PII-217 - MULTI-CARDIAC ION CHANNEL BLOCK PROFILES FOR LOPINAVIR, RITONAVIR, CHLOROQUINE AND VANOXERINE ALIGN WITH CLINICAL ECG CHANGES AND PROARRHYTHMIA: TWO CASE STUDIES IN SUPPORT OF THE CIPA INITIATIVE.

C. AlvarezBaron¹, J. Zhao², D. Guo², J. Vicente Ruiz², W. Wu²; ¹U.S. Food and Drug Administration, Silver Spring, MD, USA, ²U.S. Food and Drug Administration.

Background: The Comprehensive in vitro Proarrythmia Assay (CiPA) initiative proposes leveraging nonclinical data to predict Torsade De Pointes (TdP) risk with greater specificity than hERG block and clinical QTc prolongation alone. To support this path, in vitro patch-clamp data of drug effects on cardiac ion channels should align with ECG changes and TdP risk. However, two studies reported clinical findings not consistent with available patch-clamp data. One study showed that chloroquine and lopinavir/ritonavir are associated with PR and QRS prolongation, suggestive of CaV1.2 and NaV1.5 channel block. However, patch-clamp data available at the time showed marginal block of these channels. Vanoxerine’s patch-clamp study reported similar block potencies for hERG and CaV1.2 – a profile not expected to associate with TdP. However, a study reported three TdP cases in 26 patients treated with vanoxerine.

Methods: The effects of chloroquine, lopinavir, ritonavir, and vanoxerine on hERG, CaV1.2, and NaV1.5 were re-assessed using protocols implementing the newest ICH best practices (https://www.fda.gov/media/151418/download).

Results: At the clinical unbound maximal plasma concentration (Cmax-free) reported in the clinical studies, lopinavir showed similar block of hERG (21%) and CaV1.2 (24%), chloroquine blocked hERG by 22%, CaV1.2 by 14%, and NaV1.5 by 8%, and ritonavir did not show significant hERG or CaV1.2 block. Vanoxerine showed preferential hERG block (55%) vs. CaV1.2 (24%), and NaV1.5 (no effect) at Cmax-free.

Conclusion: The cardiac ion channel effects of these drugs aligned well with clinical ECG and proarrhythmia findings. This study underscores the importance of assessing drug block of ion channels using physiologically relevant protocols to enhance translation of nonclinical to clinical findings.