Piperidine and Piperazine Substructures are a Common Feature of Drugs Labeled for QT Prolongation Burkhart K, Division of Applied Regulatory Science, OCP/OTS/CDER, FDA

Piperidine Containing Opioids Piperazine Drug Binding HERG Introduction Results . Alfentanil, Carfentanil, Fentanyl, Remifentanyl From Lee et al . QT Prolongation (QTP) is used as a surrogate Table 1. Drugs labeled for QTP in Box . Codeine, Dihydrocodeine, Oxycodone, for drug-induced Torsade de Pointes (TdP), a Drug Piperidine/Piperazine Other Nitrogen Containing Structures Hydrocodone, Oxymorphone, Hydromorphone serious and usually fatal ventricular arrhythmia. Arsenic Trioxide . Loperamide, Meperidine, Morphine, . QTP occurs across many different drug classes. Droperidol Piperidine Benzimidazole Levorphanol, Butorphanol, Pentazocine, . Because TdP tends to be a rare event, it is Ibutilide Tertiary Amine/Methanesulfonamide Buprenorphine, Nalbuphine, Piritramide difficult to confirm without EKG monitoring Itraconazole Piperazine Triazole/Triazolone . Identifying possible toxicophores associated Ketoconazole Piperazine Imidazole Piperazine Containing with QTP could be useful in strengthening safety Nilotinib Imidazole/Pyridine/Pyrimidine/Benzamide Antidepressants/Antipsychotics signals and identifying the need for additional Vandetanib Piperidine Quinazoline studies. . Labeled QTP: Clozapine, Quetiapine, Table 2. Drugs labeled for QTP in Aripiprazole, Ziprazodone, Warnings and Precautions . Labeled QT Changes: Perphenazine, Hypotheses Prochlorperazine ,Trifluoperazine ,Lurasidone Drug Piperidine/Piperazine Other Nitrogen Containing Structures . . Structural analyses and similarity searches Amiodarone Tertiary Amine Unlabeled: Nefazodone, Mirtazapine, may identify drugs that warrant additional QTP Azithromycin Tertiary Amine in Lactone Ring Trazodone, Amoxapine, Olanzapine, Bisacodyl Pyridine Eszopiclone, Vilazodone, Vortioxetine analyses Ciprofloxacin Piperazine Quinoline . Specifically an analysis of an association of Citalopram Tertiary Amine /Carbonitrile . Launched/Development: Exoperidone, piperidines and piperazines for QTP was done Clarithromycin Tertiary Amine to 6-member O Opipramol. Isofloxythepin, Tiotixene, Clozapine Piperazine Diazepine Blonanserin, Flupentixol, Tandospirone, Cyclophosphamide Tertiary Amine /Phosphoamine Conclusions Dasatinib Piperazine Thiazole/Pyrimidine Perospirone, Clotiapine, Azaperone . Methods Dofetilide Tertiary Amine/Methanesulfonamides . Bold = Thorough QT (TQT) done A substructure analysis of approved drugs Dolasetron Indole/Azatricyclo labeled for QTP/TdP noted the prevalence of . FDA drug products were searched using natural Erythromicin Tertiary Amine to 6-member O A preliminary review of the FAERS databases nitrogenous ring and tertiary amine based language processing to identify drugs with QTP Ezogabine Secondary amine/Primary amine Famotidine Thiazole/Sulfonamide revealed reports of QTP or TdP for several of structures including piperidines and piperazines in the Warnings and Precautions sections. Fluconazole Triazole X 2 the unlabeled opioids and antipsychotics (Performed August 2013) Fluoxetine Secondary Amine . Identifying possible toxicophores associated . The structural nitrogen containing features of Gemifloxacin Pyrrolidine/Napthyridine identified in the search. Granisetron Indazole/Azabicyclo with QTP could be useful in strengthening these drugs were reviewed Haloperidol Piperidine safety signals and identifying older drugs and . Iloperidone Piperidine Benzisoxazole A chemical substructure search was performed Discussion the need for additional studies. to identify launched or withdrawn drugs that Levofloxacin Piperazine Benzoxazine . Validated structural alerts are in use at the FDA Lopinavir/Ritonavir Thiazole and Diazinane shared these common structural features for predicting carcinogenicity, mutagenicity, and Methadone Tertiary Amine . Substructure and similarity searches may (Performed August 2014) Nabilone hepatotoxicity and hERG inhibition. identify drugs that warrant additional evaluation Ofloxacin Piperazine . Literature notes structural co-occurrence of Ondansetron Imidazole/Carbazole for various adverse events and further inform nitrogen substructure and aromatic ring (Figure) Paroxetine Piperidine medicinal chemistry. Pimozide Piperidine Benzimidazole . Structures Many QTP and TdP FAERS case reports are Posaconazole Piperazine Triazole confounded by the presence of multiple QTP Piperazine Piperidine Propafenone Secondary Amine Quinine Sulfate Piperidine drugs taken in combination or overdose making Ranolazine Piperazine it difficult to identify the primary drug. Bibliography Romidepsin Azabicyclo . QTP drugs may act synergistically. Sevoflurane . Solifenacin Quinoline/Azabicyclo . The piperidine and piperazine substructures are Lee BH et al. Effects of the histamine H1 receptor antagonist Sorafenib Carbamoyl commonly found in drugs associated with QTP. hydroxyzine on hERG K+ channels and cardiac action potential Sotalol Secondary Amine/Sulfonamide . Older opioids and antipsychotics may have duration. Acta Pharmacologica Sinica 2011;32:1128–1137 Sunitinib Tertiary Amine Tacrolimus Piperidine unrecognized QTP liabilities or may contribute in Disclaimer: No conflicts of interest to disclose Oxycodone: Tolterodine Tertiary Amine drug-drug interactions that result in QTP/TdP. The findings and conclusions in this presentation reflect the views of the N-ring in Vandetanib Piperidine . Some drugs identified in this search may carry a author and should not be construed to represent FDA’s views or policies. Vardenafil Piperazine Azabicyclo The mention of commercial products, their sources, or their proximity to Vemurafenib Pyrrolopyridine low risk for QTP in the population, but may carry use in connection with material reported herein is not to be Voriconazole Triazole/Pyrimidine aromatic ring risk in susceptible populations such as those construed as either an actual or implied endorsement of such Ziprasidone Piperazine with LQT, overdose and drug combinations. products by the Department of Health and Human Services