Risk Of QTc Prolongation Research Articles

The Impact of QT-Prolonging Medications and Drug-Drug Interactions on QTc Interval Prolongation in Hospitalized Patients: A Case-Crossover Study.

Researchers have studied potential corrected QT interval (QTc) prolongation from drug-drug interactions (DDIs), raising unresolved questions about their real-world impact. This retrospective case-crossover study investigated the effects of QT-prolonging drugs and DDIs on QTc prolongation in hospitalized patients aged 45 years and above. The cohort comprised patients who had multiple hospitalizations and developed QTc prolongation (QTc > 500 ms or an increase of >60 ms from baseline) at least 24 hours after admission between 2011 and 2019. Conditional logistic regression compared drug exposure between hospitalizations with QTc prolongation (case window) and those without (reference window). Among 2,276 patients (mean age 71; 43.8% female), the use of QT-prolonging drugs significantly increased the risk of QTc prolongation (odds ratio: 2.42 (95% confidence interval: 1.95-3.02)). The risk was higher with drugs of "known risks" (OR: 3.78 (2.91-4.90)) and "conditional risk" (OR: 2.08 (1.65-2.62)). DDIs, particularly involving multiple "known risk" drugs (OR: 7.86 (4.96-12.45)), strong cytochrome P450 enzyme inhibitors (OR: 5.57 (2.75-11.30)), or the concurrent use of ≥4 QT-prolonging drugs with any risk (OR: 5.28 (3.96-7.03)) substantially increased the risk. Cautious prescribing for patients with multiple risk factors is important to minimize the likelihood of QTc prolongation. However, when considering enhanced monitoring or drug choices, it is crucial to carefully evaluate the overall risk of QT prolongation against the benefits of treatment to ensure optimal patient care.

Implementing a drug interaction protocol for oral systemic anti-cancer therapy with focus on CDK4/6 inhibitors.

302 Background: Oral anti-cancer therapies (OACTs) are being increasingly used. Despite their convenience, OACTs introduce challenges with adherence, prescribing errors, and high incidence of drug-drug interactions (DDIs). Currently, there are limited guidelines for DDI checking. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized the management of metastatic ER+/HER2- breast cancer. While an overall survival benefit has been demonstrated with Ribociclib, its use can be problematic due to frequent DDIs and the risk of QTc prolongation. DDIs are routinely checked in our center with two interaction checkers, but they are not always documented due to a lack of a standardized protocol. This study aims to evaluate current DDI checking practices, identify common DDIs, and implement a systematic DDI protocol. Methods: A retrospective review was conducted on patients (pts) prescribed CDK4/6i in our center from Jan 2023 to Apr 2024. Data on pt demographics, treatment, DDI documentation, toxicity, and survival were collected. Retrospective DDI checks using Lexi-Interact and Drugs.com were performed. Results: A total of 65 pts were included, with 38 on Ribociclib and 27 on Palbociclib. The median follow-up was 11.6 months (range: 1-71). The median age of pts on Ribociclib was 54 (range: 35-77), compared to 61 (range: 44-82) on Palbociclib. The median number of medications was three with Ribociclib and five with Palbociclib. Seven pts (26%) were prescribed Palbociclib due to contraindications to Ribociclib, including cardiac disease (n=2), QTc-prolonging medications (n=4), and advanced age (n=1). DDI checks were documented in 46% of Ribociclib and 14% of Palbociclib pts (p=0.0063). There was a weak negative correlation between DDI documentation and toxicity, stronger in the Palbociclib arm (-0.079 for Ribociclib vs. -0.335 for Palbociclib). Retrospective checks revealed DDIs in 50% of Ribociclib and 52% of Palbociclib pts. Major DDIs were identified in 21% of Ribociclib and 7% of Palbociclib pts (p=0.133). Common major DDIs involved opioids and QTc-prolonging medications, most frequently antidepressants. Grade ≥3 toxicity occurred in 49% of Ribociclib vs. 64% of Palbociclib pts (p=0.21). Ribociclib caused more rash, liver toxicity, and diarrhea, while Palbociclib had significantly more grade ≥3 neutropenia (48% vs. 21%, p=0.042). No QTc prolongation was observed. Dose reductions were more common with Palbociclib (48% vs. 32%, p=0.27). There was no significant difference in survival data. Conclusions: Our findings highlight the importance of systematic DDI checks in pts receiving OACTs. Implementing a standardized protocol could reduce adverse interactions and improve pt outcomes. Further studies are needed to validate these findings and develop DDI guidelines. A standardized DDI protocol has now been developed for our center, with plans to re-audit after implementation.

CKD4/6 inhibitors: assessing risk of QTc prolongation

CKD4/6 inhibitors: assessing risk of QTc prolongation

QTc prolongation across CDK4/6 inhibitors: a systematic review and meta-analysis of randomized controlled trials.

Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. We included 14 RCTs comprising 16 196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.

The role of mitochondrial dysfunction in the association between trace metals and QTc prolongation in the aged population

This study delves into the relationship between environmental metal exposure and QT interval corrected for heart rate (QTc) prolongation, a critical marker for cardiovascular risk in the elderly. Although the interplay between metal exposure and QTc prolongation is important for predicting sudden cardiac death, it remains underexplored. Our analysis of 6478 participants from the Shenzhen aging-related disorder cohort involved measuring urinary concentrations of 22 trace metals and using mitochondrial DNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Utilizing Bayesian kernel machine regression, and structural equation modeling, we assessed the effects of mixed trace metals on QTc prolongation. Our findings indicated a direct association between certain metals (Sb, Cu, Zn) and a 7 % increase in QTc prolongation risk, while Li, V, and Rb were associated with a 5 % reduction in risk. Elevated levels of V, Ti, and Cr corresponded to higher mtDNA-CN. Notably, restricted cubic splines revealed a U-shaped, nonlinear relationship between mtDNA-CN and QTc prolongation. After adjusting for metal exposure, an inverse correlation was observed between mtDNA-CN and QTc prolongation, suggesting mitochondrial dysfunction as a partial mediator.

The effect of intravenous ondansetron on QT interval in the emergency department

ObjectiveOndansetron, a 5HT3 receptor antagonist, is commonly used in emergency departments to treat nausea and vomiting. In 2011, the Food and Drug Administration (FDA) issued a warning that this medicine may cause QT prolongation, potentially leading to deadly arrhythmias. The objective of this study was to characterize the QT interval prolongation associated with ondansetron use in the Emergency Department. MethodsThis was a prospective, observational cohort study of adult patients who presented to the emergency department during a one-year period and were treated with intravenous ondansetron. We investigated the QT prolongation associated with dosages. ECGs were obtained before the medication and 5, 15, and 30 minutes after IV drug administration. Every QT measurement was recorded and compared to the zero point. The severity of drug-induced QT prolongation was determined according to the recommendations of the International Conference on Compliance (ICH). QTc prolongation was categorized as ‘negligible’ (<5 ms), ‘significant’ (>20 ms), ‘potential concern’ (>30 ms), or ‘definitely worrying’ (>60 ms). ResultsOf the 435 patients enrolled in the study, 60% (261 patients) were female and the mean age was 39 (±18). The QT prolongation peaked at the fifth minute and remained consistent at the fifteenth and thirty-first minutes. The maximum prolongation of the mean QT duration occured at the fifth minute (7.9 ± 18.1 ms). No patient revealed any problems with cardiac conduction. The prolonged QT interval was not related to the dose of ondansetron, but QT measurements were higher in the 30th minute in patients treated with 8 mg of ondansetron. The effect of ondansetron administration on QT prolongation was found to be above the ‘negligible’ but below the ‘significant’ value, according to the ICH recommendations. DiscussionIn this study, QT prolongation due to ondansetron administration was below the ‘important’ value according to the recommendations of the ICH. No cases of cardiac arrhythmia were reported in any of the partients. Thus, routine ECG monitoring in patients given ondansetron due to the risk of QTc prolongation does not seem cost-effective when evaluated together with additional factors such as its negative impact on emergency patient flow, waste of personnel and time, and increase in healthcare costs. In the absence of a known risk of cardiac arrhythmia, IV administration of 4 mg and 8 mg of ondansetron doses no risk of QT prolongation in the emergency population.

A Calculated Risk: Evaluation of QTc Drug-Drug Interaction (DDI) Clinical Decision Support (CDS) Alerts and Performance of the Tisdale Risk Score Calculator.

A risk factor for a potentially fatal ventricular arrhythmia Torsade de Pointes is a prolongation in the heart rate-corrected QT interval (QTc) ≥ 500milliseconds (ms) or an increase of ≥60ms from a patient's baseline value, which can cause sudden cardiac death. The Tisdale risk score calculator uses clinical variables to predict which hospitalized patients are at the highest risk for QTc prolongation. To determine the rate of overridden QTc drug-drug interaction (DDI)-related clinical decision support (CDS) alerts per patient admission and the prevalence by Tisdale risk score category of these overridden alerts. Secondary outcome was to determine the rate of drug-induced QTc prolongation (diQTP) associated with overrides. Our organization's enterprise data warehouse was used to retrospectively access QTc DDI alerts presented for patients aged ≥18years who were admitted to Brigham and Women's Hospital during 2022. The QTc DDI CDS alerts were included if shown to a physician, fellow, resident, physician assistant, or nurse practitioner when entering the order in inpatient areas for patients with a length of stay of at least 2days. Variables collected for the Tisdale calculator included age, sex, whether patient was on a loop diuretic, potassium level, admission QTc value, admitting diagnosis of acute myocardial infarction, sepsis, or heart failure, and number of QTc-prolonging drugs given to the patient. A total of 2649 patients with 3033 patient admissions had 18,432 QTc DDI alerts presented that were overridden. An average of 3 unique QTc DDI alerts were presented per patient admission and the alerts were overridden an average of 6 times per patient admission. Overall, 6% of patient admissions were low risk (score ≤ 6), 64% moderate risk (score 7-10), and 30% high risk (score ≥ 11) of QTc prolongation. The most common QTc DDI alerts overridden resulting in an diQTP were quetiapine and propofol (11%) and amiodarone and haloperidol (7%). The diQTP occurred in 883 of patient admissions (29%) and was more frequent in those with higher risk score, with 46% of patient admissions with diQTP in high risk, 23% in moderate risk, and 8% in low risk. Use of the Tisdale calculator to assess patient-specific risk of QT prolongation combined with CDS may improve overall alert quality and acceptance rate, which may decrease the diQTP rate.

QTc-verlenging door antipsychoticagebruik binnen de kinder- en jeugdpsychiatrie: een systematische literatuurstudie

QTc prolongation associated with antipsychotic treatment in child and adolescent psychiatry: a systematic review Antipsychotics play a significant role in the treatment of psychiatric disorders. Monitoring of metabolic dysregulation and cardiac rhythm disturbances is essential. Given that the pharmacokinetic profile of children differs from that of adults, the literature cannot be extrapolated without consideration. Therefore, a systematic review on the risk of QTc prolongation in minors receiving antipsychotic treatment was conducted. The literature review was conducted within PubMed, Embase and Web of Science, focusing on randomized controlled trials (RCTs). Antipsychotics were selected based on the Belgian and Dutch formulary for the treatment of psychiatric disorders in minors. The study included 28 RCTs that examined the effect and safety of antipsychotic treatment in minors, including cardiac risks. The occurrence of clinically relevant QTc prolongation development is relatively rare. The comparison of the results was hindered by differences in the acquisition and correction of electrocardiograms (ECGs). It is advisable to identify risk factors through history-taking and blood sampling. Current research indicates that the risk of QTc prolongation and torsade de pointes in minors receiving antipsychotic treatment is relatively rare. However, vigilance is warranted in the presence of specific risk factors, in which case ECG monitoring is recommended.

Should Physicians Be Aware of Rhythm Disturbances in Adults with Systemic Autoimmune Diseases and Anti-Ro52 Antibodies? A Cross-Sectional Study.

Objectives: The association between anti-Ro/SSA antibodies and the appearance of cardiac rhythm disorders in adults is discussed. We aim to study this relationship, together with active treatments and comorbidities, and its impact on daily clinical practice in adults with systemic autoimmune diseases (SADs). Methods: This cross-sectional single-center study was conducted in a tertiary hospital between January 2021 and March 2022. A sample of adult patients followed up in the SAD Unit with a diagnosis of a SAD and previously tested for anti-Ro/SSA and anti-La/SSB were recruited. All of them underwent a 12-lead electrocardiogram. Results: 167 patients were included. 90 (53.9%) were positive for anti-Ro60, 101 (60.5%) for anti-Ro52, and 45 (26.9%) for anti-La/SSB; 52 (31.3%) were triple-negative. 84% were women, and the mean age was 59 years (standard deviation 12.8). The most common SAD was primary Sjögren's syndrome (34.8%), followed by systemic lupus erythematosus (24.6%) and rheumatoid arthritis (22.8%). A statistically significant relationship was found between anti-Ro52 positivity and cardiac rhythm disorders (relative risk = 2.007 [1.197-3.366]), specifically QTc prolongation (relative risk = 4.248 [1.553-11.615]). Multivariate regressions showed a significant association, with diabetes mellitus being the most related comorbidity. The association between anti-Ro52 antibodies and atrioventricular conduction disorders was not significant. Conclusions: The presence of anti-Ro52 antibodies in adult patients with SADs is associated with an increased risk of QTc prolongation. Electrocardiographic screening of patients with SAD, anti-Ro52 antibodies, and other risk factors, like diabetes mellitus or QT-prolonging drugs, seems advisable. Those with baseline electrocardiogram abnormalities or additional risk factors should undergo electrocardiographic monitoring.

Characterization of ascending dose canine telemetry model supports its use in E14/S7B QT integrated risk assessments

IntroductionNonclinical evaluation of the cardiovascular effects of novel chemical or biological entities (NCE, NBEs) is crucial for supporting first-in-human clinical trials. One important aspect of these evaluations is the assessment of potential QT/QTc prolongation risk, as drug-induced QT prolongation can have catastrophic effects. The recent publication of E14/S7B Q&As allows for the situational incorporation of nonclinical QTc data as part of an integrated risk assessment for a Thorough QT (TQT) waiver application provided certain best practice criteria are met. Recent publications provided detailed characterization of nonclinical QTc telemetry data collected from the commonly used Latin square study design. MethodsTo understand whether data from alternate telemetry study designs were sufficient to serve as part of the E14/S7B integrated risk assessment, we report the performance and translational sensitivity to identify clinical risk of QTc prolongation risk for an ascending dose telemetry design. ResultsThe data demonstrated low variability in QTci interval within animals from day to day, indicating a well-controlled study environment and limited concern for uncontrolled effects across dosing days. Historical study variances of the ascending dose design with n = 4 subjects, measured by least significant difference (LSD) and root mean square error (RMSE) values, were low enough to detect a + 10 ms QTci interval change, and the median minimum detectable difference (MDD) for QTci interval changes was <10 ms. Furthermore, concentration-QTci (C-QTci) assessments to determine +10 ms QTci increases for known hERG inhibitors were comparable to clinical CC values listed in the E14/S7B training materials, supporting the use of the ascending dose design in an E14/S7B integrated risk assessment. DiscussionThese findings suggest that the ascending dose design can be a valuable tool in nonclinical evaluation of QT/QTc prolongation risk and the support of TQT waiver applications.

Antiviral Use in Mild-to-Moderate SARS-CoV-2 Infections during the Omicron Wave in Geriatric Patients.

(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.

Significance of QTc interval in chronic hypoparathyroidism and its correlates.

Hypocalcemia predisposes patients with chronic hypoparathyroidism (cHypoPT) to an increased risk of QTc prolongation and life-threatening arrhythmias. Information on clinical and biochemical correlates of QTc in cHypoPT is limited. Observational cohort study at tertiary-care-center. Eighty-eight non-surgical cHypoPT (mean age 44.1 ± 15.4 years, 45 males) were assessed for QTc interval and its possible correlates including arrhythmic symptoms (palpitation/giddiness/syncope), serum total-calcium, phosphate, 25(OH)D and iPTH. The mean QTc in HypoPT cohort was 428 ± 34 ms with 13.6% having prolonged QTc. There was a significant inverse correlation between QTc interval and serum total-calcium measured on the same day (r = -0.43, p < 0.001). The mean serum total-calcium was significantly lower in patients with prolonged QTc (7.05 ± 1.94 vs. 8.49 ± 1.01 mg/dL, p = 0.02). 21.6% of cHypoPT patients had arrhythmic symptoms. They had significantly higher mean QTc (p = 0.02) and also tended to have lower mean serum total-calcium during follow-up (p = 0.06). In multivariable regression, female gender, higher current-age, higher BMI, and low serum total-calcium showed significant association with prolonged QTc. For every mg/dL decrease in serum total-calcium, QTc increased by 13 ms. Receiver-operating-characteristic analysis revealed serum total-calcium at cut-off of 8.3 mg/dL discriminated prolonged QTc with area-under-curve being 0.72 [95% CI: 0.51,0.93]. One-fifth of cHypoPT had arrhythmic symptoms and a significant proportion had prolonged QTc. This highlights the need for close monitoring of cHypoPT patients for arrhythmic symptoms and QTc prolongation. The serum total-calcium should be maintained to at least 8.3 mg/dL to minimize the risk of potentially life-threatening arrhythmia in cHypoPT.

Abstract PO5-12-08: QTc prolongation as Adverse Effect of CDK4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials

Abstract Introduction: CDK4/6 inhibitors (CDK4/6i), such as abemaciclib, ribociclib, and palbociclib, have significantly improved outcomes for patients with ER+/HER2− breast cancer. Nevertheless, they differ among each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. Ribociclib causes concentration-dependent increases in the QTc interval, particularly in combination with tamoxifen. However, the pathogenesis of ribociclib-induced QTc prolongation remains unclear. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. Methods: We performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to compare QTc prolongation in patients using CDK4/6i in combination with hormonal agents to patients that did not use CDK4/6i, including neoadjuvant, adjuvant, or metastatic scenarios in breast cancer. We searched Embase, PubMed and Cochrane Library databases from inception to June 2023. The outcomes evaluated were QTc prolongation of all grades. Statistical analysis was performed with R software version 2023.03.0+386. Results: We included 14 RCTs comprising 16,013 patients in the quantitative analysis, of whom 8,585 underwent therapy with CDK4/6i, and one more paper was included only in the qualitative analysis due to not reporting the exact number of events of QTc prolongation. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR 2.32; 95% CI 1.67–3.23; p=0.000001; I²=46%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a risk ratio of 3.07 (RR 3.07; 95% CI 2.17-4.36; p&amp;lt; 0.000001; I² = 21%) while the palbociclib subgroup had a risk ratio of 1.52 (RR 1.51; 95% CI 1.05-2.16; p=0.025, I²=0%). Conclusion: Our findings suggest that QTc prolongation may be a common adverse effect of CDK4/6i, with ribociclib carrying greater risk. These results are important for guiding clinical decision-making, and further investigation is warranted to better understand the mechanisms and clinical implications of CDK4/6 i-induced QTc prolongation. Citation Format: Bruno Carvalho, Pedro Cotta Abrahão Reis, Alice Marinho, Ana Carolina Comini, Debora Xavier, Beatriz Mella S. Pessoa, Felipe Batalini. QTc prolongation as Adverse Effect of CDK4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-12-08.

QTc prolongation in patients hospitalized in enclosed psychiatric facilities in Corfu

IntroductionAn undeniably significant amount of psychotropic medication can evidently affect the corrected QT (QTc) interval, which puts patients’ lives at risk. More specifically, certain anti-psychotic medication can increase the risk of QTc prolongation and by extension the risk of a potentially fatal arrhythmia or sudden cardiac death.ObjectivesElectrocardiograms (ECG) were contacted in one hundred and four (104) chronic patients, with psychosis, through out their hospitalization in several enclosed psychiatric facilities in Corfu. Almost the entirety of the patients along side their anti-psychotic medication were also taking various other medication for their individual pathological issues. We observed any changes that might have occurred on the ECG in comparison with each patient’s medication and it’s potential effect on the QTc.MethodsThe measurements of the QT interval were made manually in lead V5 and the mathematical conversion was contacted using the Hodges correction formula.ResultsAt least one ECG (n = 104) was performed. Among them 29,8% (n=31) had ECG abnormalities, including 13,5% (n=13) with a prolonged Qtc (481.2 ± 26,8 ms). Covariates significantly associated with the QTc were gender (+17.2 ms if female, p &lt; 0.0001) and age (+0.4 ms/year, p = 0.0001).ConclusionsThe QTc prolongation that was evident in a notable number of patients, emphasizes the importance of QTc monitoring in patients who are taking anti-psychotic medication. QTc prolongation risk factors should be assessed before the administration or prescription of any anti-psychotic medication.Disclosure of InterestNone Declared

Pharmacist Reported Protocols for QTc Monitoring of Psychiatric Medications.

Background Psychiatric medications, such as antipsychotics and antidepressants, are associated with QTc interval prolongation. There is currently no consensus best practice on how to mitigate this risk. This study aimed to collect and analyze information about methods used for QTc monitoring in patients taking psychiatric medications to better understand current practice. Methods An anonymous electronic survey was distributed on September 22, 2022, using a national psychiatric pharmacist organization email list. The survey closed on December 15, 2022. Descriptive statistics were used to analyze the multiple-choice questions. Qualitative analysis applying grounded theory for thematic analysis was performed forfree response questions. Results A total of 48 initiated the survey. Of the respondents, 11.4% (5/44) reported that their institution had a formal protocol for monitoring QTc intervals in patients receiving psychiatric medications, while 32.4% (12/37) reported that their institution had an informal process. Out of those with a protocol or process, approximately half reported that it was drug-specific. Among the respondents, 88.6% (31/35) reported that there was a psychiatric clinical pharmacy specialist at their institutionand 34.3% (12/35) reported that pharmacists could order an electrocardiogram (ECG). Major themes that emerged from the qualitative analysis included pharmacist-driven QTc monitoring, referring the patient to another provider for monitoring, and encountering significant barriers to monitoring. Conclusion A variety of methodsare currently being employed to monitor QTc prolongation risk in patients taking psychiatric medications. Pharmacist authorization to order ECGs may be an opportunity to advance practice and improve care for this population. Further research is needed to more clearly understand best practices for QTc prolongation risk mitigation in patients receiving psychiatric medications.

Abstract 2113: HMPL-506, a novel, highly potent and differentiated menin-MLL inhibitor for the treatment of MLL-rearrangedand NPM1mutant acute leukemia in preclinical models

Abstract Background: Mixed-lineage leukemia (MLL, or KMT2A) gene rearrangements (MLL-r) occur in 5%-10% acute leukemias and are associated with poor prognosis. Nucleophosmin 1 mutations (NPM1m) are the most common genetic alterations in acute myeloid leukemia (AML). Multiple studies have illuminated that those leukemogenesis are dependent on the interaction of menin-MLL, which controls downstream gene expressions associated with cell proliferation and differentiation, e.g. HOXA9 and CD11b. Herein, we introduce HMPL-506, a novel and highly differentiated small molecule compound targeting menin-MLL interaction. Methods and Results: Biochemical assay revealed that HMPL-506 potently blocked menin-MLL binding with IC50 of 1.0 nM. In cell lines carrying MLL-r or NPM1m, HMPL-506 substantially down-regulated menin-MLL target genes transcription of MEIS1 and HOXA9 and upregulated the differentiation marker of CD11b by RT-PCR assay, consequently, HMPL-506 attenuated tumor cell growth, with GI50 ranging from 3.0 to 12.1 nM in MLL-r cell lines (MV-4-11, MOML-13 and RS4;11) and 22.4 nM in NPM1m cell line (OCI-AML-3) in CellTiter-Glo cell viability assay. Notably, compared with the other 5 menin inhibitors in clinical stage, HMPL-506 showed the strongest inhibitory potency in MLL-r and NPM1m cell line models. In vivo studies demonstrated the dose- and exposure- dependent target regulation of MEIS1 and anti-tumor efficacy following HMPL-506 treatment in multiple tumor xenograft models. For instance, in MV-4-11 subcutaneous model, once daily oral administration of HMPL-506 at 5, 10 and 25 mg/kg for 4 days in BALB/c nude mice induced dose-dependent inhibition of MEIS1 gene expression, positively correlating with compound exposures in tumor tissues; continuous dosing of HMPL-506 at 5 mg/kg for 28 days reduced the tumor growth by 86%, which was comparable to the efficacy induced by SNDX-5613 at 50 mg/kg. Treatment of HMPL-506 at 10 mg/kg and 25 mg/kg resulted in tumor shrinkage in all treated animals, with tumor regression rates of 72% and 100%, respectively. Furthermore, HMPL-506 synergistically improved anti-tumor effect of azacytidine, venetoclax and gilteritinib against MLL-r leukemias both in vitro and in vivo. HMPL-506 displayed favorable PK profiles and high selectivity among multiple kinases, methyltransferases and safety related targets. More importantly, the IC50 of HMPL-506 on hERG patch clamp was over 60 µM, indicating low risk of QTc prolongation in human. Conclusion: HMPL-506 is a novel and highly differentiated menin-MLL inhibitor with robust anti-tumor activities, favorable ADME properties and low risk of cardiac toxicity, warranting it further clinical development for treatment of MLL-r and NPM1m acute leukemias. HMPL-506 IND is expected to be cleared in H1 2024. Citation Format: Min Cheng, Liang Ge, Zhihu Gao, Zeyu Zhong, An Jiang, Wei Zhang, Jia Hu, Shuwen Jiang, Na Li, Na Yang, Jian Wang, Yang Sai, Weiguo Qing, Yongxin Ren, Weiguo Su. HMPL-506, a novel, highly potent and differentiated menin-MLL inhibitor for the treatment of MLL-rearrangedand NPM1mutant acute leukemia in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2113.

Scientific Review of the Proarrhythmic Risks of Oligonucleotide Therapeutics: Are Dedicated ICH S7B/E14 Studies Needed for Low-Risk Modalities?

Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current hERG/QTc evaluation practices, we reviewed US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Approval Packages (source: PharmaPendium.com) and collated preclinical and clinical studies for 17 marketed ONTs. In addition, clinical QTc data from 12 investigational ONTs were obtained from the literature. Of the marketed ONTs, eight were tested in the hERG assay with no inhibitory effect identified at the top concentration (range: 34-3,000 μM) tested. Fourteen of the ONTs were evaluated in nonhuman primate cardiovascular studies with 11 of them in dedicated telemetry studies. No effect on QTc intervals were observed (at high exposure multiples) in all studies. Clinically, four ONTs were evaluated in TQT studies; an additional six ONTs were assessed by concentration-QTc interval analysis, and six by routine safety electrocardiogram monitoring. None of the clinical studies identified a QTc prolongation risk; the same was true for the 12 investigational ONTs. A search of the FDA Adverse Event Database indicated no association between approved ONTs and proarrhythmias. Overall, the collective weight of evidence from 29 ONTs demonstrate no clinical proarrhythmic risk based on data obtained from ICH S7B/E14 studies. Thus, new ONTs may benefit from reduced testing strategies because they have no proarrhythmic risk, a similar cardiac safety profile as monoclonal antibodies, proteins, and peptides.

Developing a Model for Quantifying QTc-Prolongation Risk to Enhance Medication Safety Assessment: A Retrospective Analysis.

There are currently no established methods to predict quantitatively whether the start of a drug with the potential to prolong the QTc interval poses patients at risk for relevant QTc prolongation. Therefore, this retrospective study aimed to pave the way for the development of models for estimating QTc prolongation in patients newly exposed to medications with QTc-prolonging potential. Data of patients with a documented QTc prolongation after initiation of a QTc-prolonging drug were extracted from hospital charts. Using a standard model-building approach, general linear mixed models were identified as the best models for predicting both the extent of QTc prolongation and its absolute value after the start of a QTc-time-prolonging drug. The cohort consisted of 107 adults with a mean age of 64.2 years. Patients were taking an average of 2.4 drugs associated with QTc prolongation, with amiodarone, propofol, pipamperone, ondansetron, and mirtazapine being the most frequently involved. There was a significant but weak correlation between measured and predicted absolute QTc values under medication (r2 = 0.262, p < 0.05), as well as for QTc prolongation (r2 = 0.238, p < 0.05). As the developed models are based on a relatively small number of subjects, further research is necessary to ensure their applicability and reliability in real-world scenarios. Overall, this research contributes to the understanding of QTc prolongation and its association with medications, providing insight into the development of predictive models. With improvements, these models could potentially aid healthcare professionals in assessing the risk of QTc prolongation before adding a new drug and in making informed decisions in clinical settings.

High-dose benzodiazepine use and QTc interval prolongation, a latent class analysis study

Benzodiazepine (BDZ) addiction is a widespread and multifaceted phenomenon. For many patients, especially females, the concomitant use of other drugs also increases their risk of QTc prolongation, possibly leading to complications such as seizures and even sudden death. However, the relationship between BDZ use and QTc prolongation is currently unclear. The present study aims to examine patterns of polysubstance use among a sample of Italian adults with BDZ dependence in relation with their QTc prolongation risk. We used Latent Class Analysis (LCA) on data collected from 251 inpatients of the Addiction Medicine Unit in Verona to group patients into three classes according to their substance use and their QTc prolongation risk. Results showed no significant relationship between QTc prolongation and BDZ use in any of the classes considered. We conclude that BDZs, even if used long-term and at high dosages, can be considered safe in terms of cardiovascular complications for patients.

QTc interval changes among patients on psychotropic medications: A prospective observational study

Background: Psychotropic medications are commonly prescribed for the treatment of psychiatric disorders. Various studies have reported QT interval (QTc) prolongation with the use of psychotropics. However, some studies have found no significant risk of QTc changes with these medications. Aim: To assess the effect of psychotropics on QTc in drug-naive psychiatric patients. Materials and Methods: Our study was a prospective observational study, conducted at a tertiary care hospital. Patients aged 18–45 years, drug-naïve, with no medical comorbidity or substance use history, were recruited for the study. ECG to assess QTc was recorded at baseline, second and fourth week after the starting of psychotropic medications. Results: N=8 (4%) patients had QTc prolongation at baseline and were excluded. No clinically significant QTc prolongation was noticed, after 2 weeks and 4 weeks of treatment with any of the psychotropic medications. However, among patients on escitalopram, a significant effect on QTc was noted (P = 0.001) as compared to those on sertraline, risperidone, and olanzapine (P &gt; 0.05). Conclusion: The short-term risk of QTc prolongation with the use of newer psychotropics at optimal doses appears low among young patients with normal baseline QTc and no significant medical or substance use comorbidity.