Linear mixed-effects model of QTc prolongation for olmesartan medoxomil.
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ABSTRACT:
SUBMITTER: Song S
PROVIDER: S-EPMC5049657 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
Publications
Linear mixed-effects model of QTc prolongation for olmesartan medoxomil.
Song SaeHeum S Matsushima Nobuko N Lee James J Mendell Jeanne J
Journal of clinical pharmacology 20150824 1
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Project description:Two studies (ROADMAP and ORIENT) evaluating the renoprotective effects of olmesartan medoxomil (OM) in patients with type 2 diabetes suggested OM is associated with increased cardiovascular mortality. We conducted a thorough QTc study to evaluate the effects of OM on cardiac repolarization. A randomized, double-blind, phase 1 study was conducted per E14 Guidance to assess the effects of single doses of OM therapeutic dose (40 mg), OM supratherapeutic dose (160 mg), placebo, or moxifloxacin (MOXI; 400 mg) on QTc in 56 healthy subjects. The primary endpoint was the baseline-adjusted, placebo-corrected QTc interval using Fridericia's formula (ΔΔQTcF) for OM and MOXI. Assay sensitivity was concluded if lower limit of 1-sided 95%CI > 5 milliseconds of ΔΔQTcF for MOXI. No threshold pharmacologic effect for OM was concluded if upper limit of 1-sided 95%CI <10 milliseconds for ΔΔQTcF at any timepoint. Pharmacokinetics, ECGs, and safety were assessed. Assay sensitivity was demonstrated. The largest upper limit of the 1-sided 95%CI for ΔΔQTcF was <5 milliseconds for OM. No clinically significant changes were observed in ECGs. Pharmacokinetics and safety profile were consistent with previous data. Therapeutic and supratherapeutic OM doses had no clinically significant effect on cardiac repolarization and were well tolerated.
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Project description:The current study assesses the antihypertensive efficacy and safety of the investigational angiotensin receptor blocker (ARB), azilsartan medoxomil (AZL-M), compared with placebo and the ARB olmesartan medoxomil (OLM-M). This randomized, double-blind, placebo-controlled, multicenter study assessed change from baseline in mean 24-hour ambulatory systolic blood pressure (SBP) following 6 weeks of treatment. Patients with primary hypertension (n=1275) and baseline 24-hour mean ambulatory systolic pressure ≥ 130 mm Hg and ≤ 170 mm Hg were studied; 142 received placebo and the remainder received 20 mg, 40 mg, or 80 mg AZL-M or 40 mg OLM-M. Mean age of participants was 58 ± 11 years, baseline mean 24-hour SBP was 146 mm Hg. Dose-dependent reductions in 24-hour mean SBP at study end occurred in all AZL-M groups. Reduction in 24-hour mean SBP was greater with AZL-M 80 mg than OLM-M 40 mg by 2.1 mm Hg (95% confidence interval, -4.0 to -0.1; P=.038), while AZL-M 40 mg was noninferior to OLM-M 40 mg. The side effect profiles of both ARBs were similar to placebo. AZL-M is well tolerated and more efficacious at its maximal dose than the highest dose of OLM-M.
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Project description:This 52-week, randomized, open-label study evaluated long-term safety/tolerability of fixed-dose combination azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs fixed-dose combination olmesartan medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with essential hypertension (stage 2; clinic systolic blood pressure 160-190 mm Hg). Initial AZL-M/CLD 40/12.5 mg/d (n=418) or OLM/HCTZ 20/12.5 mg/d (n=419) could be uptitrated during weeks 4 to 52 (AZL-M/CLD to 80/25 mg; OLM/HCTZ to 40/25 mg [United States] or 20/25 mg [Europe]) to meet blood pressure targets. Treatment-emergent adverse events/serious adverse events occurred in 78.5%/5.7% of patients taking AZL-M/CLD vs 76.4%/6.2% taking OLM/HCTZ. The most frequent adverse events were dizziness (16.3% vs 12.6%), blood creatinine increase (21.5% vs 8.6%), headache (7.4% vs 11.0%), and nasopharyngitis (12.2% vs 11.5%). Hypokalemia was uncommon (1.0% vs 0.7%). Greater blood pressure reductions with AZL-M/CLD by week 2 were maintained throughout the study, despite less uptitration (32.3% vs 48.9% with OLM/HCTZ). Fixed-dose combination AZL-M/CLD showed an encouraging benefit-risk profile when used per standard clinical practice in a titrate-to-target strategy.
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Project description:QT/QTc interval prolongation reflects delayed cardiac repolarization which can lead to Torsade de Pointes and sudden death. Many antimalarial drugs prolong QT/QTc interval. However, due to confounding factors in patients with malaria, the precise extent of this effect has been found to be highly variable among studies. We compared the effects of dihydroartemisinin-piperaquine phosphate (DHA-PQP) and artemether-lumefantrine (A-L) on QT interval duration in healthy volunteers. In this randomized, parallel groups, active moxifloxacin- and placebo-controlled study, prolongation of the QT/QTc interval following treatment with DHA-PQP in fasted and fed condition and A-L in fed state was investigated in healthy subjects (n = 287; Clinicaltrials.gov: NCT01103830). DHA-PQP resulted in significant mean (95% confidence interval (CI)) maximum increases in QTc Fridericia (QTcF) of 21.0 ms (15.7, 26.4) for DHA-PQP fasted, 35.9 ms (31.1, 40.6) for DHA-PQP high-fat/low-caloric and 46.0 ms (39.6, 52.3) for DHA-PQP high-fat/high-caloric breakfast. For A-L, the largest difference from baseline relative to placebo was 9.9 ms (95% CI: 6.8, 12.9). Increases in QTcF related to maximum plasma concentrations of piperaquine. Moxifloxacin demonstrated assay sensitivity. Increases in QTcF following DHA-PQP and A-L were clinically relevant. Food increased piperaquine exposure and QTcF interval prolongation emphasizing the need to administer DHA-PQP in the fasting state.
| S-EPMC6349839 | biostudies-literature
Project description:An open-label, long-term study evaluated safety and tolerability of azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs olmesartan/hydrochlorothiazide (OLM/HCTZ) in hypertensive participants with stage 3 chronic kidney disease. Initial therapy was AZL-M/CLD 20/12.5 mg (n = 77) or OLM/HCTZ 20/12.5 mg (n = 76), but could be up-titrated (AZL-M/CLD to 40/25 mg; OLM/HCTZ to 40/25 mg [US] or 20/25 mg [Europe]) with other agents added during weeks 4-52. Primary endpoint was proportion of participants with ≥ 1 adverse event (AE) through week 52. Baseline demographics were similar. AEs did not differ between groups (88.3%, AZL-M/CLD vs 76.3%, OLM/HCTZ; P = .058). AZL-M/CLD showed greater systolic BP reductions after initial dosing (P = .037) but not during long-term follow-up (P = .588). A greater proportion of participants up-titrated to the highest dose with OLM/HCTZ (48.7%) vs AZL-M/CLD (29.9%) (P = .021) and were taking additional antihypertensive medications (26.3% vs 16.9%). Both AZL-M/CLD and OLM/HCTZ showed similar efficacy and tolerability.
| S-EPMC8031057 | biostudies-literature
Project description:In concentration-QTc modeling, oscillatory functions have been used to characterize biological rhythms in QTc profiles. Fitting such functions is not always feasible because it requires sufficient electrocardiograph sampling. In this study, drug concentration and QTc data were simulated using a published biological QTc model (oscillatory functions). Then, linear mixed-effect models and the biological model were fitted and evaluated in terms of biases, precisions, and qualities of inferences. The simpler linear mixed-effect model with day and time as a factor variables provided similar accuracy of the concentration-QTc slope estimates to the complex biological model and was able to accurately predict the drug-induced QTc prolongation with less than 1 ms bias, despite its empirical nature to account for biological rhythm. The current study may guide a concentration-QTc modeling strategy that can be easily prespecified, does not suffer from poor convergence, and achieves little bias in drug-induced QTc estimates.
| S-EPMC4337253 | biostudies-literature
Project description:In adults, alcohol intoxication is associated with prolongation of the QT interval corrected for heart rate (QTc). The QTc is influenced by age and sex. Although alcohol intoxication is increasingly common in adolescents, there are no data on the prevalence of QTc prolongation in adolescents with alcohol intoxication. This study aimed to determine the prevalence of QTc prolongation in adolescents with alcohol intoxication and identify at-risk adolescents. In this observational study including adolescents aged 10-18 years, heart rate and QT interval were automatically assessed from an electrocardiogram (ECG) at alcohol intoxication using a validated algorithm. The QTc was calculated using both the Bazett formula (QTcB) and Fridericia formula (QTcF). If present, an ECG recorded within 1 year of the date of admission to the emergency department was obtained as a reference ECG. A total of 317 adolescents were included; 13.3% had a QTcB and 7.9% a QTcF longer than the sex- and age-specific 95th-percentile. None of the adolescents had a QTcB or QTcF > 500 ms, but 11.8% of the adolescents with a reference ECG had a QTcB prolongation of > 60 ms, while no adolescents had a QTcF prolongation of > 60 ms. QTc prolongation was mainly attributable to an increase in heart rate rather than QT prolongation, which underlies the differences between QTcB and QTcF. Male sex and hypokalaemia increased the likelihood of QTc prolongation.Conclusion: QTc prolongation was seen in approximately 10% of the adolescents presenting with alcohol intoxication, and although no ventricular arrhythmias were observed in this cohort, QTc prolongation increases the potential for malignant QT-related arrhythmias. Clinicians must be aware of the possibility of QTc prolongation during alcohol intoxication and make an effort to obtain an ECG at presentation, measure the QT interval, and give an adequate assessment of the findings. We advocate admitting adolescents with alcohol intoxication and QTc prolongation. During hospital admission, we recommend limiting exposure to QTc-prolonging medication, increasing potassium levels to a high-normal range (4.5-5.0 mmol/L) and obtaining a reference ECG at discharge.
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Project description:Chloroquine is used in the treatment of patients with COVID-19 infection, although there is no substantial evidence for a beneficial effect. Chloroquine is known to prolong the QRS and QTc interval on the ECG. To assess the effect of chloroquine on QRS and QTc intervals in COVID-19 patients, we included all inpatients treated with chloroquine for COVID-19 in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands) and had an ECG performed both in the 72 h before and during or at least 48 h after treatment. We analyzed the (change in) QRS and QTc interval using the one-sample t-test. Of the 106 patients treated with chloroquine, 70 met the inclusion criteria. The average change in QRS interval was 6.0 ms (95% CI 3.3-8.7) and the average change in QTc interval was 32.6 ms (95% CI 24.9-40.2) corrected with the Bazett's formula and 38.1 ms (95% CI 30.4-45.9) corrected with the Fridericia's formula. In 19 of the 70 patients (27%), the QTc interval was above 500 ms after start of chloroquine treatment or the change in QTc interval was more than 60 ms. A heart rate above 90 bpm, renal dysfunction, and a QTc interval below 450 ms were risk factors for QTc interval prolongation. Chloroquine prolongs the QTc interval in a substantial number of patients, potentially causing rhythm disturbances. Since there is no substantial evidence for a beneficial effect of chloroquine, these results discourage its use in COVID-19 patients.
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Project description:Drug-induced QTc interval prolongation (Δ QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog Δ QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only). Scaling parameters for translational in vivo extrapolation of drug effects were derived based on the assumption of system-specific myocardial ion channel densities and transduction of ion channel block: the operational efficacy (transduction of hERG block) in dogs was drug specific (1-19% hERG block corresponded to ≥10 msec Δ QTc). System-specific maximal achievable Δ QTc was estimated to 28% from baseline in both dog and human, while %hERG block leading to half-maximal effects was 58% lower in human, suggesting a higher contribution of hERG-mediated potassium current to cardiac repolarization. These results suggest that differences in sensitivity to drug-induced QTc prolongation may be well explained by drug- and system-specific differences in operational efficacy (transduction of hERG block), consistent with experimental reports. The proposed scaling approach may thus assist the translational risk assessment of QTc prolongation in different species and patient populations, if mediated by the hERG channel.
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Project description:Olmesartan medoxomil (OLM) is one of the prominent antihypertensive drug that suffers from low aqueous solubility and dissolution rate leading to its low bioavailability. To improve the oral bioavailability of OLM, a delivery system based on ethylcellulose (EC, a biobased polymer) nanosponges (NSs) was developed and evaluated for cytotoxicity against the A549 lung cell lines and antihypertensive potential in a rat model. Four OLM-loaded NSs (ONS1-ONS4) were prepared and fully evaluated in terms of physicochemical properties. Among these formulations, ONS4 was regarded as the optimized formulation with particle size (487 nm), PDI (0.386), zeta potential (ζP = -18.1 mV), entrapment efficiency (EE = 91.2%) and drug loading (DL = 0.88%). In addition, a nanosized porous morphology was detected for this optimized system with NS surface area of about 63.512 m2/g, pore volume and pore radius Dv(r) of 0.149 cc/g and 15.274 Å, respectively, measured by nitrogen adsorption/desorption analysis. The observed morphology plus sustained release rate of OLM caused that the optimized formulation showed higher cytotoxicity against A549 lung cell lines in comparison to the pure OLM. Finally, this system (ONS4) reduced the systolic blood pressure (SBP) significantly (p < 0.01) as compared to control and pure OLM drug in spontaneously hypertensive rats. Overall, this study provides a scientific basis for future studies on the encapsulation efficiency of NSs as promising drug carriers for overcoming pharmacokinetic limitations.
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