Peringatan Keamanan

Healthy male adult volunteers were administered single or multiple daily doses of up to 3600 mg for 14 days and experienced elevated liver transaminases, vomiting, and panic attacks. Pediatric HAT patients given higher than recommended doses experienced vomiting, increased potassium, and decreased calcium levels. There is no specific antidote to fexinidazole; symptomatic and supportive measures are recommended in case of overdose.L35940

Rats and beagles given up to 800 mg/kg/day of fexinidazole showed mild appetite and body weight alterations but no clear hepatotoxicity. Fexinidazole did not induce any effects on embryo-fetal and postnatal development when administered to pregnant rats. Although fexinidazole is mutagenic in a standard Ames test, it is not anticipated to be genotoxic in humans.A237560

Fexinidazole

DB12265

small molecule approved investigational

Deskripsi

Human African trypanosomiasis (HAT, also colloquially referred to as sleeping sickness), caused by T. brucei gambiense and T. brucei rhodesiense, remains a moderate risk (>1/10,000 inhabitants per year in endemic areas) despite focussed control efforts. Transmitted by the bite of an infected tsetse fly, HAT is biphasic with a first (hemolymphatic) stage that progresses to a second (meningoencephalitic) stage in which patients experience progressively worsening neurological symptoms and eventually die if left untreated.A237550 Historical treatment options for meningoencephalitic HAT include melarsoprol, eflornithine, and nifurtimox/eflornithine combination therapy (NECT), though melarsoprol is highly toxic and each treatment requires lengthy infusions that are difficult to administer in resource-limited settings.A237550, A237560 Fexinidazole, which was originally developed in the 1970s/80s by Hoechst AG and subsequently rediscovered through the Drugs for Neglected Diseases Initiative (DNDi) in 2005, is the first all-oral treatment for first and second stage HAT caused by T. brucei gambiense.A237555, A237560

Fexinidazole received a positive opinion from the European Medicines Agency (EMA) in November 2018 and was approved by the FDA on July 16, 2021.A237555, L35940 It is currently marketed by Sanofi-Aventis.L35940

Struktur Molekul 2D

Berat 279.31
Wujud solid

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

Profil Farmakokinetik

Waktu Paruh (Half-Life) Fexinidazole, M1, and M2 have mean day 10 half-lives of 15 ± 6, 16 ± 6, and 23 ± 4 hours, respectively.[A237570, L35940]
Volume Distribusi Fexinidazole has an apparent volume of distribution of 3222 ± 1199 L.[L35940]
Klirens (Clearance) Fexinidazole has a mean apparent day 4 clearance of 161 ± 37 L/h.[L35940]

Absorpsi

Fexinidazole is well absorbed, although the rate and extent of absorption are less than dose-proportional; after a 14-day administration schedule, the mean Cmax and AUClast increased by 1.17 and 1.34, or by 1.5 and 1.61, when the dose was either doubled or tripled.A237570 Following absorption, fexinidazole is rapidly converted to its M1 metabolite, which undergoes a slower transformation to M2 over time. This is reflected in the Tmax of fexinidazole, M1, and M2 as 4 (0-9), 4 (0-6), and 6 (0-24) hours, respectively.A237570, L35940 In healthy adults given an 1800 mg loading dose followed by 1200 mg daily over 14 days, the mean Cmax for fexinidazole was 1.6 ± 0.4 ?g/mL on day 1, 0.8 ± 0.3 ?g/mL on day 2, and 0.5 ± 0.2 ?g/mL on day 3. The relevant values for M1 were 8.1 ± 2.2, 8.0 ± 2.3, and 5.9 ± 2.1, while for M2 they were 7.5 ± 3.3, 19.6 ± 5.4, and 12.5 ± 3.5 ?g/mL. Similarly, the AUC for fexinidazole was 14.3 ± 2.6, 11.6 ± 2.2, and 7.0 ± 2.5, for M1 was 102.3 ± 28.5, 127.9 ± 49.2, and 84.2 ± 36.3, and for M2 was 110.1 ± 41.1, 391.5 ± 126.7, and 252.4 ± 73.6 ?g\*h/mL.A237570, L35940 Concomitant food intake increases the Cmax and AUC of fexinidazole, M1, and M2 by 2-5 fold without significantly changing the metabolite ratios.A237570, L35940 There are no clear effects of age, renal, or hepatic impairment on absorption or plasma parameters of fexinidazole or its metabolites; further studies may be required to confirm/refute these observations.L35940

Metabolisme

Fexinidazole is metabolized by a variety of enzymes including the CYP450 enzymes CYP1A2, 2B6, 2C19, 2D6, 3A4, and 3A5 as well as flavin mono-oxygenase-3 (FMO-3). Fexinidazole is first transformed to the sulfoxide M1 and then the sulfone M2, which does not appear to undergo further metabolism.A237560, A237570, L35940

Rute Eliminasi

Elimination is almost entirely extra-renal; roughly 0.75-3.15% of a fexinidazole dose was recovered in urine over 168 h, primarily as M1 and M2 metabolites.A237570, L35940

Interaksi Makanan

1 Data
  • 1. Take with food. Food assists in fexinidazole absorption.

Interaksi Obat

1159 Data
Cilostazol The serum concentration of Cilostazol can be increased when it is combined with Fexinidazole.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Fexinidazole.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Fexinidazole.
Colchicine The metabolism of Colchicine can be decreased when combined with Fexinidazole.
Fentanyl The risk or severity of adverse effects can be increased when Fentanyl is combined with Fexinidazole.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Fexinidazole.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Fexinidazole.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Fexinidazole.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Fexinidazole.
Eszopiclone The metabolism of Eszopiclone can be decreased when combined with Fexinidazole.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Fexinidazole.
Lovastatin The metabolism of Lovastatin can be decreased when combined with Fexinidazole.
Zolmitriptan The metabolism of Zolmitriptan can be decreased when combined with Fexinidazole.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Fexinidazole.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Fexinidazole.
Succinic acid The excretion of Succinic acid can be decreased when combined with Fexinidazole.
Citrulline The excretion of Citrulline can be decreased when combined with Fexinidazole.
Pravastatin The excretion of Pravastatin can be decreased when combined with Fexinidazole.
Oseltamivir The excretion of Oseltamivir can be decreased when combined with Fexinidazole.
Cefotiam The excretion of Cefotiam can be decreased when combined with Fexinidazole.
Conjugated estrogens The excretion of Conjugated estrogens can be decreased when combined with Fexinidazole.
Tenofovir disoproxil The excretion of Tenofovir disoproxil can be decreased when combined with Fexinidazole.
Valproic acid The risk or severity of adverse effects can be increased when Valproic acid is combined with Fexinidazole.
Piperacillin The excretion of Piperacillin can be decreased when combined with Fexinidazole.
Indomethacin The excretion of Indomethacin can be decreased when combined with Fexinidazole.
Aminohippuric acid The excretion of Aminohippuric acid can be decreased when combined with Fexinidazole.
Trifluridine The excretion of Trifluridine can be decreased when combined with Fexinidazole.
Allopurinol The excretion of Allopurinol can be decreased when combined with Fexinidazole.
Zidovudine The excretion of Zidovudine can be decreased when combined with Fexinidazole.
Cimetidine The excretion of Cimetidine can be decreased when combined with Fexinidazole.
Cefdinir The excretion of Cefdinir can be decreased when combined with Fexinidazole.
Methotrexate The serum concentration of Methotrexate can be increased when it is combined with Fexinidazole.
Cephalexin The excretion of Cephalexin can be decreased when combined with Fexinidazole.
Valaciclovir The excretion of Valaciclovir can be decreased when combined with Fexinidazole.
Levocarnitine The excretion of Levocarnitine can be decreased when combined with Fexinidazole.
Oxytetracycline The excretion of Oxytetracycline can be decreased when combined with Fexinidazole.
Pemetrexed Fexinidazole may decrease the excretion rate of Pemetrexed which could result in a higher serum level.
Leucovorin The excretion of Leucovorin can be decreased when combined with Fexinidazole.
Acamprosate The excretion of Acamprosate can be decreased when combined with Fexinidazole.
Fluorescein The excretion of Fluorescein can be decreased when combined with Fexinidazole.
Hydrocortisone The excretion of Hydrocortisone can be decreased when combined with Fexinidazole.
Tetracycline The excretion of Tetracycline can be decreased when combined with Fexinidazole.
Estradiol The excretion of Estradiol can be decreased when combined with Fexinidazole.
Acyclovir The excretion of Acyclovir can be decreased when combined with Fexinidazole.
Cefaclor The excretion of Cefaclor can be decreased when combined with Fexinidazole.
Ranitidine The excretion of Ranitidine can be decreased when combined with Fexinidazole.
Quinapril The excretion of Quinapril can be decreased when combined with Fexinidazole.
Bumetanide The excretion of Bumetanide can be decreased when combined with Fexinidazole.
Dinoprostone The excretion of Dinoprostone can be decreased when combined with Fexinidazole.
Famotidine The risk or severity of adverse effects can be increased when Famotidine is combined with Fexinidazole.
Fexofenadine The excretion of Fexofenadine can be decreased when combined with Fexinidazole.
Hydrochlorothiazide The risk or severity of adverse effects can be increased when Hydrochlorothiazide is combined with Fexinidazole.
Mercaptopurine The excretion of Mercaptopurine can be decreased when combined with Fexinidazole.
Benzylpenicillin The excretion of Benzylpenicillin can be decreased when combined with Fexinidazole.
Rosuvastatin The excretion of Rosuvastatin can be decreased when combined with Fexinidazole.
Captopril The excretion of Captopril can be decreased when combined with Fexinidazole.
Dexamethasone The metabolism of Fexinidazole can be increased when combined with Dexamethasone.
Sitagliptin The excretion of Sitagliptin can be decreased when combined with Fexinidazole.
Polythiazide The excretion of Polythiazide can be decreased when combined with Fexinidazole.
Cefazolin The excretion of Cefazolin can be decreased when combined with Fexinidazole.
Ceftizoxime The excretion of Ceftizoxime can be decreased when combined with Fexinidazole.
Cefacetrile The excretion of Cefacetrile can be decreased when combined with Fexinidazole.
Ceftibuten The excretion of Ceftibuten can be decreased when combined with Fexinidazole.
Tazobactam The excretion of Tazobactam can be decreased when combined with Fexinidazole.
Cyclic adenosine monophosphate The excretion of Cyclic adenosine monophosphate can be decreased when combined with Fexinidazole.
Cholic Acid The excretion of Cholic Acid can be decreased when combined with Fexinidazole.
Glutaric Acid The excretion of Glutaric Acid can be decreased when combined with Fexinidazole.
Oxalic Acid The excretion of Oxalic Acid can be decreased when combined with Fexinidazole.
Taurocholic acid The excretion of Taurocholic acid can be decreased when combined with Fexinidazole.
Doripenem The excretion of Doripenem can be decreased when combined with Fexinidazole.
Saxagliptin The excretion of Saxagliptin can be decreased when combined with Fexinidazole.
Ellagic acid The excretion of Ellagic acid can be decreased when combined with Fexinidazole.
Cefaloridine The excretion of Cefaloridine can be decreased when combined with Fexinidazole.
Avibactam The excretion of Avibactam can be decreased when combined with Fexinidazole.
Eluxadoline The excretion of Eluxadoline can be decreased when combined with Fexinidazole.
Silibinin The excretion of Silibinin can be decreased when combined with Fexinidazole.
Tenofovir alafenamide The excretion of Tenofovir alafenamide can be decreased when combined with Fexinidazole.
Baricitinib The serum concentration of Baricitinib can be increased when it is combined with Fexinidazole.
Relebactam The excretion of Relebactam can be decreased when combined with Fexinidazole.
Tenofovir The excretion of Tenofovir can be decreased when combined with Fexinidazole.
Prednisolone phosphate The excretion of Prednisolone phosphate can be decreased when combined with Fexinidazole.
Dexamethasone acetate The excretion of Dexamethasone acetate can be decreased when combined with Fexinidazole.
Warfarin The serum concentration of Warfarin can be increased when it is combined with Fexinidazole.
Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Fexinidazole.
(R)-warfarin The serum concentration of (R)-warfarin can be increased when it is combined with Fexinidazole.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Fexinidazole.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Fexinidazole.
(S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Fexinidazole.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Fexinidazole.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Fexinidazole.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Fexinidazole.
Tipiracil The excretion of Tipiracil can be decreased when combined with Fexinidazole.
Aripiprazole The risk or severity of adverse effects can be increased when Aripiprazole is combined with Fexinidazole.
Aripiprazole lauroxil The risk or severity of adverse effects can be increased when Aripiprazole lauroxil is combined with Fexinidazole.
Varenicline The excretion of Varenicline can be decreased when combined with Fexinidazole.
Choline The serum concentration of Choline can be increased when it is combined with Fexinidazole.
Dofetilide The risk or severity of adverse effects can be increased when Dofetilide is combined with Fexinidazole.
Reserpine The serum concentration of Reserpine can be increased when it is combined with Fexinidazole.
Metformin The serum concentration of Metformin can be increased when it is combined with Fexinidazole.
Norepinephrine The serum concentration of Norepinephrine can be increased when it is combined with Fexinidazole.

Referensi & Sumber

Synthesis reference: Winkelmann E, Raether W, Gebert U, Sinharay A (1977) Chemotherapeutically active nitro compounds. 4. 5-nitroimidazoles (Part I-IV). Arzneimittelforschung 27-28.
Artikel (PubMed)
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    Tarral A, Blesson S, Mordt OV, Torreele E, Sassella D, Bray MA, Hovsepian L, Evene E, Gualano V, Felices M, Strub-Wourgaft N: Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: first-in-human studies. Clin Pharmacokinet. 2014 Jun;53(6):565-80. doi: 10.1007/s40262-014-0136-3.
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    Mesu VKBK, Kalonji WM, Bardonneau C, Mordt OV, Blesson S, Simon F, Delhomme S, Bernhard S, Kuziena W, Lubaki JF, Vuvu SL, Ngima PN, Mbembo HM, Ilunga M, Bonama AK, Heradi JA, Solomo JLL, Mandula G, Badibabi LK, Dama FR, Lukula PK, Tete DN, Lumbala C, Scherrer B, Strub-Wourgaft N, Tarral A: Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet. 2018 Jan 13;391(10116):144-154. doi: 10.1016/S0140-6736(17)32758-7. Epub 2017 Nov 4.
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Contoh Produk & Brand

Produk: 1 • International brands: 0
Produk
  • Fexinidazole
    Tablet • 600 mg/1 • Oral • US • Approved

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