Peringatan Keamanan

There is no information available regarding the LD50 and overdose profile of mitapivat.

Mitapivat

DB16236

small molecule approved investigational

Deskripsi

Mitapivat is a novel, first-in-class pyruvate kinase activator. It works to increase the activity of erythrocyte pyruvate kinase, a key enzyme involved in the survival of red blood cells. Defects in the pyruvate kinase enzyme in various red blood cells disorders lead to the lack of energy production for red blood cells, leading to lifelong premature destruction of red blood cells or chronic hemolytic anemia.A245478

On February 17, 2022, the FDA approved mitapivat as the first disease-modifying treatment for hemolytic anemia in adults with pyruvate kinase (PK) deficiency, a rare, inherited disorder leading to lifelong hemolytic anemia.L40533 Mitapivat has also been investigated in other hereditary red blood cell disorders associated with hemolytic anemia, such as sickle cell disease and alpha- and beta-thalassemia.A245478

Struktur Molekul 2D

Berat 450.56
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) In patients with pyruvate kinase deficiency receiving multiple doses of 5 mg mitapivat twice daily to 20 mg twice daily, the mean effective half-life (t<sub>1/2</sub>) of mitapivat ranged from 3 to 5 hours.[L40528]
Volume Distribusi The mean volume of distribution at steady state (V<sub>ss</sub>) was 42.5 L. [L40528]
Klirens (Clearance) Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and 14.4 L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively.[L40528]

Absorpsi

The absolute bioavailability of mitapivat after a single dose is approximately 73%. Mitapivat exposure increases dose-proportionally. Following twice-daily oral administration of mitapivat at the dose of 5 mg, 20 mg, and 50 mg, the mean (CV%) Cmax at steady state were 101.2 (17%) ng/mL, 389.9 (18%) ng/mL, and 935.2 (18%) ng/mL, respectively. The mean (CV%) AUC were 450.4 (28%) ng x h/mL, 1623.8 (28%) ng x h/mL, and 3591.4 (28%) ng x h/mL, respectively. The median Tmax values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily. In healthy subjects, a high-fat meal did not affect the drug exposure but reduced the rate of mitapivat absorption, with a 42% reduction in Cmax and a delay in Tmax of 2.3 hours when compared to dosing under fasted conditions.L40528

Metabolisme

According to in vitro studies, mitapivat is primarily metabolized by CYP3A4.L40528 It is also a substrate of CYP1A2, CYP2C8, and CYP2C9.A245478 Following a single oral dose administration of 120 mg of radiolabeled mitapivat in healthy subjects, unchanged mitapivat was the major circulating component in plasma.L40528

Rute Eliminasi

Mitapivat is primary eliminated via hepatic metabolism.A245478 After a single oral administration of radiolabeled mitapivat in healthy subjects, the total recovery of administered radioactive dose was 89.2%. About 49.6% of radioactivity was recovered in the urine with 2.6% excreted as unchanged mitapivat. About 39.6% of radioactivity was recovered in the feces with less than 1% being the unchanged drug.L40528

Interaksi Makanan

1 Data
  • 1. Take with or without food. Food has a negligible effect on the exposure of mitapivat, but may reduce the rate of drug absorption, Cmax, and Tmax.

Interaksi Obat

668 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Mitapivat.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Mitapivat.
Brentuximab vedotin The metabolism of Brentuximab vedotin can be increased when combined with Mitapivat.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Mitapivat.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Mitapivat.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Mitapivat.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Mitapivat.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Mitapivat.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Mitapivat.
Ranolazine The metabolism of Ranolazine can be increased when combined with Mitapivat.
Silodosin The excretion of Silodosin can be decreased when combined with Mitapivat.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Mitapivat.
Aripiprazole The metabolism of Aripiprazole can be increased when combined with Mitapivat.
Aripiprazole lauroxil The metabolism of Aripiprazole lauroxil can be increased when combined with Mitapivat.
Everolimus The metabolism of Everolimus can be increased when combined with Mitapivat.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Mitapivat.
Nicotine The risk or severity of adverse effects can be increased when Mitapivat is combined with Nicotine.
Mecamylamine The risk or severity of adverse effects can be increased when Mitapivat is combined with Mecamylamine.
Pentolinium The risk or severity of adverse effects can be increased when Mitapivat is combined with Pentolinium.
Trimethaphan The risk or severity of adverse effects can be increased when Mitapivat is combined with Trimethaphan.
Hexamethonium The risk or severity of adverse effects can be increased when Mitapivat is combined with Hexamethonium.
Cyclopentamine The risk or severity of adverse effects can be increased when Mitapivat is combined with Cyclopentamine.
Methotrexate The protein binding of Methotrexate can be increased when combined with Mitapivat.
Deferasirox The metabolism of Deferasirox can be increased when combined with Mitapivat.
Ifosfamide The metabolism of Ifosfamide can be increased when combined with Mitapivat.
Perampanel The metabolism of Perampanel can be increased when combined with Mitapivat.
Warfarin The metabolism of Warfarin can be increased when combined with Mitapivat.
Acenocoumarol The metabolism of Acenocoumarol can be increased when combined with Mitapivat.
(R)-warfarin The metabolism of (R)-warfarin can be increased when combined with Mitapivat.
R,S-Warfarin alcohol The metabolism of R,S-Warfarin alcohol can be increased when combined with Mitapivat.
S,R-Warfarin alcohol The metabolism of S,R-Warfarin alcohol can be increased when combined with Mitapivat.
(S)-Warfarin The metabolism of (S)-Warfarin can be increased when combined with Mitapivat.
Tramadol The metabolism of Tramadol can be increased when combined with Mitapivat.
Troglitazone The metabolism of Troglitazone can be increased when combined with Mitapivat.
Phenytoin The metabolism of Mitapivat can be increased when combined with Phenytoin.
Liothyronine The metabolism of Liothyronine can be increased when combined with Mitapivat.
Morphine The metabolism of Morphine can be increased when combined with Mitapivat.
Valproic acid The metabolism of Valproic acid can be increased when combined with Mitapivat.
Acetaminophen The metabolism of Acetaminophen can be increased when combined with Mitapivat.
Indomethacin The metabolism of Indomethacin can be increased when combined with Mitapivat.
Minoxidil The metabolism of Minoxidil can be increased when combined with Mitapivat.
Cerivastatin The metabolism of Cerivastatin can be increased when combined with Mitapivat.
Levothyroxine The metabolism of Levothyroxine can be increased when combined with Mitapivat.
Raloxifene The metabolism of Raloxifene can be increased when combined with Mitapivat.
Zidovudine The metabolism of Zidovudine can be increased when combined with Mitapivat.
Lamotrigine The metabolism of Lamotrigine can be increased when combined with Mitapivat.
Diclofenac The metabolism of Diclofenac can be increased when combined with Mitapivat.
Labetalol The metabolism of Labetalol can be increased when combined with Mitapivat.
Simvastatin The metabolism of Simvastatin can be increased when combined with Mitapivat.
Mycophenolate mofetil The metabolism of Mycophenolate mofetil can be increased when combined with Mitapivat.
Furosemide The metabolism of Furosemide can be increased when combined with Mitapivat.
Naltrexone The metabolism of Naltrexone can be increased when combined with Mitapivat.
Flurbiprofen The metabolism of Flurbiprofen can be increased when combined with Mitapivat.
Irinotecan The metabolism of Irinotecan can be increased when combined with Mitapivat.
Etoposide The metabolism of Etoposide can be increased when combined with Mitapivat.
Estradiol The metabolism of Estradiol can be increased when combined with Mitapivat.
Naproxen The metabolism of Naproxen can be increased when combined with Mitapivat.
Propofol The metabolism of Propofol can be increased when combined with Mitapivat.
Tiagabine The metabolism of Tiagabine can be increased when combined with Mitapivat.
Zonisamide The metabolism of Zonisamide can be increased when combined with Mitapivat.
Metronidazole The metabolism of Metronidazole can be increased when combined with Mitapivat.
Buprenorphine The metabolism of Buprenorphine can be increased when combined with Mitapivat.
Fulvestrant The metabolism of Fulvestrant can be increased when combined with Mitapivat.
Norgestimate The metabolism of Norgestimate can be increased when combined with Mitapivat.
Ezetimibe The metabolism of Ezetimibe can be increased when combined with Mitapivat.
Ethinylestradiol The metabolism of Ethinylestradiol can be increased when combined with Mitapivat.
Ketoprofen The risk or severity of adverse effects can be increased when Ketoprofen is combined with Mitapivat.
Mycophenolic acid The metabolism of Mycophenolic acid can be increased when combined with Mitapivat.
Abacavir The metabolism of Abacavir can be increased when combined with Mitapivat.
Ibuprofen The metabolism of Ibuprofen can be increased when combined with Mitapivat.
Glipizide The metabolism of Glipizide can be increased when combined with Mitapivat.
Atorvastatin The metabolism of Atorvastatin can be increased when combined with Mitapivat.
Fluvastatin The metabolism of Fluvastatin can be increased when combined with Mitapivat.
Carvedilol The metabolism of Carvedilol can be increased when combined with Mitapivat.
Naloxone The metabolism of Naloxone can be increased when combined with Mitapivat.
Gemfibrozil The metabolism of Gemfibrozil can be increased when combined with Mitapivat.
Fusidic acid The metabolism of Mitapivat can be decreased when combined with Fusidic acid.
Alvocidib The metabolism of Alvocidib can be increased when combined with Mitapivat.
Febuxostat The metabolism of Febuxostat can be increased when combined with Mitapivat.
Ezogabine The metabolism of Ezogabine can be increased when combined with Mitapivat.
Belinostat The metabolism of Belinostat can be increased when combined with Mitapivat.
Indacaterol The metabolism of Indacaterol can be increased when combined with Mitapivat.
Lumateperone The serum concentration of Lumateperone can be decreased when it is combined with Mitapivat.
Eltrombopag The metabolism of Eltrombopag can be increased when combined with Mitapivat.
Bazedoxifene The metabolism of Bazedoxifene can be increased when combined with Mitapivat.
Muraglitazar The metabolism of Muraglitazar can be increased when combined with Mitapivat.
Axitinib The metabolism of Axitinib can be increased when combined with Mitapivat.
Gavestinel The metabolism of Gavestinel can be increased when combined with Mitapivat.
Raltegravir The metabolism of Raltegravir can be increased when combined with Mitapivat.
Dolutegravir The metabolism of Dolutegravir can be increased when combined with Mitapivat.
Nintedanib The metabolism of Nintedanib can be increased when combined with Mitapivat.
Elvitegravir The metabolism of Mitapivat can be decreased when combined with Elvitegravir.
Eslicarbazepine acetate The metabolism of Eslicarbazepine acetate can be increased when combined with Mitapivat.
Dexibuprofen The metabolism of Dexibuprofen can be increased when combined with Mitapivat.
Propacetamol The metabolism of Propacetamol can be increased when combined with Mitapivat.
Selumetinib The metabolism of Selumetinib can be increased when combined with Mitapivat.
Cabotegravir The metabolism of Cabotegravir can be increased when combined with Mitapivat.
Bictegravir The metabolism of Bictegravir can be increased when combined with Mitapivat.
Delafloxacin The metabolism of Delafloxacin can be increased when combined with Mitapivat.
Binimetinib The metabolism of Binimetinib can be increased when combined with Mitapivat.

Target Protein

Pyruvate kinase PKLR PKLR
Aromatase CYP19A1

Referensi & Sumber

Artikel (PubMed)
  • PMID: 34987744
    Al-Samkari H, van Beers EJ: Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi: 10.1177/20406207211066070. eCollection 2021.
  • PMID: 16986348
    Perez EA, Weilbaecher K: Aromatase inhibitors and bone loss. Oncology (Williston Park). 2006 Aug;20(9):1029-39; discussion 1039-40, 1042, 1048.
  • PMID: 33822774
    Matte A, Federti E, Kung C, Kosinski PA, Narayanaswamy R, Russo R, Federico G, Carlomagno F, Desbats MA, Salviati L, Leboeuf C, Valenti MT, Turrini F, Janin A, Yu S, Beneduce E, Ronseaux S, Iatcenko I, Dang L, Ganz T, Jung CL, Iolascon A, Brugnara C, De Franceschi L: The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a beta-thalassemia mouse model. J Clin Invest. 2021 May 17;131(10). pii: 144206. doi: 10.1172/JCI144206.
  • PMID: 31974203
    Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R: AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865.

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