A Phase II Double Blind, Placebo-Controlled, Parallel Group, Two-Cohort study of nilotinib to determine the safety and tolerability in participants with Parkinson’s Disease (PD).
As you may know, nilotinib is a marketed drug and approved by the Food and Drug Administration (FDA) for the treatment of certain types of leukemia. The drug is not currently indicated for treatment in Parkinson’s disease but there is preclinical data and a small open label clinical trial suggesting nilotinib may hold promise as a treatment for PD.
Nilotinib has a number of safety concerns specifically related to potential risk of cardiac and hematologic toxicity. The current study protocol was designed with tight adherence to the safety monitoring recommendations as described in the package insert. Please use the following link to view the nilotinib package insert.
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tasigna.pdf
In addition, below is a summary of dosing instructions for commonly prescribed medications:
1) H2 blockers are allowed. However, these medicines should be taken 10 hours before or 2 hours after taking the study drug.
2) Antacid that contains aluminum hydroxide, magnesium hydroxide or simethicone are allowed. However, these medications should be taken about 2 hours before or about 2 hours after taking the study drug.
3) Use of grapefruit juice and grapefruit products will be prohibited (due to inhibition of CYP3A4)
The following medications are restricted or not allowed during subject participation in the study
If any disallowed medications are required and cannot be discontinued, study drug should be stopped and the subject should continue to be followed in the study off of study drug. Please notify the study team immediately regarding initiation of disallowed medications.
EXCLUSIONARY AND PRECAUTIONARY MEDICATIONS
NOTE: This list is not exhaustive but is designed to give examples of more commonly used drug classes.
Table 1. Exclusionary Medications: Known risk to prolong the QT interval
Antimicrobials
Erythromycin
Azithromycin (systemic)
Levofloxacin (systemic)
Sparfloxacin
Ciprofloxacin (systemic)
Clarithromycin
Telithromycin
Moxifloxacin
Fluconazole (systemic)
Antiprotozoal, Antimalarials, AntituberculosisPentamidine
Mefloquine
Chloroquine
Quinine
Delamanid
Bedaquiline
Mesoridazine
Antiarrhythmics
Dronedarone
Sotalol
Dofetilide
Ibutilide
Quinidine
Amiodarone
Disopyramide
Antiplatelet
Cilostazol
Antiemetics
Domperidone
Cisapride
Granisetron
Droperidol
Ondansetron//Granisetron
Propafenone
Procainamide
Flecainide
Others
Methadone
Sevoflurane
Anagrelide
Levomethadyl
Vilanterol
Propofol
Probucol
Halofantrine
Tacrolimus
Nicardipine
Antipsychotics (all have some risk)
Fluphenazine
Haloperidol
Pimozide
Chlorpromazine
Droperidol
Aripiprazole
Thioridazine
Sulpiride
Sertindole
Antidepressant
Citalopram/escitalopram*
Trimipramine
Clomipramine
Dosulepin
Mirtazapine
Trazodone
Venlafaxine
Lofepramine
Antineoplastics
Arsenic trioxide
Ceritinib
Dabrafenib
Dasatinib
Pazopanib
Bosutinib
Panobinostat
Lapatinib
Crizotinib
Bortezomib
Oxaliplatin
Ribociclib
Vandetanib
Osimertinib
Pazopanib
Romidepsin
Sunitinib
Tamoxifen
Toremifene
Vemurafenib
Hepatitis C Antivirals
Telaprevir
Boceprevir
Anticholinergic
Solifenacin
*stable regimen of Citalopram (<20mg) or escitalopram (<10mg) will be allowed provided that the baseline EKG did not demonstrate QT prolongation
Table 2. Exclusionary Medications: Strong CYP3A4 Inhibitors
Generic
Ketoconazole (systemic use)
Itraconazole
Posaconazole
Clarithromycin
Aprepitant
Domperidone
Atazanavir
Indinavir
Nefazodone
Nelfinavir
Ritonavir
Saquinavir
Telithromycin
Voriconazole
Brand
--
Onmel; Sporanox; Sporanox Pulsepak
Noxafil
Biaxin; Biaxin XL; Biaxin XL Pac; Prevpac; Omeclamox-Pak
Emend
--
Reyataz; Evotaz
Crixivan
--
Viracept
Norvir; Kaletra; Technivie; Viekira Pak; Viekira XR
Invirase
Ketek
Vfend
Table 3. Exclusionary Medications: Proton Pump Inhibitors
Generic
Dexlansoprazole
Esomeprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Brand
Dexilant
Nexium; Vimovo
First-Lansoprazole; GoodSense Lansoprazole [OTC]; Heartburn Relief 24 Hour [OTC]; Heartburn Treatment 24 Hour [OTC]; Prevacid 24HR [OTC]; Prevacid SoluTab; Prevpac
First-Omeprazole; Omeclamox-Pak; Omeprazole+Syrspend SF Alka; Prilosec [OTC]; Yosprala; Zegrid
Protonix
Aciphex; AcipHex Sprinkle
Table 4. Exclusionary Medications: Strong CYP3A4 Inducers
Generic
Carbamazepine
Dexamethasone (systemic use)
Phenytoin
Phenobarbital
Rifampin
Rifabutin
St. John’s Wort
Brand
Carbatrol; Epitol; Equetro; TEGretol; TEGretol-XR
Dexamethasone Intensol; DexPak; DoubleDex
Dilantin; Dilantin Infatabs; Phenytek; Phenytoin Infatabs
Phenobarb; Donnatal; Donnatal Extentabs; Phenohytro
Rifadin; Rifamate; Rifater
Mycobutin
--
Table 5. Exclusionary Medications: P-glycoprotein Inhibitors
Generic
Amiodarone
Clarithromycin
Erythromycin (systemic use)
Ketoconazole (systemic use)
Quinidine
Saquinavir
Verapamil
Brand
Cordarone; Nexterone; Pacerone
Biaxin; Biaxin XL; Biaxin XL Pac; Prevpac; Omeclamox-Pak
EES; Ery-Tab; EryPed; Erythrocin; PCE
--
BioQuin Durules; Quinate; Nudexta
Invirase
Calan; Calan SR; Isoptin SR; Verelan; Tarka
Table 6. Exclusionary Medications: P-glycoprotein Inducers
Generic
Carbamazepine
Rifampin
St. John’s wort
Tipranavir
Brand
Carbatrol; Epitol; Equetro; TEGretol; TEGretol-XR
Rifadin; Rifamate; Rifater
--
Aptivus
Table 7. Exclusionary Medications: Anticoagulants
Generic Name
Warfarin
Dabigatran
Edoxaban
Rivaroxaban
Apixaban
Brand Name
Coumadin
Pradaxa
Savaysa
Xarelto
Eliquis
Table 8. Precautionary Medications: Drugs with possible or conditional risk of Torsades de Pointes
Anticholinergic
Tolterodine
Anticonvulsants
Ezogabine
Felbamate
Fosphenytoin
Antidepressants
Amitriptyline
Desipramine
Doxepin
Fluoxetine
Fluvoxamine
Imipramine
Maprotiline
Nortriptyline
Paroxetine
Sertraline
Antiemetics
Dolasetron
Promethazine
Tropisetron
Antihistamines
Diphenhydramine
Hydroxyzine
Antifungals
Amphotericin B
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Antimalarials
Artenimol + piperaquine
Hydroxychloroquine
Antiretrovirals
Atazanavir
Efavirenz
Nelfinavir
Rilpivirine
Ritonavir
Saquinavir
Antiviral
Foscarnet
Antibiotics
Garenoxacin
Gemifloxacin
Norfloxacin
Ofloxacin
Metronidazole
Sulfamethoxazole and Trimethoprim
Telavancin
Antineoplastics
Capecitabine
Degarelix
Eribulin
Lenvatinib
Leuprolide
Sorafenib
Vorinostat
Antipsychotics
Amisulpiride
Asenapine
Clozapine
Cyamemazine
Flupentixol
Iloperidone
Olanzapine
Paliperidone
Perphenazine
Pimavanserin**
Pipamperone
Quetiapine**
Risperidone
Ziprasidone
Zotepine
Beta-agonists
Albuterol
Arformoterol
Formoterol
Isoproterenol
Levalbuterol
Metaproterenol
Olodaterol
Salmetrol
Terbutaline
Calcium Channel Blockers
Isradipine
CNS Stimulants
Amphetamine
Dexmethylphenidate
Dextroamphetamine
Lisdexamfetamine
Methamphetamine
Methylphenidate
Phentermine
Contrast Media
Gadobenate
Iodinated ionic contrast media
Perflutren lipid microspheres
Diuretics
Bendroflumethiazide
Furosemide
Hydrochlorothiazide
Indapamide
Torsemide
GI Agents
Famotidine
Metoclpramide
Opioids
Buprenorphine
Hydrocodone
Miscellaneous
Alfuzosin
Apomorphine
Atomoxetine
Chloral hydrate
Fingolimod
Galantamine
Ivabradine
Lithium
Loperamide
Mifeprisfepristone
Mirabegron
Moxepril
Octreotide
Oxytocin
Pasireotide
Ranolazine
Tetrabenazine
Tiapride
Vardenafil
Tizanidine
**Pimavanserin and Quetiapine are also metabolized by CYP3A4. Therefore, low doses of quetiapine should be used when given with nilotinib (moderate inhibitor of CYP3A4). For pimavanserin, a dose of 17 mg once daily is recommended when given with a strong CYP3A4 inhibitor. For quetiapine, it is recommended to decrease the dose by one-sixth when given with a strong CYP3A4 inhibitor
Nilotinib AEs (adverse events) in CML population:
The percentages below were taken from a randomized trial of nilotinib 300mg BID in newly diagnosed Ph+ CML patients (N=279)—taken from the Tasigna 2017 package insert.
• The most common (>10%) non-hematologic adverse drug reactions were rash, pruritis, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain.
• Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (≤10% and>5%). These have been of mild to moderate severity, manageable and generally did not require dose reduction.
• The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (8%).
Please click on the link to see the following information in regards to specific AEs: