Peringatan Keamanan

Toxicity information regarding lonafarnib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as altered electrolyte, blood cell, and liver enzyme levels, retinal toxicity, nephrotoxicity, fertility impairment, and embryo-fetal toxicity. Symptomatic and supportive measures are recommended.L23414

Lonafarnib

DB06448

small molecule approved investigational

Deskripsi

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in adverse symptoms associated with premature ageing: skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive; HGPS is uniformly fatal.A224379, A224384, A224389, A224394, A224399 Mechanistically, HGPS is underpinned by a single heterozygous C-to-T mutation at position 1824 of the LMNA gene, which results in the accumulation of an aberrant farnesylated form of lamin A called progerin in the inner nuclear membrane.A224379, A224394 Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), which reduces the farnesylation of numerous cellular proteins, including progerin; as progerin farnesylation is important for localization to the nuclear membrane, lonafarnib inhibits progerin accumulation and improves symptoms in HGPS patients.A224379, A224414, A224419, L23414

Merck originally developed Lonafarnib and subsequently licensed it to Eiger Biopharmaceuticals Inc., which currently markets it under the trademark ZOKINVY™.L23414, L23544 Lonafarnib was granted FDA approval on November 20, 2020, and is the first FDA-approved treatment for HGPS and other related progeroid laminopathies.L23414, L23549

Struktur Molekul 2D

Berat 638.822
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Lonafarnib has a mean half-life of approximately 4-6 hours following oral administration of 100 mg twice daily in healthy subjects.[L23414]
Volume Distribusi In healthy patients administered either 75 or 100 mg lonafarnib twice daily, the steady-state apparent volumes of distribution were 97.4 L and 87.8 L, respectively.[L23414]
Klirens (Clearance) -

Absorpsi

The absolute oral bioavailability of lonafarnib is unknown; in healthy subjects administration of either 75 or 100 mg of lonafarnib twice daily resulted in mean peak plasma concentrations (%CV) of 834 (32%) and 964 (32%) ng/mL, respectively. Twice daily administration of 115 mg/m2 lonafarnib in HGPS patients resulted in a median tmax of 2 hours (range 0-6), mean Cmax of 1777 ± 1083 ng/mL, mean AUC0-8hr of 9869 ± 6327 ng\*hr/mL, and a mean AUCtau of 12365 ± 9135 ng\*hr/mL. The corresponding values for a dose of 150 mg/m2 are: 4 hours (range 0-12), 2695 ± 1090 ng/mL, 16020 ± 4978 ng\*hr/mL, and 19539 ± 6434 ng\*hr/mL, respectively.L23414 Following a single oral dose of 75 mg in healthy subjects, the Cmax of lonafarnib decreased by 55% and 25%, and the AUC decreased by 29% and 21% for a high/low-fat meal compared to fasted conditions.L23414

Metabolisme

Lonafarnib is metabolized in vitro primarily by CYP3A4/5 and partially by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1.A224439, L23414 Formation of the primary metabolites involves oxidation and subsequent dehydration in the pendant piperidine ring.A224439, A224444

Rute Eliminasi

Up to 240 hours following oral administration of 104 mg 14C-lonafarnib in fasted healthy subjects, approximately 62% and <1% of the initial radiolabeled dose was recovered in feces and urine, respectively. The two most prevalent metabolites were the active HM21 and HM17, which account for 14% and 15% of plasma radioactivity.L23414

Interaksi Makanan

2 Data
  • 1. Avoid grapefruit products. Co-administration with strong or moderate CYP3A inhibitors is contraindicated; avoid consuming grapefruit or Seville oranges.
  • 2. Take with food. Administration with food is recommended to reduce gastrointestinal adverse reactions. However, co-administration with food does affect lonafarnib absorption.

Interaksi Obat

1007 Data
Afatinib The serum concentration of Afatinib can be increased when it is combined with Lonafarnib.
Bosutinib The serum concentration of Bosutinib can be increased when it is combined with Lonafarnib.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be increased when it is combined with Lonafarnib.
Colchicine The serum concentration of Colchicine can be increased when it is combined with Lonafarnib.
Edoxaban The serum concentration of Edoxaban can be increased when it is combined with Lonafarnib.
Ledipasvir The serum concentration of Ledipasvir can be increased when it is combined with Lonafarnib.
Naloxegol The serum concentration of Naloxegol can be increased when it is combined with Lonafarnib.
Pazopanib The serum concentration of Pazopanib can be increased when it is combined with Lonafarnib.
Prucalopride The serum concentration of Prucalopride can be increased when it is combined with Lonafarnib.
Silodosin The excretion of Silodosin can be decreased when combined with Lonafarnib.
Topotecan The serum concentration of Topotecan can be increased when it is combined with Lonafarnib.
Cilostazol The serum concentration of Cilostazol can be increased when it is combined with Lonafarnib.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Lonafarnib.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Lonafarnib.
Everolimus The serum concentration of Everolimus can be increased when it is combined with Lonafarnib.
Rifaximin The serum concentration of Rifaximin can be increased when it is combined with Lonafarnib.
Fentanyl The metabolism of Fentanyl can be decreased when combined with Lonafarnib.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Lonafarnib.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Lonafarnib.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Lonafarnib.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Lonafarnib.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Lonafarnib.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Lonafarnib.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Lonafarnib.
Vincristine The excretion of Vincristine can be decreased when combined with Lonafarnib.
Doxorubicin The serum concentration of Doxorubicin can be increased when it is combined with Lonafarnib.
Troglitazone The metabolism of Lonafarnib can be decreased when combined with Troglitazone.
Valproic acid The metabolism of Lonafarnib can be decreased when combined with Valproic acid.
Nabilone The metabolism of Nabilone can be decreased when combined with Lonafarnib.
Iproniazid The metabolism of Lonafarnib can be decreased when combined with Iproniazid.
Miconazole The metabolism of Lonafarnib can be decreased when combined with Miconazole.
Fluconazole The metabolism of Lonafarnib can be decreased when combined with Fluconazole.
Floxuridine The metabolism of Lonafarnib can be decreased when combined with Floxuridine.
Betrixaban The serum concentration of Betrixaban can be increased when it is combined with Lonafarnib.
Pitolisant The serum concentration of Lonafarnib can be decreased when it is combined with Pitolisant.
Tenofovir disoproxil The serum concentration of Tenofovir disoproxil can be increased when it is combined with Lonafarnib.
Mannitol The serum concentration of Mannitol can be increased when it is combined with Lonafarnib.
Clomifene The serum concentration of Clomifene can be increased when it is combined with Lonafarnib.
Fexofenadine The serum concentration of Fexofenadine can be increased when it is combined with Lonafarnib.
Tegaserod The serum concentration of Tegaserod can be increased when it is combined with Lonafarnib.
Belinostat The serum concentration of Belinostat can be increased when it is combined with Lonafarnib.
Dolutegravir The serum concentration of Dolutegravir can be increased when it is combined with Lonafarnib.
Sofosbuvir The serum concentration of Sofosbuvir can be increased when it is combined with Lonafarnib.
Umeclidinium The serum concentration of Umeclidinium can be increased when it is combined with Lonafarnib.
Technetium Tc-99m sestamibi The serum concentration of Technetium Tc-99m sestamibi can be increased when it is combined with Lonafarnib.
Ombitasvir The serum concentration of Ombitasvir can be increased when it is combined with Lonafarnib.
Lasmiditan The serum concentration of Lasmiditan can be increased when it is combined with Lonafarnib.
Talinolol The serum concentration of Talinolol can be increased when it is combined with Lonafarnib.
Revefenacin The serum concentration of Revefenacin can be increased when it is combined with Lonafarnib.
Valspodar The serum concentration of Valspodar can be increased when it is combined with Lonafarnib.
Elagolix The serum concentration of Elagolix can be increased when it is combined with Lonafarnib.
Omadacycline The serum concentration of Omadacycline can be increased when it is combined with Lonafarnib.
Grapiprant The serum concentration of Grapiprant can be increased when it is combined with Lonafarnib.
Lusutrombopag The serum concentration of Lusutrombopag can be increased when it is combined with Lonafarnib.
Pibrentasvir The serum concentration of Pibrentasvir can be increased when it is combined with Lonafarnib.
Glecaprevir The serum concentration of Glecaprevir can be increased when it is combined with Lonafarnib.
Belantamab mafodotin The serum concentration of Belantamab mafodotin can be increased when it is combined with Lonafarnib.
Lenvatinib The serum concentration of Lenvatinib can be increased when it is combined with Lonafarnib.
Trilaciclib The serum concentration of Trilaciclib can be increased when it is combined with Lonafarnib.
Daptomycin The serum concentration of Daptomycin can be increased when it is combined with Lonafarnib.
Tenofovir The serum concentration of Tenofovir can be increased when it is combined with Lonafarnib.
Tivozanib The serum concentration of Tivozanib can be increased when it is combined with Lonafarnib.
Loncastuximab tesirine The serum concentration of Loncastuximab tesirine can be increased when it is combined with Lonafarnib.
Dabigatran etexilate The serum concentration of Dabigatran etexilate can be increased when it is combined with Lonafarnib.
Gemcitabine The serum concentration of Gemcitabine can be increased when it is combined with Lonafarnib.
Dactinomycin The serum concentration of Dactinomycin can be increased when it is combined with Lonafarnib.
Talazoparib The serum concentration of Talazoparib can be increased when it is combined with Lonafarnib.
Trimipramine The serum concentration of Trimipramine can be increased when it is combined with Lonafarnib.
Bendamustine The serum concentration of Bendamustine can be increased when it is combined with Lonafarnib.
Carfilzomib The serum concentration of Carfilzomib can be increased when it is combined with Lonafarnib.
Binimetinib The serum concentration of Binimetinib can be increased when it is combined with Lonafarnib.
Metreleptin The metabolism of Lonafarnib can be increased when combined with Metreleptin.
Apomorphine The metabolism of Apomorphine can be decreased when combined with Lonafarnib.
Pentamidine The metabolism of Pentamidine can be decreased when combined with Lonafarnib.
Dutasteride The metabolism of Dutasteride can be decreased when combined with Lonafarnib.
Lorlatinib The metabolism of Lorlatinib can be decreased when combined with Lonafarnib.
Fluticasone The metabolism of Fluticasone can be decreased when combined with Lonafarnib.
Tegafur The metabolism of Tegafur can be decreased when combined with Lonafarnib.
Ciprofloxacin The metabolism of Lonafarnib can be decreased when combined with Ciprofloxacin.
Chloramphenicol The metabolism of Lonafarnib can be decreased when combined with Chloramphenicol.
Clofazimine The metabolism of Lonafarnib can be decreased when combined with Clofazimine.
Letermovir The metabolism of Lonafarnib can be decreased when combined with Letermovir.
Curcumin sulfate The metabolism of Lonafarnib can be decreased when combined with Curcumin sulfate.
Levoketoconazole The metabolism of Lonafarnib can be decreased when combined with Levoketoconazole.
Reserpine The metabolism of Lonafarnib can be increased when combined with Reserpine.
Daunorubicin The metabolism of Lonafarnib can be increased when combined with Daunorubicin.
Mometasone The metabolism of Lonafarnib can be increased when combined with Mometasone.
Oxcarbazepine The metabolism of Lonafarnib can be increased when combined with Oxcarbazepine.
Thalidomide The metabolism of Thalidomide can be decreased when combined with Lonafarnib.
Prednisolone hemisuccinate The metabolism of Lonafarnib can be increased when combined with Prednisolone hemisuccinate.
Prednisone acetate The metabolism of Lonafarnib can be increased when combined with Prednisone acetate.
Clocortolone acetate The metabolism of Lonafarnib can be increased when combined with Clocortolone acetate.
Melengestrol acetate The metabolism of Lonafarnib can be increased when combined with Melengestrol acetate.
Formoterol The metabolism of Formoterol can be decreased when combined with Lonafarnib.
Gliclazide The metabolism of Gliclazide can be decreased when combined with Lonafarnib.
Proguanil The metabolism of Proguanil can be decreased when combined with Lonafarnib.
Hexobarbital The metabolism of Hexobarbital can be decreased when combined with Lonafarnib.
Timolol The metabolism of Timolol can be decreased when combined with Lonafarnib.
Carisoprodol The metabolism of Carisoprodol can be decreased when combined with Lonafarnib.
Labetalol The metabolism of Labetalol can be decreased when combined with Lonafarnib.

Target Protein

Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha FNTA
Protein farnesyltransferase subunit beta FNTB

Referensi & Sumber

Synthesis reference: Njoroge FG, Taveras AG, Kelly J, Remiszewski S, Mallams AK, Wolin R, Afonso A, Cooper AB, Rane DF, Liu YT, Wong J, Vibulbhan B, Pinto P, Deskus J, Alvarez CS, del Rosario J, Connolly M, Wang J, Desai J, Rossman RR, Bishop WR, Patton R, Wang L, Kirschmeier P, Ganguly AK, et al.: (+)-4-2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6cyclohepta1,2-b- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem. 1998 Nov 19;41(24):4890-902.
Artikel (PubMed)
  • PMID: 32404427
    Cubria MB, Suarez S, Masoudi A, Oftadeh R, Kamalapathy P, DuBose A, Erdos MR, Cabral WA, Karim L, Collins FS, Snyder BD, Nazarian A: Evaluation of musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib, pravastatin, and zoledronic acid as treatment groups. Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12029-12040. doi: 10.1073/pnas.1906713117. Epub 2020 May 13.
  • PMID: 29466530
    Prakash A, Gordon LB, Kleinman ME, Gurary EB, Massaro J, D'Agostino R Sr, Kieran MW, Gerhard-Herman M, Smoot L: Cardiac Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA Cardiol. 2018 Apr 1;3(4):326-334. doi: 10.1001/jamacardio.2017.5235.
  • PMID: 23897869
    Ullrich NJ, Kieran MW, Miller DT, Gordon LB, Cho YJ, Silvera VM, Giobbie-Hurder A, Neuberg D, Kleinman ME: Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment. Neurology. 2013 Jul 30;81(5):427-30. doi: 10.1212/WNL.0b013e31829d85c0. Epub 2013 Jun 28.
  • PMID: 23390246
    Young SG, Yang SH, Davies BS, Jung HJ, Fong LG: Targeting protein prenylation in progeria. Sci Transl Med. 2013 Feb 6;5(171):171ps3. doi: 10.1126/scitranslmed.3005229.
  • PMID: 31036409
    Xu S, Jin ZG: Hutchinson-Gilford Progeria Syndrome: Cardiovascular Pathologies and Potential Therapies. Trends Biochem Sci. 2019 Jul;44(7):561-564. doi: 10.1016/j.tibs.2019.03.010. Epub 2019 Apr 26.
  • PMID: 31077852
    Gordon CM, Cleveland RH, Baltrusaitis K, Massaro J, D'Agostino RB Sr, Liang MG, Snyder B, Walters M, Li X, Braddock DT, Kleinman ME, Kieran MW, Gordon LB: Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome. Bone. 2019 Aug;125:103-111. doi: 10.1016/j.bone.2019.05.008. Epub 2019 May 8.
  • PMID: 31152494
    Li Y, Zhou G, Bruno IG, Zhang N, Sho S, Tedone E, Lai TP, Cooke JP, Shay JW: Transient introduction of human telomerase mRNA improves hallmarks of progeria cells. Aging Cell. 2019 Aug;18(4):e12979. doi: 10.1111/acel.12979. Epub 2019 May 31.
  • PMID: 9822558
    Njoroge FG, Taveras AG, Kelly J, Remiszewski S, Mallams AK, Wolin R, Afonso A, Cooper AB, Rane DF, Liu YT, Wong J, Vibulbhan B, Pinto P, Deskus J, Alvarez CS, del Rosario J, Connolly M, Wang J, Desai J, Rossman RR, Bishop WR, Patton R, Wang L, Kirschmeier P, Ganguly AK, et al.: (+)-4-2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6cyclohepta1,2-b- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem. 1998 Nov 19;41(24):4890-902.
Menampilkan 8 dari 12 artikel.

Contoh Produk & Brand

Produk: 4 • International brands: 1
Produk
  • Zokinvy
    Capsule • 50 mg/1 • Oral • US • Approved
  • Zokinvy
    Capsule • 50 mg • Oral • EU • Approved
  • Zokinvy
    Capsule • 75 mg/1 • Oral • US • Approved
  • Zokinvy
    Capsule • 75 mg • Oral • EU • Approved
International Brands
  • Sarasar

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