Concentration-QT modelling shows no evidence of clinically significant QT interval prolongation with capivasertib at expected therapeutic concentrations.
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ABSTRACT:
SUBMITTER: Voronova V
PROVIDER: S-EPMC9292875 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common reasons for withdrawal of drugs from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient. Identifying genetic variants associated with drug-induced QT prolongation might add to tailored pharmacotherapy and prevent beneficial drugs from being withdrawn unnecessarily. In this review, our objective was to provide an overview of the genetic background of drug-induced QT prolongation, distinguishing pharmacokinetic and pharmacodynamic pathways. Pharmacokinetic-mediated genetic susceptibility is mainly characterized by variation in genes encoding drug-metabolizing cytochrome P450 enzymes or drug transporters. For instance, the P-glycoprotein drug transporter plays a role in the pharmacokinetic susceptibility of drug-induced QT prolongation. The pharmacodynamic component of genetic susceptibility is mainly characterized by genes known to be associated with QT interval duration in the general population and genes in which the causal mutations of congenital long QT syndromes are located. Ethnicity influences susceptibility to drug-induced QT interval prolongation, with Caucasians being more sensitive than other ethnicities. Research on the association between pharmacogenetic interactions and clinical endpoints such as sudden cardiac death is still limited. Future studies in this area could enable us to determine the risk of arrhythmias more adequately in clinical practice.
| S-EPMC4579250 | biostudies-literature
Project description:AimIn spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans.MethodsUsing estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between -0.98 ms μM-1 and 6.1 ms μM-1 in dogs and -10 ms μM-1 and 90 ms μM-1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species.ResultsFor compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x; R2 = 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs.ConclusionsTogether with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans.
| S-EPMC5237692 | biostudies-literature
Project description:Concentration-QTcF data obtained from two phase I studies in healthy volunteers treated with a novel phosphodiesterase-4 inhibitor currently under development for the treatment of chronic obstructive pulmonary disease were analyzed by means of mixed-effects modeling. A simple linear mixed-effects model and a more complex model that included oscillatory functions were employed and compared. The slope of the concentration-QTcF relationship was not significantly greater than 0 in both approaches, and the simulations showed that the upper limit of the 90% confidence interval around the mean ΔΔQTcF is not expected to exceed 10 ms within the range of clinically relevant concentrations. An additional simulation study confirmed the robustness of the simple linear mixed-effects model for the analysis of concentration-QT data and supported the modeling of data obtained from studies with different designs (parallel and crossover).
| S-EPMC6656937 | biostudies-literature
Project description:Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.
| S-EPMC8347245 | biostudies-literature
Project description:Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure-response (E-R) analysis may be more sensitive than simple changes in QT(c) interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT study from one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E-R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn.
| S-EPMC3579250 | biostudies-literature
Project description:BackgroundAbnormal cardiac repolarization, indicated by a prolongation of the QT interval, increases the risk for torsades de pointes, a potentially life-threatening arrhythmia. Many perioperatively administered drugs and conditions prolong the QT interval. Despite several reports of perioperative torsades de pointes, systematic evidence regarding perioperative QT interval prolongation is limited.MethodsSerial postoperative 12-lead electrocardiograms were obtained from 469 adult patients undergoing major noncardiac surgery under general anesthesia. Heart rate corrected QT-interval duration (Fridericia formula) was the primary outcome. All perioperatively administered drugs were recorded. Emphasis was placed on absolute QTc prolongation greater than 500 ms and relative increases of 30 and 60 ms.ResultsAt the end of surgery, 80% of the patients (345 of 429) experienced a significant QTc interval prolongation (ΔQTc 23 ± 26 ms (mean and SD), 95% CI 20-25 ms, P less than 0.001). Approximately 51% (219 of 429) had a QTc greater than 440 ms, and 4% (16 of 429) a QTc greater than 500 ms. In 39% (166 of 429), the ΔQTc was greater than 30 ms, in 8% (34 of 429) >60 ms, and in greater than 0.5% (2 of 429) >100 ms. No changes in ΔQTc occurred at subsequent time points. One patient developed torsades de pointes with a ΔQTc: 29 ms (0.4% incidence rate). Several drugs had a large effect on ΔQTc: isoflurane, methadone, ketorolac, cefoxitin, zosyn, unasyn, epinephrine, ephedrine, and calcium. Postoperative body temperature had a weak negative correlation with ΔQTc (r = -0.15, P = 0.02); serum magnesium, potassium, and calcium concentrations were not correlated.ConclusionPostoperative QT-interval prolongation is common. Several perioperatively administered drugs are associated with a substantial QT-interval prolongation. The exact cause and its clinical relevance are, however, unclear. Nevertheless, an association between postoperative QT prolongation and risk for torsades de pointes is likely.
| S-EPMC3406265 | biostudies-literature
Project description:Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration versus time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QT interval of ?5 and ?10 ms. Point estimates for the slope in dogs suggested low probability of ?10 ms prolongation in humans, whereas an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals of the drug-specific parameter in dogs. Interspecies differences in drug disposition appear to explain the discrepancies between predicted and observed QT prolonging effects in humans. Extrapolation of the effects of racemic compound may not be sufficient to describe the increase in QT interval observed after administration of methadone to patients. Assessment of the contribution of enantioselective metabolism and active metabolites is critical.
| S-EPMC5461648 | biostudies-literature
Project description:SARS-CoV-2 is a rapidly evolving pandemic causing great morbimortality. Medical therapy with hydroxicloroquine, azitromycin and protease inhibitors is being empirically used, with reported data of QTc interval prolongation. Our aim is to assess QT interval behaviour in a not critically ill and not monitored cohort of patients. We evaluated admitted and ambulatory patients with COVID-19 patients with 12 lead electrocardiogram at 48 h after treatment initiation. Other clinical and analytical variables were collected. Statistical analysis was performed to assess the magnitude of the QT interval prolongation under treatment and to identify clinical, analytical and electrocardiographic risk markers of QT prolongation independent predictors. We included 219 patients (mean age of 63.6 ± 17.4 years, 48.9% were women and 16.4% were outpatients. The median baseline QTc was 416 ms (IQR 404-433), and after treatment QTc was prolonged to 423 ms (405-438) (P < 0.001), with an average increase of 1.8%. Most of the patients presented a normal QTc under treatment, with only 31 cases (14.1%) showing a QTc interval > 460 ms, and just one case with QTc > 500 ms. Advanced age, longer QTc basal at the basal ECG and lower potassium levels were independent predictors of QTc interval prolongation. Ambulatory and not critically ill patients with COVID-19 treated with hydroxychloroquine, azithromycin and/or antiretrovirals develop a significant, but not relevant, QT interval prolongation.
| S-EPMC7722753 | biostudies-literature
Project description:Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor. To evaluate the cardiac safety of luseogliflozin, a thorough QT/QTc study was conducted in healthy Japanese subjects. The effects of moxifloxacin on QT prolongation in Japanese subjects were also evaluated. In this double-blind, placebo- and open-label positive-controlled, 4-way crossover study, 28 male and 28 female subjects received a single dose of luseogliflozin 5 mg (therapeutic dose), luseogliflozin 20 mg (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Serial triplicate digital 12-lead electrocardiograms (ECGs) were recorded before and after dosing, and results were analyzed using the Fridericia correction (QTcF) method. Serial blood sampling was performed for pharmacokinetic analyses of luseogliflozin and moxifloxacin to analyze the relationship between QTcF interval and plasma concentration. The upper limits of the two-sided 90% confidence intervals (CIs) for baseline and placebo-adjusted QTcF intervals (ΔΔQTcF) in the 5 mg and 20 mg luseogliflozin groups were less than 10 ms at all time points. No correlation between plasma luseogliflozin concentrations and ΔΔQTcF was observed. In the moxifloxacin group, the lower limits of the two-sided 90% CIs for ΔΔQTcF were greater than 5 ms at all time points. A positive relationship was observed between plasma moxifloxacin concentration and change in ΔΔQTcF. Luseogliflozin was well tolerated at both dose levels. The majority of adverse events were mild in severity, and no serious or life-threatening adverse events occurred. Neither therapeutic (5 mg) nor supratherapeutic (20 mg) doses of luseogliflozin affected QT prolongation in healthy Japanese subjects.
| S-EPMC4596473 | biostudies-literature
Project description:Importance:Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial. Objective:To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills. Design, Setting, and Participants:A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018. Main Outcomes and Measures:Electrocardiographic changes 3 hours after sotalol administration. Results:A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P?=?.005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P?=?.005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n?=?13 of 61 [21.0%]) than those taking levonorgestrel (n?=?20 of 137 [14.6%]) or women taking no OCs (n?=?24 of 207 [11.6%]; P?=?.01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P?=?.01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P?<?.001). Conclusions and Relevance:Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.
| S-EPMC6233640 | biostudies-literature