460

In female rats, 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) of crizotinib for 3 days induced single-cell necrosis of ovarian follicles. In male rats, 50 mg/kg/day of crizotinib (greater than 1.7 times the recommended human dose) for 28 days induced testicular pachytene spermatocyte degeneration.L42460

Crizotinib

DB08865

small molecule approved investigational

Deskripsi

Crizotinib is a tyrosine kinase receptor inhibitor used for the treatment of anaplastic lymphoma kinase (ALK) or ROS1-positive non-small cell lung cancer (NSCLC) tumors, as well as ALK-positive anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT).L42460 By targeting the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein, crizotinib offers robust effectiveness in treating NSCLC in patients with this type of rearrangement.A250785 Crizotinib was the first-in-class drug used to treat ALK-positive tumors. Second- and third-generation ALK-tyrosine kinase-inhibitors have overcome many of the pharmacodynamic and genetic resistance mechanisms crizotinib is prone to.A250785 Crizotinib was approved by the FDA in 2011, and its use is accompanied by FDA-approved tests used to detect ALK and ROS1 rearrangements.L42460

Struktur Molekul 2D

Berat 450.337
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Following single doses of crizotinib, the plasma terminal half-life was 42 hours.[L42460]
Volume Distribusi Following a single intravenous dose, the mean volume of distribution (Vss) of crizotinib was 1772 L.[L42460]
Klirens (Clearance) At steady-state (250 mg twice daily), crizotinib has a mean apparent clearance (CL/F) of 60 L/hr. This value is lower than the one detected after a single 250 mg oral dose (100 L/hr),[L42460], possibly due to CYP3A auto-inhibition.[L42465]

Absorpsi

In patients with pancreatic, colorectal, sarcoma, anaplastic large-cell lymphoma and non-small cell lung cancer (NSCLC) treated with crizotinib doses ranging from 100 mg once a day to 300 mg twice a day, the mean AUC and Cmax increased in a dose-proportional manner.A7419 A single crizotinib dose of crizotinib is absorbed with a median tmax 4 to 6 hours.L42460 In patients receiving multiple doses of crizotinib 250 mg twice daily (n=167), the mean AUC was is 2321.00 ng?hr/mL, the mean Cmax was 99.60 ng/mL, and the median tmax was 5.0 hours.A7418 The mean absolute bioavailability of crizotinib is 43%, ranging from 32% to 66%. High-fat meals reduce the AUC0-INF and Cmax of crizotinib by approximately 14%.L42460 Age, sex at birth, and ethnicity (Asian vs non-Asian patients) did not have a clinically significant effect on crizotinib pharmacokinetics. In patients less than 18 years old, higher body weight was associated with a lower crizotinib exposure.L42460

Metabolisme

Crizotinib is mainly metabolized in the liver by CYP3A4 and CYP3A5, and undergoes an O-dealkylation, with subsequent phase 2 conjugation.A7418 Non-metabolic elimination, such as biliary excretion, can not be excluded.L42465 PF-06260182 (with two constituent diastereomers, PF-06270079 and PF-06270080) is the only active metabolite of crizotinib that has been identified. In vitro studies suggest that, compared to crizotinib, PF-06270079 and PF-06270080 are approximately 3- to 8-fold less potent against anaplastic lymphoma kinase (ALK) and 2.5- to 4-fold less potent against Hepatocyte Growth Factor Receptor (HGFR, c-Met).L42465

Rute Eliminasi

After administering a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose were recovered in feces and urine. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.L42460

Interaksi Makanan

3 Data
  • 1. Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of crizotinib.
  • 2. Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of crizotinib.
  • 3. Take with or without food. High-fat food decreases drug absorption, but not to a clinically significant extent.

Interaksi Obat

1069 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Crizotinib.
Modafinil The metabolism of Crizotinib can be increased when combined with Modafinil.
Armodafinil The metabolism of Crizotinib can be increased when combined with Armodafinil.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Crizotinib.
Cyclosporine The serum concentration of Cyclosporine can be increased when it is combined with Crizotinib.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Crizotinib.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Crizotinib.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Crizotinib.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Crizotinib.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Crizotinib.
Ranolazine The serum concentration of Ranolazine can be increased when it is combined with Crizotinib.
Silodosin The excretion of Silodosin can be decreased when combined with Crizotinib.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Crizotinib.
Ceritinib Crizotinib may increase the bradycardic activities of Ceritinib.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Crizotinib.
Everolimus The metabolism of Everolimus can be decreased when combined with Crizotinib.
Flibanserin The serum concentration of Crizotinib can be increased when it is combined with Flibanserin.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Crizotinib.
Ivabradine Crizotinib may increase the bradycardic activities of Ivabradine.
Ivacaftor The serum concentration of Crizotinib can be increased when it is combined with Ivacaftor.
Lurasidone The risk or severity of QTc prolongation can be increased when Lurasidone is combined with Crizotinib.
Olaparib The metabolism of Olaparib can be decreased when combined with Crizotinib.
Sonidegib The metabolism of Sonidegib can be decreased when combined with Crizotinib.
Avanafil The serum concentration of Avanafil can be increased when it is combined with Crizotinib.
Eplerenone The metabolism of Crizotinib can be decreased when combined with Eplerenone.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Crizotinib.
Cilostazol The metabolism of Cilostazol can be decreased when combined with Crizotinib.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Crizotinib.
Fentanyl Crizotinib may increase the bradycardic activities of Fentanyl.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Crizotinib.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Crizotinib.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Crizotinib.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Crizotinib.
Eszopiclone The metabolism of Eszopiclone can be decreased when combined with Crizotinib.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Crizotinib.
Lovastatin The metabolism of Lovastatin can be decreased when combined with Crizotinib.
Metreleptin The metabolism of Crizotinib can be increased when combined with Metreleptin.
Propacetamol The serum concentration of Propacetamol can be increased when it is combined with Crizotinib.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Crizotinib.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Crizotinib.
(R)-warfarin The serum concentration of (R)-warfarin can be increased when it is combined with Crizotinib.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Crizotinib.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Crizotinib.
(S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Crizotinib.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Crizotinib.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Crizotinib.
Brentuximab vedotin The metabolism of Brentuximab vedotin can be decreased when combined with Crizotinib.
Ruxolitinib The metabolism of Ruxolitinib can be decreased when combined with Crizotinib.
Quinidine The metabolism of Quinidine can be decreased when combined with Crizotinib.
Doxorubicin The metabolism of Doxorubicin can be decreased when combined with Crizotinib.
Erlotinib The metabolism of Erlotinib can be decreased when combined with Crizotinib.
Nilotinib The metabolism of Nilotinib can be decreased when combined with Crizotinib.
Vandetanib The metabolism of Vandetanib can be decreased when combined with Crizotinib.
Romidepsin The metabolism of Romidepsin can be decreased when combined with Crizotinib.
Ribociclib The risk or severity of QTc prolongation can be increased when Ribociclib is combined with Crizotinib.
Bortezomib The metabolism of Bortezomib can be decreased when combined with Crizotinib.
Cyclophosphamide The metabolism of Cyclophosphamide can be decreased when combined with Crizotinib.
Ifosfamide The metabolism of Ifosfamide can be decreased when combined with Crizotinib.
Vincristine The metabolism of Vincristine can be decreased when combined with Crizotinib.
Carbamazepine The metabolism of Carbamazepine can be decreased when combined with Crizotinib.
Sirolimus The metabolism of Sirolimus can be decreased when combined with Crizotinib.
Paclitaxel The metabolism of Paclitaxel can be decreased when combined with Crizotinib.
Digitoxin The metabolism of Digitoxin can be decreased when combined with Crizotinib.
Temsirolimus The metabolism of Temsirolimus can be decreased when combined with Crizotinib.
Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Crizotinib.
Sorafenib The metabolism of Sorafenib can be decreased when combined with Crizotinib.
Vinblastine The metabolism of Vinblastine can be decreased when combined with Crizotinib.
Tamoxifen The metabolism of Tamoxifen can be decreased when combined with Crizotinib.
Etoposide The metabolism of Etoposide can be decreased when combined with Crizotinib.
Cabazitaxel The metabolism of Cabazitaxel can be decreased when combined with Crizotinib.
Trastuzumab emtansine The metabolism of Trastuzumab emtansine can be decreased when combined with Crizotinib.
Panobinostat The metabolism of Panobinostat can be decreased when combined with Crizotinib.
Regorafenib The metabolism of Regorafenib can be decreased when combined with Crizotinib.
Ponatinib The metabolism of Ponatinib can be decreased when combined with Crizotinib.
Pomalidomide The metabolism of Pomalidomide can be decreased when combined with Crizotinib.
Dabrafenib The metabolism of Dabrafenib can be decreased when combined with Crizotinib.
Palbociclib The metabolism of Palbociclib can be decreased when combined with Crizotinib.
Osimertinib The metabolism of Osimertinib can be decreased when combined with Crizotinib.
Venetoclax The metabolism of Venetoclax can be decreased when combined with Crizotinib.
Vinflunine The metabolism of Vinflunine can be decreased when combined with Crizotinib.
Dacomitinib The metabolism of Dacomitinib can be decreased when combined with Crizotinib.
Copanlisib The metabolism of Copanlisib can be decreased when combined with Crizotinib.
Ivosidenib The metabolism of Ivosidenib can be decreased when combined with Crizotinib.
Neratinib The metabolism of Neratinib can be decreased when combined with Crizotinib.
Enasidenib The metabolism of Enasidenib can be decreased when combined with Crizotinib.
Erdafitinib The metabolism of Erdafitinib can be decreased when combined with Crizotinib.
Fosphenytoin The metabolism of Fosphenytoin can be decreased when combined with Crizotinib.
Warfarin The metabolism of Warfarin can be decreased when combined with Crizotinib.
Acenocoumarol The metabolism of Acenocoumarol can be decreased when combined with Crizotinib.
Idelalisib The metabolism of Idelalisib can be decreased when combined with Crizotinib.
Dofetilide The metabolism of Dofetilide can be decreased when combined with Crizotinib.
Theophylline The metabolism of Theophylline can be decreased when combined with Crizotinib.
Phenprocoumon The metabolism of Phenprocoumon can be decreased when combined with Crizotinib.
Busulfan The metabolism of Busulfan can be decreased when combined with Crizotinib.
Pimozide The metabolism of Pimozide can be decreased when combined with Crizotinib.
Amiodarone The metabolism of Amiodarone can be decreased when combined with Crizotinib.
Aminophylline The metabolism of Aminophylline can be decreased when combined with Crizotinib.
Dasatinib The metabolism of Dasatinib can be decreased when combined with Crizotinib.
Dronedarone The metabolism of Dronedarone can be decreased when combined with Crizotinib.
Tianeptine The metabolism of Tianeptine can be decreased when combined with Crizotinib.

Target Protein

ALK tyrosine kinase receptor ALK
Hepatocyte growth factor receptor MET
Proto-oncogene tyrosine-protein kinase ROS ROS1
Macrophage-stimulating protein receptor MST1R

Referensi & Sumber

Synthesis reference: Cui, JJ., et al. (2014). Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors (U.S. Patent No. US 8,785,632 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/d5/82/7a/7fec499c2af772/US8785632.pdf
Artikel (PubMed)
  • PMID: 23686600
    Timm A, Kolesar JM: Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7. doi: 10.2146/ajhp120261.
  • PMID: 22594847
    Forde PM, Rudin CM: Crizotinib in the treatment of non-small-cell lung cancer. Expert Opin Pharmacother. 2012 Jun;13(8):1195-201. doi: 10.1517/14656566.2012.688029.
  • PMID: 30069759
    Heigener DF, Reck M: Crizotinib. Recent Results Cancer Res. 2018;211:57-65. doi: 10.1007/978-3-319-91442-8_4.

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