a phase 1b/2 study of
appendix a. cytochrome p450 drug

Physicians should be aware of the possibility of drug interactions when TP-0903 is co-administered with drugs that are inhibitors or inducers of CYP2C19. Physicians should refer to the products label and to the drug interaction website provided below. The website listing Cytochrome P450 inhibitors and inducers is updated on an ongoing basis and can be found at *http://medicine.iupui.edu/clinpharm/ddis/main-table*. Below is a snapshot of the website as of August 2018. **Attention should be focused on the 2C19 column**. Please note that the website also lists substrates of CYP2C19.  
| Substrates 1A2                                                                                                                                                                                                                                                                      | 2B6                                                                                                                                               | 2C8                                                                      | 2C9   | 2C19                                                         | 2D6       | 2E1   | 3A 4,5,6                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|-------|--------------------------------------------------------------|-----------|-------|-------------------------------------------------------------------|
| amitriptyline  caffeine2  clomipramine  clozapine  cyclobenzaprine  duloxetine  estradiol  fluvoxamine  haloperidol  imipramine N-DeMe  mexiletine  nabumetone  naproxen  olanzapine  ondansetron  phenacetin1→  acetaminophen → NAPQI propranolol  riluzole  ropivacaine  tacrine2 | artemisinin  bupropion1  cyclophosphamid e  efavirenz1  ifosphamide  ketamine  meperidine  methadone  nevirapine  propafol  selegiline  sorafenib | amodiaquine  cerivastatin  paclitaxel  repaglinide  sorafenib  torsemide | NSAIDs:  diclofenac  ibuprofen  lornoxicam  meloxicam Snaproxen→  Norpiroxicam  suprofen       | PPIs:  esomeprazole  lansoprazole  omeprazole2  pantoprazole | tamoxifen | Anesthetics:  enflurane  halothane  isoflurane  methoxyflurane  sevoflurane  acetaminophen→ NAPQI  aniline2  benzene  chlorzoxazone1  ethanol  N,Ndimethylformamid e  theophylline→8- OH       | Macrolide  clarithromycin  erythromycin2  (not NOT  telithromycin |
| Beta Blockers:  carvedilol  S-metoprolol  propafenone  timolol                                                                                                                                                                                                                      |                                                                                                                                                   |                                                                          |       |                                                              |           |       |                                                                   |
| Anti-epileptics:  diazepam→ Nor phenytoin(O)  S-mephenytoin1  phenobarbitone                                                                                                                                                                                                        | Anti-arrhythmics:  quinidine→3-OH                                                                                                                 |                                                                          |       |                                                              |           |       |                                                                   |
| Antidepressants:  amitriptyline  clomipramine  desipramine  fluoxetine  imipramine  paroxetine  venlafaxine                                                                                                                                                                         |                                                                                                                                                   |                                                                          |       |                                                              |           |       |                                                                   |
| Oral  Hypoglycemic  Agents:  tolbutamide  glipizide                                                                                                                                                                                                                                 | Benzodiazepines:  alprazolam  diazepam→3OH  midazolam1  triazolam2                                                                                |                                                                          |       |                                                              |           |       |                                                                   |
| amitriptyline  carisoprodol  citalopram  chloramphenicol  clomipramine  clopidogrel  cyclophosphamid e  hexobarbital                                                                                                                                                                |                                                                                                                                                   |                                                                          |       |                                                              |           |       |                                                                   |
| Angiotensin II  Blockers:  losartan  irbesartan                                                                                                                                                                                                                                     | Immune:  cyclosporine  tacrolimus (FK506)                                                                                                         |                                                                          |       |                                                              |           |       |                                                                   |
| Antipsychotics:  haloperidol  perphenazine  risperidone→9-OH                                                                                                                                                                                                                        | HIV  indinavir                                                                                                                                    |                                                                          |       |                                                              |           |       |                                                                   |
| Sulfonylureas:                                                                                                                                                                                                                                                                      |                                                                                                                                                   |                                                                          |       |                                                              |           |       |                                                                   |  
| IRB Approval date:                                                                                                                                                       | 03/11/2021                                                                                                                                                                                                                                                                                                     |    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                           |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------|
| Version:                                                                                                                                                                 | 03/03/2021                                                                                                                                                                                                                                                                                                     |    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                           |
| theophylline2  tizanidine  triamterene  verapamil  (R)warfarin  zileuton  zolmitriptan                                                                                   | glyburide  glibenclamide  glipizide  glimepiride  tolbutamide                                                                                                                                                                                                                                                  | imipramine N - DeME  indomethacin  labetalol Rmephobarbital  moclobemide  nelfinavir  nilutamide  primidone  progesterone  proguanil  propranolol  teniposide Rwarfarin→8-OH  voriconazole    | thioridazinezuclopenthix ol alprenolol  amphetamine  aripiprazole  atomoxetine  bufuralol1  chlorpheniramine  chlorpromazine  clonidine codeine (→O - desMe)  debrisoquine2  dexfenfluramine  dextromethorphan1  donepezil  duloxetine  encainide  flecainide  fluvoxamine  lidocaine  metoclopramide  methoxyamphetamine  mexiletine  minaprine  nebivolol  nortriptyline  ondansetron  oxycodone  perhexiline  phenacetin  phenformin  promethazine  propafenone  propranolol  risperidone  sparteine | nelfinavir  ritonavir  saquinavir  Prokinetic:  cisapride |
| amitriptyline  celecoxib  fluoxetine  fluvastatin  glyburide  nateglinide  phenytoin-4- OH2  rosiglitazone  tamoxifen  torsemide  valproic acid  S-warfarin  zakirlukast | Antihistamines:  astemizole  chlorpheniramine  terfenadine2 Calcium  amlodipine  diltiazem  felodipine  lercanidipine  nifedipine2  nisoldipine  nitrendipine  verapamil  HMG:  atorvastatin  cerivastatin  lovastatin  NOT  NOT  simvastatin  Steroid  estradiol  hydrocortisone  progesterone  testosterone1 |    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                           |  
| IRB Approval date:   | 03/11/2021   |
|----------------------|--------------|
| Version:             | 03/03/2021   |
| tramadol             | Miscellaneous:  alfentanil  aprepitant  aripiprazole  boceprevir  buspirone  carbamazepine  cafergot  caffeine→TMU  cilostazol cocaine  codeine-Ndemethylation  dapsone  dexamethasone  dextromethorphan 2  docetaxel  domperidone  eplerenone  fentanyl finasteride  gleevec  haloperidol  irinotecan  LAAM  lidocaine  methadone  nateglinide  nevirapine  ondansetron  pimozide  propranolol  quetiapine  quinine              |  
| Version:                                                                                                                                                                                                   | 03/03/2021                                       |                                                                    |                                                                                                                                                                                    |                                                              |                                                                                                                                                                                             |     |                                                                                                                                                                                                         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------|--------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| risperidone  romidepsin  salmeterol  sildenafil  sirolimus  sorafenib  sunitinib  tamoxifen  taxol  telaprevir  terfenadine  torisel  trazodone  vemurafenib  vincristine  zaleplon  ziprasidone  zolpidem |                                                  |                                                                    |                                                                                                                                                                                    |                                                              |                                                                                                                                                                                             |     |                                                                                                                                                                                                         |
| Inhibitors 1A2                                                                                                                                                                                             | 2B6                                              | 2C8                                                                | 2C9                                                                                                                                                                                | 2C19                                                         | 2D6                                                                                                                                                                                         | 2E1 | 3A 4, 5, 6                                                                                                                                                                                              |
| fluvoxamine  ciprofloxacin  cimetidine  amiodarone  efavirenz  fluoroquinolones  fluvoxamine  furafylline1  interferon  methoxsalen  mibefradil  ticlopidine                                               | clopidogrel  thiotepa  ticlopidine  voriconazole | gemfibrozil2  trimethoprim 2  glitazones  montelukast1  quercetin1 | fluconazole2  amiodarone  efavirenz  fenofibrate  fluconazole  fluvastatin  fluvoxamine2  isoniazid  lovastatin  metronidazole  paroxetine  phenylbutazone  probenicid  sertraline | PPIs:  esomeprazole  lansoprazole  omeprazole2  pantoprazole | bupropion  cinacalcet  fluoxetine  paroxetine  quinidine1  duloxetine  sertraline  terbinafine  amiodarone  cimetidine  celecoxib  chlorpheniramine  chlorpromazine  citalopram  clemastine | diethyldithiocarbamate2  disulfiram     | HIV Antivirals:  indinavir  nelfinavir ritonavir  clarithromycin  itraconazole1  ketoconazole  nefazodone  saquinavir  suboxone  telithromycin  aprepitant  erythromycin  fluconazole  grapefruit juice |
| Other:  chloramphenicol  cimetidine  felbamate  fluoxetine  fluvoxamine  indomethacin  isoniazid  ketoconazole                                                                                             |                                                  |                                                                    |                                                                                                                                                                                    |                                                              |                                                                                                                                                                                             |     |                                                                                                                                                                                                         |  
| Version:                                                                                              | 03/03/2021                                                                            |                                                                                                                                                                                                                                                                                                                                             |                                                                                                 |                                                                                                  |                         |                   |                                                                                                               |
|-------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|-------------------------|-------------------|---------------------------------------------------------------------------------------------------------------|
| sulfamethoxazol e  sulfaphenazole1  teniposide  voriconazole  zafirlukast                             | modafinil                                                                             | clomipramine  cocaine  diphenhydramine  doxepin  doxorubicin  escitalopram  halofantrine  haloperidol  histamine H1 receptor  antagonists  hydroxyzine  levomepromazine  methadone  metoclopramide  mibefradil  midodrine  moclobemide  perphenazine  promethazine  ranitidine  reduced-haloperidol  ritonavir  ticlopidine  tripelennamine | verapamil2  diltiazem  cimetidine  amiodarone  chloramphenicol  boceprevir  ciprofloxacin  delaviridine  diethyldithiocarbamate  fluvoxamine  gestodene  imatinib  mibefradil  mifepristone  norfloxacin  norfluoxetine  starfruit  telaprevir  voriconazole                                                                                                 |                                                                                                  |                         |                   |                                                                                                               |
| Oral  contraceptives:  oxcarbazepine  probenicid  ticlopidine2  topiramate  voriconazole              |                                                                                       |                                                                                                                                                                                                                                                                                                                                             |                                                                                                 |                                                                                                  |                         |                   |                                                                                                               |
| Inducers 1A2                                                                                          | 2B6                                                                                   | 2C8                                                                                                                                                                                                                                                                                                                                         | 2C9                                                                                             | 2C19                                                                                             | 2D6                     | 2E1               | 3A 4, 5, 6                                                                                                    |
| broccoli  brussel sprouts  carbamazepine  char-grilled meat  insulin  methylcholanthrene 1  modafinil | artemisinin  carbamazepine  efavirenz  nevirapine  phenobarbital  phenytoin  rifampin | rifampin                                                                                                                                                                                                                                                                                                                                    | carbamazepine  enzalutamide  nevirapine  phenobarbital  rifampin  secobarbital  St. John's Wort | carbamazepine  efavirenz  enzalutamide norethindrone  NOT  pentobarbital  prednisone  rifampicin | dexamethasone  rifampin | Ethanol isoniazid | HIV Antivirals:  efavirenz  nevirapine  barbiturates  carbamazepine  enzalutamide  glucocorticoids  modafinil |  
| Version:                                                          | 03/03/2021                 |                                                                                                             |
|-------------------------------------------------------------------|----------------------------|-------------------------------------------------------------------------------------------------------------|
| nafcillin  beta - naphthoflavone1  omeprazole1  rifampin  tobacco | ritonavir  St. John's Wort | oxcarbazepine  phenobarbital2  phenytoin2  pioglitazone  rifabutin  rifampin  St. John's Wort  troglitazone |