Since 2005, FDA has required almost all new drugs be tested for their ability to prolong the QT interval through clinical studies. This requirement stems from the increased TdP risk QT interval prolongation can cause. However, the QT interval is an imperfect biomarker, as there are multiple drugs that can prolong the QT interval, without causing increased TdP occurrence. As such, numerous drugs labeled as causing QT prolongation, may in fact have no impact on TdP occurrence. To address this problem, FDA, in collaboration with multiple external partners, has led an initiative to combine novel preclinical in vitro experiments within silico modeling and simulation followed by pharmacodynamic electrocardiographic (ECG) biomarkers. The goal is to use these novel computational and analytical tools to better predict TdP risk (beyond just the QT interval) by focusing on understanding the underlying mechanisms and applying an integrated biological systems approach. This clinical study consists of 2 parts: a 3-arm, 22-subject crossover study (Part 1) and a 4-arm, 22-subject crossover study (Part 2). These parts are included in the same protocol and study due to the similarity of the inclusion and exclusion criteria, similar procedures, and similar primary goals.
The risk of drug-induced Torsades de Pointes (TdP), a potentially fatal ventricular arrhythmia, has resulted in multiple drugs worldwide being removed from the market, as well as over 150 drugs being listed on CredibleMeds.org for QT prolongation or TdP association. In response, since 2005, FDA has required almost all new drugs be tested for their ability to prolong the QT interval through clinical studies. This requirement stems from the increased TdP risk QT interval prolongation can cause. However, the QT interval is an imperfect biomarker, as there are multiple drugs that can prolong the QT interval, without causing increased TdP occurrence. As such, numerous drugs labeled as causing QT prolongation, may in fact have no impact on TdP occurrence. While this labeling affects physician prescribing, it also has the potential to limit effective therapeutic options for patients. To address this problem, FDA, in collaboration with multiple external partners, has led an initiative to combine novel preclinical in vitro experiments within silico modeling and simulation followed by pharmacodynamic electrocardiographic (ECG) biomarkers. The goal is to use these novel computational and analytical tools to better predict TdP risk (beyond just the QT interval) by focusing on understanding the underlying mechanisms and applying an integrated biological systems approach. Recently, the International Council on Harmonization (ICH) released a new Guideline with updated Questions and Answers (Q\&As) to the clinical (ICH E14) and nonclinical (ICH S7B) Guidelines for assessing the QT prolongation and proarrhythmic risk of non-antiarrhythmic drugs. The Q\&A provides more guidance on the use of an integrated nonclinical analysis to support clinical QT assessment. This includes the comparison of the hERG safety margin of the investigational product to the safety margin of predominant hERG (the human Ether-à-go-go-Related Gene) blockers with a characterization of the concentration-QTc relationship based on a limited set of example drugs, i.e., ondansetron, moxifloxacin and dofetilide. This clinical study consists of 2 parts: a 3-arm, 22-subject crossover study (Part 1) and a 4-arm, 22-subject crossover study (Part 2). These parts are included in the same protocol and study due to the similarity of the inclusion and exclusion criteria, similar procedures, and similar primary goals. Part 1: Intermediate risk predominant hERG blocking drugs The FDA performed a literature review and identified 28 proarrhythmic drugs from available in vitro studies of cardiac ion channel IC50 (using HEK293 cells and the hERG 1a subunit). Two of these drugs, classified as intermediate risk "predominant hERG blocking" (pimozide and clarithromycin), have been identified as candidates for evaluation in Part 1. An aim of this study will be generating higher quality QT data on "intermediate risk" "predominant hERG" blocking drugs' effect on both electrocardiographic biomarkers, QTc and J-Tpeakc interval prolongation, at therapeutic and supratherapeutic exposures. These data will also be used to support assessment of the hERG safety margin threshold together with moxifloxacin, dofetilide, and ondansetron as described in the recently released ICH Q\&A's. Part 2: Combination of hERG and multi-ion channel block Part 2 of this study will assess the effects of a mixed ion channel blocking drug, cobicistat, on the QTc and J-Tpeakc interval alone and in combination with a predominant hERG blocking drug (moxifloxacin). Clinical data with cobicistat, a structural analog of ritonavir used as a pharmacokinetic enhancer in various anti-viral regimens, has demonstrated QTc shortening and PR prolongation with supratherapeutic doses. Whether this is a results of late sodium block, calcium channel block, or other features is unclear. Additional clinical data with cobicistat alone or in combination with moxifloxacin will enhance our understanding of the effects of mixed ion channel blocking on electrocardiographic biomarkers (QTc and J-Tpeakc interval).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
QUADRUPLE
Enrollment
44
Subjects receive the Clarithromycin intervention orally according to the following schedule: Day 1: 1 Clarithromycin 500 mg immediate release (IR) tablet twice (Clarithromycin 500 mg BID). Day 2: 2 Clarithromycin 500 mg immediate release (IR) tablets twice (Clarithromycin 1000 mg BID). Day 3: 2 Clarithromycin 500 mg immediate release (IR) tablets once (Clarithromycin 1000 mg QD).
Subjects receive the Pimozide intervention orally according to the following schedule: Days 1-3: Pimozide 6 mg immediate release (IR) once per day.
Subjects receive matching placebo for treatments.
Subjects receive Moxifloxacin 800 mg orally once on day 1.
Subjects receive Cobicistat 450 mg orally once on day 1.
Subjects receive Moxifloxacin 800 mg and Cobicistat 450 mg orally once on day 1.
Subjects receive matching placebo for treatments.
Spaulding Clinical Research
West Bend, Wisconsin, United States
Part 1: Plasma concentration of pimozide and clarithromycin associated with ΔΔQTc prolongation of 10 ms based on concentration-QTc analysis.
Time frame: 1, 2, 2.5, 3, 4, 6, 8, 14, and 24 hours
Part 2: ΔΔJ-TpeakC between cobicistat and moxifloxacin compared to moxifloxacin based on ECG timepoint analysis.
Time frame: -1, -0.5, 0 (pre-dose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 14, and 24 hours
Part 1: ΔΔQTc for pimozide and clarithromycin at maximum drug concentration on day 3 based on concentration-QTc analysis.
Time frame: 1, 2, 2.5, 3, 4, 6, 8, 14, and 24 hours
Part 1: ΔΔJ-TpeakC for pimozide and clarithromycin at maximum drug concentration on day 3 based on concentration-QTc analysis.
Time frame: 1, 2, 2.5, 3, 4, 6, 8, 14, and 24 hours
Part 1: The margin (ratio) between hERG IC50 and free plasma concentration causing 10 ms QTc prolongation.
Time frame: 1, 2, 2.5, 3, 4, 6, 8, 14, and 24 hours
Part 2: ΔΔQTc between cobicistat and moxifloxacin compared to moxifloxacin based on ECG timepoint analysis.
Time frame: -1, -0.5, 0 (pre-dose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 14, and 24 hours
Part 2: ΔΔQTc for moxifloxacin, cobicistat, and moxifloxacin + cobicistat compared to placebo based on ECG timepoint analysis.
Time frame: -1, -0.5, 0 (pre-dose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 14, and 24 hours
Part 2: ΔΔJ-Tpeakc for moxifloxacin, cobicistat, and moxifloxacin + cobicistat compared to placebo based on ECG timepoint analysis.
Time frame: -1, -0.5, 0 (pre-dose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 14, and 24 hours
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