Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-Tpeak) and late repolarization (global Tpeak-Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.

IMPORTANCEThe US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. OBJECTIVE To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018.INTERVENTIONS Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm 2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. MAIN OUTCOMES AND MEASURESThe primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. RESULTS Among 24 participants randomized (mean age, 35.5 [SD, 10.5] years; 12 [50%] women; 14 [58%] black or African American), 23 (96%) completed the trial. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash (1 participant with each sunscreen).

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-T peak (J-T peak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from Correspondence: DG Strauss David.Strauss@fda.hhs.gov. Additional Supporting Information may be found in the online version of this article.Author Contributions: All authors have contributed as follows: protocol development (L.J., J.V., J.W.M., C.S., K.W.L., J.F., N.S., D.G.S.), data collection (C.E., C.S., K.W.L., M.H., J.L., P.G., A.M., J.W., W.J.C.), data analysis (L.J., J.V., J.F., D.G.S.), and preparing the manuscript (L.J., D.G.S.). All authors discussed the results and implications and commented on the manuscript. Conflict of HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript hERG potassium channel block and assessment of J-T peak c may add value beyond only assessing QTc.Drug-induced QT prolongation increases the risk for torsade de pointes, a potentially fatal ventricular arrhythmia. 1 QT prolongation and increased risk for torsade de pointes have resulted in 14 drugs being removed from the market worldwide. 2 Furthermore, many drugs remain on the market with a known torsade de pointes risk, including numerous antibiotics, antimalarial, antiviral, psychiatric, oncology, and cardiac drugs. 3 At the same time, the current regulatory paradigm for assessing drug effects on cardiac repolarization is preventing potentially effective medicines from reaching the market, sometimes inappropriately. 2 To address this, the US Food and Drug Administration (FDA) and multiple public-private partnerships are studying novel approaches to assess the cardiac safety of new drugs with a Comprehensive in vitro Proarrhythmia Assay and in Phase 1 clinical trials. 4,5 Essential to the novel approaches is a focus on understanding mechanisms by studying the effects of drugs on multiple cardiac ion channels, which can be either proarrhythmic or antiarrhythmic depending on the combination. 6Almost all drugs on the market that can cause torsade de pointes block the hERG potassium channel 7 and prolong the QT interval of the electrocardiogram (ECG). 8 However, some drugs block the hERG potassium channel and prolong QT with a minimal torsade de pointes risk (e....

IMPORTANCE A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). OBJECTIVE To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single-and maximal-use conditions. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. INTERVENTIONS Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm 2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. MAIN OUTCOMES AND MEASURES The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. RESULTS Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. The overall maximum plasma concentrations for each active ingredient for each product formulation are shown in the table. The most common adverse event was rash, which developed in 14 participants.

Balanced multi‐ion channel‐blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (Ci PA ) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J‐T peak (J‐T peak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10‐subject‐per‐drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ‐T peak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether‐à‐go‐go related gene (hERG), prolonged ΔΔ QT c and ΔΔJ‐T peak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced Δ QT c prolongation, but shortened ΔJ‐T peak c and prolonged ΔT peak ‐T end . Absence of J‐T peak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration‐response in some cases.