Peringatan Keamanan

Pralsetinib administered to rats at 20 mg/kg (roughly 2.5-3.6 times the recommended human exposure) resulted in resorption of litters in pregnant female mice in 92% of pregnancies (82% complete resorption); resorption occurred at doses as low as 5 mg/kg (0.3 times the recommended human exposure). Both male and female rats given 10 mg/kg pralsetinib or more had observable degeneration within the testis/ovaries. In 28-day rat and monkey studies, once-daily pralsetinib resulted in histological necrosis at doses 1.1 or more times the recommended human dose and myocardial hemorrhage at doses 2.6 or more times the recommended human dose. Also, pralsetinib induced hyperphosphatemia (rats only, dose 2.4-3.5 times the recommended human dose) and multi-organ mineralization (dose 0.11 or more times the recommended human dose).L15986

Pralsetinib

DB15822

small molecule approved investigational

Deskripsi

Pralsetinib, similar to the previously approved selpercatinib, is a kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs) over other RTK classes.A202055, A219751, L15986 Enhanced RET (Rearranged during transfection) oncogene expression is a hallmark of many cancers, including non-small cell lung cancer. Although multikinase inhibitors, including cabozantinib, ponatinib, sorafenib, sunitinib, and vandetanib, have shown efficacy in RET-driven cancers, their lack of specificity is generally associated with substantial toxicity.A202055 Pralsetinib (BLU-667) and selpercatinib (LOXO-292) represent the first generation of specific RET RTK inhibitors for the treatment of RET-driven cancers.A202049, A202055, L15986

Although a phase 1/2 trial of pralsetinib termed ARROW (NCT03037385) is still ongoing, pralsetinib was granted accelerated FDA approval on September 4, 2020, for the treatment of metastatic RET-fusion positive non-small cell lung cancer. It is currently marketed under the brand name GAVRETO™ by Blueprint Medicines.L15986

Struktur Molekul 2D

Berat 533.612
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Pralsetinib has a plasma elimination half-life of 14.7 ± 6.5 hours following a single dose and 22.2 ± 13.5 hours following multiple doses.[L15986]
Volume Distribusi Pralsetinib has a mean apparent volume of distribution of 228 L (CV 75%).[L15986]
Klirens (Clearance) Pralsetinib has a mean apparent steady-state oral clearance of 9.1 L/h (CV 60%).[L15986]

Absorpsi

Pralsetinib given at 400 mg once daily resulted in a mean steady-state Cmax of 2830 ng/mL (coefficient of variation, CV, 52.5%) and AUC0-24h of 43900 ng\*h/mL (CV 60.2%). The Cmax and AUC of pralsetinib increased inconsistently with increasing doses between 60 and 600 mg once daily, with a median Tmax across this range of between two and four hours. At 400 mg once daily, pralsetinib reached steady-state plasma concentration by three to five days.L15986 Pralsetinib absorption is affected by food. A single dose of 400 mg given with a high-fat meal (800 to 1000 calories with 50 to 60% of calories coming from fat) increased the mean Cmax by 104% (95% CI 65-153%), mean AUC0-? by 122% (95% CI 96-152%), and the median Tmax from four to 8.5 hours.L15986

Metabolisme

Pralsetinib is metabolized in vitro primarily by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Pralsetinib given as a single oral dose of 310 mg in healthy volunteers led to the detection of metabolites from both oxidation (M453, M531, and M549b) and glucuronidation (M709), although these constituted less than 5% of the detected material.L15986

Rute Eliminasi

Pralsetinib is primarily eliminated through the fecal route (73%, 66% unchanged) with a small amount found in the urine (6%, 4.8% unchanged).L15986

Interaksi Makanan

1 Data
  • 1. Take on an empty stomach. Food affects the absorption of pralsetinib. Patients should take pralsetinib either at least one hour before or at least two hours after a meal.

Interaksi Obat

869 Data
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Pralsetinib.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Pralsetinib.
Pravastatin Pralsetinib may decrease the excretion rate of Pravastatin which could result in a higher serum level.
Fluvoxamine The serum concentration of Pralsetinib can be increased when it is combined with Fluvoxamine.
Glimepiride Pralsetinib may decrease the excretion rate of Glimepiride which could result in a higher serum level.
Diethylstilbestrol Pralsetinib may decrease the excretion rate of Diethylstilbestrol which could result in a higher serum level.
Isradipine The serum concentration of Pralsetinib can be increased when it is combined with Isradipine.
Flucloxacillin Pralsetinib may decrease the excretion rate of Flucloxacillin which could result in a higher serum level.
Indomethacin Pralsetinib may decrease the excretion rate of Indomethacin which could result in a higher serum level.
Atenolol Pralsetinib may decrease the excretion rate of Atenolol which could result in a higher serum level.
Rosiglitazone Pralsetinib may decrease the excretion rate of Rosiglitazone which could result in a higher serum level.
Cerivastatin Pralsetinib may decrease the excretion rate of Cerivastatin which could result in a higher serum level.
Loratadine Pralsetinib may decrease the excretion rate of Loratadine which could result in a higher serum level.
Atropine Pralsetinib may decrease the excretion rate of Atropine which could result in a higher serum level.
Diclofenac Pralsetinib may decrease the excretion rate of Diclofenac which could result in a higher serum level.
Nicardipine The serum concentration of Pralsetinib can be increased when it is combined with Nicardipine.
Losartan The metabolism of Losartan can be decreased when combined with Pralsetinib.
Fluorescein Pralsetinib may decrease the excretion rate of Fluorescein which could result in a higher serum level.
Nitrofurantoin Pralsetinib may decrease the excretion rate of Nitrofurantoin which could result in a higher serum level.
Naproxen Pralsetinib may decrease the excretion rate of Naproxen which could result in a higher serum level.
Disulfiram Pralsetinib may decrease the excretion rate of Disulfiram which could result in a higher serum level.
Cefaclor Pralsetinib may decrease the excretion rate of Cefaclor which could result in a higher serum level.
Tinidazole Pralsetinib may decrease the excretion rate of Tinidazole which could result in a higher serum level.
Repaglinide Pralsetinib may decrease the excretion rate of Repaglinide which could result in a higher serum level.
Telmisartan Pralsetinib may decrease the excretion rate of Telmisartan which could result in a higher serum level.
Ezetimibe Pralsetinib may decrease the excretion rate of Ezetimibe which could result in a higher serum level.
Dipyridamole Pralsetinib may decrease the excretion rate of Dipyridamole which could result in a higher serum level.
Sulfamethoxazole Pralsetinib may decrease the excretion rate of Sulfamethoxazole which could result in a higher serum level.
Glyburide Pralsetinib may decrease the excretion rate of Glyburide which could result in a higher serum level.
Felodipine Pralsetinib may decrease the excretion rate of Felodipine which could result in a higher serum level.
Fenofibrate Pralsetinib may decrease the excretion rate of Fenofibrate which could result in a higher serum level.
Nitrendipine Pralsetinib may decrease the excretion rate of Nitrendipine which could result in a higher serum level.
Glipizide Pralsetinib may decrease the excretion rate of Glipizide which could result in a higher serum level.
Rosuvastatin Pralsetinib may decrease the excretion rate of Rosuvastatin which could result in a higher serum level.
Nifedipine Pralsetinib may decrease the excretion rate of Nifedipine which could result in a higher serum level.
Sulfinpyrazone Pralsetinib may decrease the excretion rate of Sulfinpyrazone which could result in a higher serum level.
Ofloxacin Pralsetinib may decrease the excretion rate of Ofloxacin which could result in a higher serum level.
Budesonide Pralsetinib may decrease the excretion rate of Budesonide which could result in a higher serum level.
Ursodeoxycholic acid Pralsetinib may decrease the excretion rate of Ursodeoxycholic acid which could result in a higher serum level.
Glycochenodeoxycholic Acid Pralsetinib may decrease the excretion rate of Glycochenodeoxycholic Acid which could result in a higher serum level.
Cholic Acid Pralsetinib may decrease the excretion rate of Cholic Acid which could result in a higher serum level.
Taurocholic acid Pralsetinib may decrease the excretion rate of Taurocholic acid which could result in a higher serum level.
Prasterone sulfate Pralsetinib may decrease the excretion rate of Prasterone sulfate which could result in a higher serum level.
Indocyanine green acid form Pralsetinib may decrease the excretion rate of Indocyanine green acid form which could result in a higher serum level.
Benzbromarone Pralsetinib may decrease the excretion rate of Benzbromarone which could result in a higher serum level.
Pilsicainide Pralsetinib may decrease the excretion rate of Pilsicainide which could result in a higher serum level.
Dihydroergocristine Pralsetinib may decrease the excretion rate of Dihydroergocristine which could result in a higher serum level.
Glycyrrhizic acid Pralsetinib may decrease the excretion rate of Glycyrrhizic acid which could result in a higher serum level.
Belantamab mafodotin Pralsetinib may decrease the excretion rate of Belantamab mafodotin which could result in a higher serum level.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Pralsetinib.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Pralsetinib.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Pralsetinib.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Pralsetinib.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Pralsetinib.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Pralsetinib.
Silodosin The excretion of Silodosin can be decreased when combined with Pralsetinib.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Pralsetinib.
Aripiprazole The metabolism of Aripiprazole can be increased when combined with Pralsetinib.
Aripiprazole lauroxil The metabolism of Aripiprazole lauroxil can be increased when combined with Pralsetinib.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Pralsetinib.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Pralsetinib.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Pralsetinib.
Cilostazol The metabolism of Cilostazol can be decreased when combined with Pralsetinib.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Pralsetinib.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Pralsetinib.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Pralsetinib.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Pralsetinib.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Pralsetinib.
Lovastatin The metabolism of Lovastatin can be decreased when combined with Pralsetinib.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Pralsetinib.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Pralsetinib.
Ifosfamide The metabolism of Ifosfamide can be increased when combined with Pralsetinib.
Perampanel The metabolism of Perampanel can be increased when combined with Pralsetinib.
Warfarin The serum concentration of Warfarin can be increased when it is combined with Pralsetinib.
Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Pralsetinib.
(R)-warfarin The serum concentration of (R)-warfarin can be increased when it is combined with Pralsetinib.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Pralsetinib.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Pralsetinib.
(S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Pralsetinib.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Pralsetinib.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Pralsetinib.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Pralsetinib.
Eluxadoline The serum concentration of Eluxadoline can be increased when it is combined with Pralsetinib.
Vincristine The excretion of Vincristine can be decreased when combined with Pralsetinib.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Pralsetinib.
Erlotinib The serum concentration of Erlotinib can be decreased when it is combined with Pralsetinib.
Betrixaban The serum concentration of Betrixaban can be increased when it is combined with Pralsetinib.
Vemurafenib The serum concentration of Pralsetinib can be increased when it is combined with Vemurafenib.
Apalutamide The serum concentration of Pralsetinib can be decreased when it is combined with Apalutamide.
Pitolisant The serum concentration of Pralsetinib can be decreased when it is combined with Pitolisant.
Caffeine Caffeine may decrease the excretion rate of Pralsetinib which could result in a higher serum level.
Pantoprazole Pantoprazole may decrease the excretion rate of Pralsetinib which could result in a higher serum level.
Gefitinib Gefitinib may decrease the excretion rate of Pralsetinib which could result in a higher serum level.
Beclomethasone dipropionate Beclomethasone dipropionate may decrease the excretion rate of Pralsetinib which could result in a higher serum level.
Progesterone Progesterone may decrease the excretion rate of Pralsetinib which could result in a higher serum level.
Lansoprazole Lansoprazole may decrease the excretion rate of Pralsetinib which could result in a higher serum level.
Dronabinol The serum concentration of Dronabinol can be increased when it is combined with Pralsetinib.
Estradiol Estradiol may decrease the excretion rate of Pralsetinib which could result in a higher serum level.
Sulfasalazine Sulfasalazine may decrease the excretion rate of Pralsetinib which could result in a higher serum level.
Buprenorphine Buprenorphine may decrease the excretion rate of Pralsetinib which could result in a higher serum level.

Target Protein

Proto-oncogene tyrosine-protein kinase receptor Ret RET
Epithelial discoidin domain-containing receptor 1 DDR1
NT-3 growth factor receptor NTRK3
Receptor-type tyrosine-protein kinase FLT3 FLT3
Tyrosine-protein kinase JAK1 JAK1
Tyrosine-protein kinase JAK2 JAK2
High affinity nerve growth factor receptor NTRK1
Vascular endothelial growth factor receptor 2 KDR
Platelet-derived growth factor receptor beta PDGFRB
Fibroblast growth factor receptor 1 FGFR1
Fibroblast growth factor receptor 2 FGFR2

Referensi & Sumber

Synthesis reference: Jason D. Brubaker, Joseph L. Kim, Kevin J. Wilson, Douglas Wilson, Lucian V. DiPietro, "Inhibitors of ret." U.S. Patent US20170121312A1, issued July 24, 2018.
Artikel (PubMed)
  • PMID: 32296961
    Russo A, Lopes AR, McCusker MG, Garrigues SG, Ricciardi GR, Arensmeyer KE, Scilla KA, Mehra R, Rolfo C: New Targets in Lung Cancer (Excluding EGFR, ALK, ROS1). Curr Oncol Rep. 2020 Apr 16;22(5):48. doi: 10.1007/s11912-020-00909-8.
  • PMID: 31715421
    Li AY, McCusker MG, Russo A, Scilla KA, Gittens A, Arensmeyer K, Mehra R, Adamo V, Rolfo C: RET fusions in solid tumors. Cancer Treat Rev. 2019 Dec;81:101911. doi: 10.1016/j.ctrv.2019.101911. Epub 2019 Oct 30.
  • PMID: 32083997
    Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F: State-of-the-Art Strategies for Targeting RET-Dependent Cancers. J Clin Oncol. 2020 Apr 10;38(11):1209-1221. doi: 10.1200/JCO.19.02551. Epub 2020 Feb 21.
  • PMID: 32782485
    Stinchcombe TE: Current management of RET rearranged non-small cell lung cancer. Ther Adv Med Oncol. 2020 Jul 26;12:1758835920928634. doi: 10.1177/1758835920928634. eCollection 2020.
  • PMID: 29657135
    Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP, Wilson D, Wilson KJ, DiPietro L, Fleming P, Palmer M, Hu MI, Wirth L, Brose MS, Ou SI, Taylor M, Garralda E, Miller S, Wolf B, Lengauer C, Guzi T, Evans EK: Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov. 2018 Jul;8(7):836-849. doi: 10.1158/2159-8290.CD-18-0338. Epub 2018 Apr 15.
  • PMID: 2992805
    Takahashi M, Ritz J, Cooper GM: Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985 Sep;42(2):581-8. doi: 10.1016/0092-8674(85)90115-1.
  • PMID: 25047660
    Qian Y, Chai S, Liang Z, Wang Y, Zhou Y, Xu X, Zhang C, Zhang M, Si J, Huang F, Huang Z, Hong W, Wang K: KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer. Mol Cancer. 2014 Jul 21;13:176. doi: 10.1186/1476-4598-13-176.
  • PMID: 30257958
    Piotrowska Z, Isozaki H, Lennerz JK, Gainor JF, Lennes IT, Zhu VW, Marcoux N, Banwait MK, Digumarthy SR, Su W, Yoda S, Riley AK, Nangia V, Lin JJ, Nagy RJ, Lanman RB, Dias-Santagata D, Mino-Kenudson M, Iafrate AJ, Heist RS, Shaw AT, Evans EK, Clifford C, Ou SI, Wolf B, Hata AN, Sequist LV: Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion. Cancer Discov. 2018 Dec;8(12):1529-1539. doi: 10.1158/2159-8290.CD-18-1022. Epub 2018 Sep 26.

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