Peringatan Keamanan

According to the bacterial reverse mutation (Ames) assay, abemaciclib and its active metbolites M2 and M20 did not display mutagenic properties. Abemaciclib was not clastogenic *in vitro* rat bone marrow micronucleus assay. Repeat-dose toxicity studies were performed to assess the effects of abemaciclib in testis, epididymis, prostate, and seminal vesicle at doses ?10 mg/kg/day in rats and ?0.3 mg/kg/day in dogs which exceed the recommeded therapeutic doses in humans. The findings included decreased organ weights, intratubular cellular debris, hypospermia, tubular distillation, atrophy and degeneration or necrosis FDA Label.

Abemaciclib

DB12001

small molecule approved investigational

Deskripsi

Abemaciclib is an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) that are involved in the cell cycle and promotion of cancer cell growth in case of unregulated activity. On September 28, 2017, FDA granted approval of abemaciclib treatment under the market name Verzenio for the treatment of HR-positive and HER2-negative advanced or metastatic breast cancer that has progressed after unsuccessful endocrine therapy. It is either given alone in patients who has undergone endocrine therapy and chemotherapy after the metastasis of cancer, or in combination with DB00947. Following oral treatment in patients with HR-positive, HER2-negative breast cancer, abemaciclib demonstrated increased progression-free survival rates and objective response rates. Abemaciclib has been used in trials studying the treatment of melanoma, lymphoma, neoplasm, solid tumor, and glioblastoma.

Struktur Molekul 2D

Berat 506.606
Wujud -

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) The mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV) [FDA Label].
Volume Distribusi The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV) [FDA Label].
Klirens (Clearance) The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV) [FDA Label].

Absorpsi

The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg A27282, but may range up to 24 hours FDA Label. The absolute bioavailability of the drug is reported to be 45% FDA Label.

Metabolisme

Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively FDA Label.

Rute Eliminasi

Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites FDA Label.

Interaksi Makanan

4 Data
  • 1. Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of abemaciclib.
  • 2. Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of abemaciclib.
  • 3. Take at the same time every day.
  • 4. Take with or without food.

Interaksi Obat

703 Data
Modafinil The metabolism of Abemaciclib can be increased when combined with Modafinil.
Armodafinil The metabolism of Abemaciclib can be increased when combined with Armodafinil.
Metreleptin The metabolism of Abemaciclib can be increased when combined with Metreleptin.
Crizotinib The metabolism of Abemaciclib can be decreased when combined with Crizotinib.
Pitolisant The serum concentration of Abemaciclib can be decreased when it is combined with Pitolisant.
Sulfasalazine Sulfasalazine may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Novobiocin Novobiocin may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Hesperetin Hesperetin may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Daidzin Daidzin may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Naringenin Naringenin may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Eltrombopag Eltrombopag may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Safinamide Safinamide may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Teriflunomide Teriflunomide may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Cannabidiol The serum concentration of Abemaciclib can be increased when it is combined with Cannabidiol.
Folic acid Abemaciclib may decrease the excretion rate of Folic acid which could result in a higher serum level.
Allopurinol Abemaciclib may decrease the excretion rate of Allopurinol which could result in a higher serum level.
Celecoxib Abemaciclib may decrease the excretion rate of Celecoxib which could result in a higher serum level.
Oxaliplatin Abemaciclib may decrease the excretion rate of Oxaliplatin which could result in a higher serum level.
Fluorouracil Abemaciclib may decrease the excretion rate of Fluorouracil which could result in a higher serum level.
Methotrexate Abemaciclib may decrease the excretion rate of Methotrexate which could result in a higher serum level.
Clofarabine Abemaciclib may decrease the excretion rate of Clofarabine which could result in a higher serum level.
Nitrofurantoin Abemaciclib may decrease the excretion rate of Nitrofurantoin which could result in a higher serum level.
Riluzole Abemaciclib may decrease the excretion rate of Riluzole which could result in a higher serum level.
Tegaserod Abemaciclib may decrease the excretion rate of Tegaserod which could result in a higher serum level.
Leflunomide Abemaciclib may decrease the excretion rate of Leflunomide which could result in a higher serum level.
Alvocidib Abemaciclib may decrease the excretion rate of Alvocidib which could result in a higher serum level.
Riociguat Abemaciclib may decrease the excretion rate of Riociguat which could result in a higher serum level.
Fimasartan Abemaciclib may decrease the excretion rate of Fimasartan which could result in a higher serum level.
Revefenacin Abemaciclib may decrease the excretion rate of Revefenacin which could result in a higher serum level.
Delafloxacin Abemaciclib may decrease the excretion rate of Delafloxacin which could result in a higher serum level.
Nabiximols Nabiximols may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Caffeine Caffeine may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Vincristine Abemaciclib may decrease the excretion rate of Vincristine which could result in a higher serum level.
Pravastatin Pravastatin may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Pantoprazole Pantoprazole may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Estradiol Estradiol may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Telmisartan Telmisartan may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Quercetin Quercetin may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Taurocholic acid Taurocholic acid may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Vismodegib Vismodegib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Dasabuvir Dasabuvir may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Paritaprevir Paritaprevir may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Alectinib Alectinib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Conjugated estrogens Abemaciclib may decrease the excretion rate of Conjugated estrogens which could result in a higher serum level.
Prazosin Abemaciclib may decrease the excretion rate of Prazosin which could result in a higher serum level.
Zidovudine Abemaciclib may decrease the excretion rate of Zidovudine which could result in a higher serum level.
Sumatriptan Abemaciclib may decrease the excretion rate of Sumatriptan which could result in a higher serum level.
Mycophenolate mofetil Abemaciclib may decrease the excretion rate of Mycophenolate mofetil which could result in a higher serum level.
Lamivudine Abemaciclib may decrease the excretion rate of Lamivudine which could result in a higher serum level.
Irinotecan Abemaciclib may decrease the excretion rate of Irinotecan which could result in a higher serum level.
Donepezil Abemaciclib may decrease the excretion rate of Donepezil which could result in a higher serum level.
Dactinomycin Abemaciclib may decrease the excretion rate of Dactinomycin which could result in a higher serum level.
Ezetimibe Abemaciclib may decrease the excretion rate of Ezetimibe which could result in a higher serum level.
Camptothecin Abemaciclib may decrease the excretion rate of Camptothecin which could result in a higher serum level.
Rivaroxaban Abemaciclib may decrease the excretion rate of Rivaroxaban which could result in a higher serum level.
Apixaban Abemaciclib may decrease the excretion rate of Apixaban which could result in a higher serum level.
Dolutegravir Abemaciclib may decrease the excretion rate of Dolutegravir which could result in a higher serum level.
Sofosbuvir Abemaciclib may decrease the excretion rate of Sofosbuvir which could result in a higher serum level.
Ombitasvir Abemaciclib may decrease the excretion rate of Ombitasvir which could result in a higher serum level.
Talazoparib The serum concentration of Talazoparib can be increased when it is combined with Abemaciclib.
Copanlisib Abemaciclib may decrease the excretion rate of Copanlisib which could result in a higher serum level.
Lusutrombopag Abemaciclib may decrease the excretion rate of Lusutrombopag which could result in a higher serum level.
Selumetinib Abemaciclib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
Pralatrexate Abemaciclib may decrease the excretion rate of Pralatrexate which could result in a higher serum level.
Fostemsavir Fostemsavir may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Testosterone cypionate Abemaciclib may decrease the excretion rate of Testosterone cypionate which could result in a higher serum level.
Testosterone enanthate Abemaciclib may decrease the excretion rate of Testosterone enanthate which could result in a higher serum level.
Progesterone Progesterone may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Lansoprazole Lansoprazole may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Sunitinib Sunitinib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Ivermectin Abemaciclib may decrease the excretion rate of Ivermectin which could result in a higher serum level.
Mitoxantrone Abemaciclib may decrease the excretion rate of Mitoxantrone which could result in a higher serum level.
Lenvatinib Abemaciclib may decrease the excretion rate of Lenvatinib which could result in a higher serum level.
Gefitinib Gefitinib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Etoposide Abemaciclib may decrease the excretion rate of Etoposide which could result in a higher serum level.
Avanafil The serum concentration of Avanafil can be increased when it is combined with Abemaciclib.
Rabeprazole Rabeprazole may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Tivozanib Tivozanib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
Venlafaxine Venlafaxine may increase the excretion rate of Abemaciclib which could result in a lower serum level and potentially a reduction in efficacy.
Cholesterol Cholesterol may increase the excretion rate of Abemaciclib which could result in a lower serum level and potentially a reduction in efficacy.
Levothyroxine The serum concentration of Abemaciclib can be decreased when it is combined with Levothyroxine.
Trazodone The serum concentration of Abemaciclib can be decreased when it is combined with Trazodone.
Dexamethasone acetate The serum concentration of Abemaciclib can be decreased when it is combined with Dexamethasone acetate.
Glasdegib The serum concentration of Abemaciclib can be increased when it is combined with Glasdegib.
Vandetanib The serum concentration of Abemaciclib can be increased when it is combined with Vandetanib.
Dacomitinib The serum concentration of Abemaciclib can be increased when it is combined with Dacomitinib.
Fedratinib The serum concentration of Abemaciclib can be increased when it is combined with Fedratinib.
Istradefylline The serum concentration of Abemaciclib can be increased when it is combined with Istradefylline.
Afatinib The serum concentration of Abemaciclib can be increased when it is combined with Afatinib.
Elacridar The serum concentration of Abemaciclib can be increased when it is combined with Elacridar.
Ponatinib The serum concentration of Abemaciclib can be increased when it is combined with Ponatinib.
Daclatasvir The serum concentration of Abemaciclib can be increased when it is combined with Daclatasvir.
Rolapitant The serum concentration of Abemaciclib can be increased when it is combined with Rolapitant.
Velpatasvir The serum concentration of Abemaciclib can be increased when it is combined with Velpatasvir.
Voxilaprevir The serum concentration of Abemaciclib can be increased when it is combined with Voxilaprevir.
Pibrentasvir The serum concentration of Abemaciclib can be increased when it is combined with Pibrentasvir.
Ripretinib The serum concentration of Abemaciclib can be increased when it is combined with Ripretinib.
Vorapaxar The serum concentration of Abemaciclib can be increased when it is combined with Vorapaxar.
Suvorexant The serum concentration of Abemaciclib can be increased when it is combined with Suvorexant.
Sildenafil The serum concentration of Abemaciclib can be increased when it is combined with Sildenafil.

Target Protein

Cyclin-dependent kinase 4 CDK4
Cyclin-dependent kinase 6 CDK6

Referensi & Sumber

Artikel (PubMed)
  • PMID: 24919854
    Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL, Young J, Chan EM, Iversen P, Cronier D, Kreklau E, de Dios A: Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37. doi: 10.1007/s10637-014-0120-7. Epub 2014 Jun 13.
  • PMID: 27217383
    Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, Beeram M, Rasco DW, Hilton JF, Nasir A, Beckmann RP, Schade AE, Fulford AD, Nguyen TS, Martinez R, Kulanthaivel P, Li LQ, Frenzel M, Cronier DM, Chan EM, Flaherty KT, Wen PY, Shapiro GI: Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov. 2016 Jul;6(7):740-53. doi: 10.1158/2159-8290.CD-16-0095. Epub 2016 May 23.
  • PMID: 28540640
    Tate SC, Sykes AK, Kulanthaivel P, Chan EM, Turner PK, Cronier DM: A Population Pharmacokinetic and Pharmacodynamic Analysis of Abemaciclib in a Phase I Clinical Trial in Cancer Patients. Clin Pharmacokinet. 2017 May 24. doi: 10.1007/s40262-017-0559-8.
  • PMID: 26149830
    Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA, Gelbert LM, Shannon HE, Sanchez-Martinez C, De Dios A: Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft. Drug Metab Dispos. 2015 Sep;43(9):1360-71. doi: 10.1124/dmd.114.062745. Epub 2015 Jul 6.

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