Treatment of cardiac dysfunction

Abstract

To provide methods for treating cardiac arrhythmias, and for preventing subsequent cardiac arrhythmias, e.g., ventricular tachycardia or ventricular fibrillation.SOLUTION: A method for treatment of cardiac dysfunction comprises administering to a subject in need thereof a therapeutically effective amount of at least one of ANAVEX 2-73 or ANAVEX 19-144 or pharmaceutically acceptable salts thereof or a combination thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Methods for treating cardiac arrhythmias and subsequent prevention of cardiac arrhythmias, such as ventricular tachycardia or ventricular fibrillation, are disclosed herein. Agents that shorten the QT interval are particularly described. Agents include ANAVEX® 2-73 and ANAVEX® 19-144. [Background technology]

[0002] Cardiac arrest, also known as cardiopulmonary arrest, is the sudden cessation of the heart's pumping function and the cessation of normal circulation of blood due to the heart's inability to contract effectively. Cardiac arrest can be caused by a variety of factors, including, for example, coronary heart disease, hypertension, myocardial infarction and ischemia, atrial and ventricular arrhythmias (including fibrillation and flutter), and heart failure.

[0003] Cardiac arrest is often associated with ventricular arrhythmias (“VA”), such as ventricular tachycardia (“VT”) and / or ventricular fibrillation (“VF”).

[0004] Arrhythmias have been reported to occur in the upper chambers of the heart (atria) or the lower chambers of the heart (ventricles). Arrhythmias can occur at any age. Some are barely noticeable, while others can be more dramatic and can even lead to cardiac arrest and sudden cardiac death.

[0005] In adults and children 15 years of age and older, a resting heart rate faster than 100 beats per minute is called tachycardia. Tachycardia can result in palpitations, but tachycardia is not necessarily an arrhythmia. An increased heart rate is a normal response to physical exercise or emotional stress. It is mediated by the sympathetic nervous system at the sinus node and is called sinus tachycardia. Other factors that increase sympathetic nervous system activity in the heart include ingested or injected substances such as caffeine or amphetamines, and an overactive thyroid gland (hyperthyroidism).

[0006] In cardiology, the QT interval is a measure of the time between the onset of the Q wave and the end of the T wave in the cardiac electrical cycle. The QT interval represents the electrical depolarization and repolarization of the ventricles. A prolonged QT interval is a marker of possible ventricular tachyarrhythmias, such as torsades de pointes, and a risk factor for sudden death. Like the RR interval, the QT interval is trivially dependent on heart rate (i.e., the faster the heart rate, the shorter the RR and QT intervals) and can be adjusted to improve detection of patients at increased risk for ventricular arrhythmias. The RR is the interval measured in seconds from the onset of one QRS complex to the onset of the next QRS complex and is often derived from the heart rate (HR) as 60 / HR (where QT is measured in milliseconds).

[0007] The definition of a normal QTc varies between less than or equal to 0.40 s (≤400 ms), 0.41 s (≤410 ms), 0.42 s (≤420 ms), or 0.44 s (≤440 ms). For risk of sudden cardiac death, a "borderline QTc" in men is 431-450 ms and in women is 451-470 ms. An "abnormal" QTc in men is greater than 450 ms and greater than 470 ms in women.

[0008] Refer to Fridericia's QT interval correction formula, which uses the cube root of RR:

[0009]

number

[0010] The compound 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (ANAVEX® 19-144, or A19-144) is believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinity in the low micromolar range. ANAVEX® 2-73 (also referred to as A2-73), which has the systematic name 1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine hydrochloride, exhibits similar activity. Summary of the Invention

[0011] The present disclosure includes methods for treating cardiac dysfunction, comprising administering to a subject in need thereof a therapeutically effective amount of at least one of ANAVEX 2-73 or ANAVEX 19-144, or a pharmaceutically acceptable salt thereof, or a combination thereof. Treatments that shorten the QT interval are particularly described. In certain embodiments, the shortening of the QT interval is about 10 ms or about 2% to about 3%, as shown in Figures 8 and 9.

[0012] In one embodiment of the method, the cardiac dysfunction to be treated is selected from the group consisting of cardiac arrest-related dysfunction including cardiac arrhythmia, premature ventricular contraction (PVC)-induced left ventricular dysfunction, atrial fibrillation, atrial flutter, inducible left ventricular dysfunction, ventricular arrhythmia including ventricular tachycardia and fibrillation, and combinations thereof. Particular mention is made of the treatment of ventricular arrhythmia and atrial arrhythmia.

[0013] In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of ANAVEX 2-73 daily, particularly an oral dose of about 20 to about 60 mg or an intravenous dose of about 6 to about 17 mg. In some embodiments, this consists of two daily oral doses of about 20 mg, and in other embodiments, two daily doses of about 30 mg each. In other embodiments, a single daily oral dose of about 40 mg or 60 mg is administered. In some embodiments, intravenous administration includes daily doses of ANAVEX 2-73 of about 8 mg, about 10 mg, and about 15 mg.

[0014] Also described are embodiments of methods that involve administering to a subject a therapeutically effective amount of ANAVEX 19-144 daily, with particular reference to oral administration of about 20 mg to about 60 mg, including two daily doses of about 20 mg or 30 mg, or an intravenous dose of about 6 mg to about 17 mg. In other embodiments, a single daily oral dose of about 40 mg or about 60 mg is administered. In some embodiments, intravenous administration includes daily doses of about 8 mg, about 10 mg, and about 15 mg of ANAVEX 19-144. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows graphs of the distribution of continuous demographic covariates: 1A weight, 1B age, and 1C height. [Figure 2] Figure 2 shows a graph of the distribution of A2-73 (2A) and A19-144 (2B). [Figure 3] Figure 3 is a plot of QTcF by dose. [Figure 4] Figure 4 is a plot of the distribution of QTcF by dose. [Figure 5] FIG. 5 is a plot of the distribution of heart rate by dose. [Figure 6] Figure 6 is a plot of ANAVEX 2-73 (6A) and ANAVEX 19-144 (6B) exposure relative to QTcF. [Figure 7] FIG. 7 is a plot of QTcF over time from A2-73 administration. [Figure 8] Figure 8 is a plot of QTcF over time from A2-73 for the 30 mg dose. [Figure 9] Figure 9 is a plot of QTcF over time from A2-73 for the 40 mg dose. [Figure 10] FIG. 10 is a plot of QTcF over time from A2-73 for the 60 mg dose. [Figure 11] FIG. 11 is a plot of dQTcF over time from A2-73 administration. [Figure 12A]Figure 12 shows the relationship between ANAVEX 2-73 (12A) and ANAVEX 19-144 (12B) exposure and QTc over time at the 30 mg dose level. [Figure 12B] Figure 12 shows the relationship between ANAVEX 2-73 (12A) and ANAVEX 19-144 (12B) exposure and QTc over time at the 30 mg dose level. [Figure 13] Figure 13 shows the linear exposure-QTcF model using all variables (parent, metabolite, and time), 13A is the base model and 13B is the final model. [Figure 14] FIG. 14 is a goodness-of-fit plot showing improved population predictions from the final (14B) model compared to the base model (14A). [Figure 15] Figures 15A-F are plots of the relationship between model covariates and conditional weighted residuals, where 15A is the base model plot for A2-73, 15B is the final model for A2-73, 15C is the base model plot for A19-144, 15D is the final model for A19-144, 15E is the base model plot by time, and 15F is the final model by time. [Figure 16] FIG. 16 shows typical concentration-time graphs for the parent drug (A2-73) and metabolite (A19-144) for a subject after oral administration of 60 mg of A2-73. [Figure 17] Figures 17A-F show the relationship between model covariates and conditional weighted residuals for the exposure-heart rate model, where 18A is the base model plot for A2-73, 18B is the final model for A2-73, 18C is the base model plot for A19-144, 18D is the final model for A19-144, 18E is the base model plot by time, and 18F is the final model by time. [Figure 18] Figure 18 is a weighted time plot of the time-dQTcF relationship. DETAILED DESCRIPTION OF THE INVENTION

[0016] The following is a detailed description of the present invention provided to assist those skilled in the art in carrying out the present invention. Those skilled in the art can make improvements and modifications to the embodiments described herein without departing from the spirit or scope of the present invention. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. The technical terms used in the description of the present invention herein are only intended to describe specific embodiments and are not intended to limit the present invention.

[0017] Where a range of values ​​is provided, unless the context clearly dictates otherwise, each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed within the invention. Ranges from any lower limit to any upper limit are contemplated. Subject to any specifically excluded limit in a stated range, the upper and lower limits of smaller ranges that may be independently included in those smaller ranges are also encompassed within the invention. Where a stated range includes one or both of the limits, ranges excluding both of those included limits are also included in the invention.

[0018] Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0019] All numerical values ​​in the specification and claims in this application are modified by "about" or "approximately" the indicated value to account for experimental error and variations that would be expected by one of ordinary skill in the art. The present disclosure is better understood with reference to the following definitions: B.Par.Est. Bootstrap parameter estimates BQL Below the limit of quantification BSE Bootstrap Standard Error CL / F Apparent clearance Conc concentration CWRES Conditional weighted residual CWRESI Conditional weighted residuals with interactions dQTcF / ΔΔQTcF Change in QTcF from baseline DV Dependent variable (observed concentration) E. QTc response EC50: The concentration that produces 50% of the maximum change in QTc ECG electrocardiogram Emax Maximum change in QTc FDA U.S. Food and Drug Administration FO 1st FOCE First-order conditional estimation FOCEI First-order conditional estimation with interactions hr time HV Healthy Volunteer IIV Inter-individual variability IPRED Individually predicted concentrations kg kilogram LLD Log-Likelihood Difference LOQ Limit of Quantification mg milligram mL milliliter ng nanogram NONMEM: A nonlinear mixed-effects modeling software program. NPDE Normalized Prediction Distribution Error OFV Objective function value PK Pharmacokinetics PPK population pharmacokinetics PRED predicted population concentration PSN Perl Speaks NONMEM QTcF (heart rate corrected QT interval according to Fridericia's formula) RSE relative standard error SE standard error VPC visual predictive check yr year

[0020] Without being bound by any particular theory, ANAVEX 19-144 has been reported as a metabolite of ANAVEX 2-73. In the present disclosure, ANAVEX 2-73 is a compound that is subjected to enzymatic oxidation, reduction, or hydrolysis under physiological conditions in vivo and converted to ANAVEX 19-144 of the present disclosure.

[0021] Seventeen subjects contributed ECG data to the analysis dataset. The study was a randomized, single-ascending-dose, phase I, first-in-human study designed to investigate the safety, tolerability, and pharmacokinetics of increasing oral doses of ANAVEX 2-73 in healthy male subjects. It was a double-blind, placebo-controlled, two-cohort study with alternating single-ascending doses conducted in healthy male subjects. Subjects received oral doses of 10, 30, 40, 50, or 60 mg of ANAVEX 2-73 with a 4-week washout between doses. Drug sampling and ECGs were performed from predose through 48 hours. The placebo-adjusted (delta-delta) change in QTcF is expressed as ΔΔQTcF.

[0022] Subjects provided time-matched exposure-ECG data for analysis. For exposure-QTc analysis, data obtained after administration of doses greater than 1 mg were used. Data from the 1 mg dose were excluded because ANAVEX 2-73 concentrations were not quantifiable at most sampling times beyond 2-4 hours post-dose, and ANAVEX 19-144 concentrations were all below the detection limit. However, ECG data from administration of the 1 mg dose were included in categorical and outlier analyses.

[0023] analysis Data analysis proceeded from linear / nonlinear mixed-effects modeling in NONMEM to data structure analysis in S-PLUS to construct exposure-QTc relationships for ANAVEX2-73 and its active metabolite, ANAVEX19-144. The correction method used for QT interval was Fridericia's correction. Bootstrapping was used to determine the reliability / stability of the constructed exposure-QTc models. This was necessary to determine whether the modeling results obtained using data from 17 subjects were applicable to a larger population, given the sample size. Exposure-heart rate, exposure-change from baseline QTc, and exposure-placebo-adjusted QTc relationship models were constructed to elucidate any exposure-QTc relationships.

[0024] Additionally, a mixed-effects model averaging approach was also used to characterize the exposure-QTc relationship, using cutoff criteria to delineate the "top model set" with the top two corrected Akaike Information Criterion (AICc) models and 95% confidence (total weight). These were used to determine the top model set used to calculate the model-averaged parameters. Furthermore, there are two methods for weighting the estimates and errors for each parameter: the natural mean method and the zero method. The natural mean method is used to generate conditional coverage parameter estimates, and the zero method is used to generate full coverage parameter estimates. The zero method reduces the effect size (and error) of predictors that appear only in models with small model weights (especially when the predictors have a weak effect) and dilutes (shrinks to zero) the parameter estimates for these predictors.

[0025] Additionally, categorical summaries of ECG data were generated using categories defined by ICH E14 guidance as well as change from baseline in QTc interval duration.

[0026] These data are summarized as follows: Categorical analysis by indicated time point at which Fridericia-corrected QTc (i.e., QTcF) values ​​were consistently <450 ms across the sampling time, including baseline, for the 10-60 mg doses. One subject receiving the 1 mg dose had a QTcF of 450 ms at one time point (36 hours). This occurred 34 hours after ANAVEX 2-73 concentrations were below the limit of detection and ANAVEX 19-144 was not detectable in the subject.

[0027] No subject had a dQTcF>30 ms at any time point.

[0028] The two-sided 90% CI for dQTcF indicated that the upper bound of the 90% CI was lower than 20 ms at each time point, except for one subject at the 40 mg dose, when the ANAVEX 2-73 concentration was 2.23 ng / mL and the ANAVEX 19-144 concentration was 3.33 ng / mL at 24 hours, and another subject at the 1 mg dose level at 36 hours. For the latter subject, the ANAVEX 2-73 concentration was below the limit of quantification at 2 hours. There were no quantifiable concentrations of ANAVEX 19-144. There was no apparent delayed QTc response with counterclockwise hysteresis.

[0029] Exposure-dQTcF characterization did not show any effect of ANAVEX 2-73 and ANAVEX 19-144 on dQTcF.

[0030] ANAVEX 19-144 is an antiarrhythmic agent.

[0031] There was no relationship between ANAVEX2-73 and ANAVEX19-144 for ΔΔQTcF.

[0032] Overall, ANAVEX2-73 treatment did not prolong the QT interval, regardless of whether a forward / backward stepping frequentist statistical approach or an information-theoretic model averaging approach was used to analyze the data.

[0033] Overall, the QTc interval tended to decrease over time and remained stable over the observation period following ANAVEX2-73 administration.

[0034] The protocol presented herein was a single-ascending-dose (SAD) Phase I first-in-human study designed to investigate the safety, tolerability, and pharmacokinetics of increasing oral doses of ANAVEX 2-73 in healthy male subjects. The study was randomized, double-blind, and placebo-controlled within each dosing step. It was a two-cohort study with alternating single-ascending doses conducted in healthy male subjects. Subjects were divided into two cohorts of eight subjects each: Cohort A (n = 8) and Cohort B (n = 8). However, 17 evaluable subjects were studied in an 8:9 ratio in Cohort A and Cohort B, respectively. The study included repeated treatment periods with an interim washout period of at least four weeks.

[0035] Blood samples for determination of plasma concentrations of ANAVEX2-73 and metabolite ANAVEX19-144 were collected at time 0 (TO) (before drug administration), T+0.25h (15 min), T+0.5h (30 min), T+1h, T+1.5h, T+2h, T+3h, T+3.5h, T+4h, T+6h, T+8h and T+12h on day 1, T+24h and T+36h on day 2, and T+48h on day 3.

[0036] Per study protocol, triplicate 12-lead ECG safety recordings were obtained at the following time points: T0 / pre-dose (three baseline ECGs), T+0.25 h (15 min), T+0.5 h (30 min), T+1 h, T+2 h, T+4 h, T+8 h, and T+12 h on Day 1, T+24 h, T+36 h on Day 2, and T+48 h on Day 3. ECGs were recorded at each PK sampling time (i.e., 0.25, 0.5, 1, 2, 3, 4, 6, 8, 24, 36, and 48 hours after initiation of treatment). Thus, ECG recordings were time-matched to the PK sampling.

[0037] PK variables used in the analysis were patient-, regimen-, and time-specific observed plasma concentrations of ANAVEX 2-73 and ANAVEX 19-144.

[0038] ECG metrics assessed included heart rate (HR), QT interval duration, and heart rate-corrected QT interval (QTcF) according to Fridericia's formula.

[0039] Changes in QTcF from baseline (dQTcF) and placebo-corrected QTcF (ΔΔQTcF) were generated from the data and used for analysis.

[0040] The ECG-evaluable population included all subjects who received at least one dose of study drug (1, 10, 30, 40, or 60 mg), a pre-dose baseline ECG, and a post-dose ECG assessment.

[0041] The concentration-QTc evaluable population included all patients in the ECG-evaluable population who had at least one matched PK-ECG pair available post-dose. However, data for the 1 mg dose were excluded from the exposure-QTc analysis because ANAVEX 2-73 concentrations were available for up to 2 to 4 hours, and subjects had unquantifiable drug concentrations for 2 to 4 hours. ANAVEX 19-144 concentrations were not quantifiable after administration of the 1 mg dose.

[0042] As shown in Table 1, 17 subjects had evaluable time-matched concentration-QTc measurements over the study sampling duration.

[0043] [Table 1]

[0044] Three replicate ECGs were recorded at each nominal time point and served as the mean observation, which was used for statistical evaluation and exposure-QTc analysis, etc.

[0045] The baseline ECG was defined as the pre-dose baseline at each dosing occasion. Given the 4-week washout between doses, the pre-dose baseline ECG was used as the baseline ECG for a particular dose / dose occasion. The change from baseline for the QTc interval (ΔQTcF) was calculated using the pre-dose baseline.

[0046] The ΔΔQTcF data were from a single-dose escalation study. Therefore, all subjects did not receive placebo during each study period. Only nine subjects received placebo during the course of the study. As a result, subject-specific placebo corrections could not be performed. Therefore, the calculation of ΔΔQTcF was performed in three steps as follows: Step 1: Calculation of the overall mean of placebo QTcF data using data from subjects who received placebo. Step 2: Below: dQTcF 薬物,時間=t =QTcF 薬物,時間=t -QTcF 薬物,時間=0 , Calculation of dQTcF drug at a given time as, and the following: dQTcF プラセボ,時間=t =QTcF プラセボ,時間=t -QtcF プラセボ,時間=t dQTcF at a given time as プラセボ Calculation of. Step 3: Below: ΔΔQTcF 時間=t =dQTcF 薬物,時間=t -dQTcF プラセボ,t Calculation of ΔΔQTcF as

[0047] Concentration-QTc modeling was performed using the software NONMEM v7.3 (Icon Development Solutions, Ellicott City, MD), and graphical analysis, diagnostic plots, and auxiliary analyses were performed using S Plus v8.2 (TIBCO Software, Boston, MA) and R packages.

[0048] The dataset included observed ANAVEX2-73 and ANAVEX19-144 plasma concentrations, which were directly time-matched to the QT interval measurements. The analytical variables of interest were QT interval duration corrected for RR interval duration according to the Fridericia formula (i.e., QTcF), HR, and change from baseline QT interval duration corrected for RR interval duration according to the Fridericia formula (ΔQTcF or dQTcF). Baseline was defined as the mean of any and all values ​​obtained immediately prior to ANAVEX2-73 administration.

[0049] Selection of the most appropriate model was based on likelihood ratio tests for nested models as well as graphical diagnostics for non-nested models.

[0050] The approach used in characterizing the exposure-QTc relationship was as follows: 1) Concentration and QTc versus time plots were examined for any apparent trends or associations. 2) Subject and dose-specific QTc versus concentration plots were also examined for the presence of any hysteresis indicative of temporal dissociation, ie, indirect effects, in addition to association. 3) All QTc measurements were plotted against the paired concentration measurements, and a smoothing spline or locally weighted regression curve was overlaid to visually identify any trends and the approximate shape of the trends. 4) Taking into account the results of steps 1–3 above, a model of appropriate structure was fitted to the observed data. Where possible, stepwise hierarchical modeling was performed, and models were compared using likelihood ratio tests to assess statistical significance. The prespecified α was 0.05. The simplest model estimating concentration effects, i.e., a linear model, was fitted first. This model was compared with a concentration-naive model, i.e., an intercept-only model. Subsequently, one or more nonlinear models, such as a simple Emax model or an Emax model with two sites of drug action, were fitted to the data. Furthermore, models incorporating cooperativity of drug action, such as competitive antagonism between ANAVEX2-73 and ANAVEX19-144 concentrations and QTc effects, were evaluated using nonlinear mixed-effects modeling, as warranted. Any presence of hysteresis in the concentration-QTc profile signaled the use of a model characterizing temporal dissociation to fit the data.

[0051] Statistical evaluation was performed using S Plus v8.2 (TIBCO Software, Boston, MA).

[0052] Continuous ECG data (QTcF, HR) were summarized using descriptive statistics (number of patients, mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum). A summary of ECG parameters and corresponding changes from baseline is shown at each time point. Subject- and regimen-specific listings are the mean interval values ​​at each time point.

[0053] QTcF measurements at each time point were averaged across subjects within a regimen using the arithmetic mean. Change from baseline was the mean change from baseline in QTcF at each time point. Change from baseline across all study time points was calculated as above.

[0054] A two-sided 90% CI for the mean ΔQTcF was calculated at each time point. The 90% CI for ΔQTcF was considered the primary analysis variable. The upper limit of the 90% CI [per ICH Guidance (ICH E14 2005)] at each time point was compared with a threshold of 20 ms. If the upper limit of the 90% CI is lower than 20 ms at all time points, it is concluded that ANAVEX2-73 is unlikely to prolong the mean QTc interval to a clinically significant extent.

[0055] The following categories: >30msec increase >60msec increase ECG data were summarized categorically using the number and percentage of subjects with the greatest change from baseline in QTcF using the .

[0056] For the determination of the proportion, the denominator was the number of ECG-evaluable subjects. All subjects in the dataset were ECG-evaluable.

[0057] The subject and maximum post-treatment observed values ​​for QTcF within the regimen were divided into three groups: >450 msec >480msec >500msec were classified as follows.

[0058] Carefully select the method used to define the top model set for calculating model parameter estimates and to calculate the model-averaged parameters. There are two ways to weight the estimates and errors for each parameter (see Burnham KP, Anderson DR. Model Selection and Multimodel Inference: "A Practical Information-Theoretic Approach, 2nd ed." 2002. Springer, Berlin, and Lukacs PM, Burnham KP, Anderson DR. “Model selection bias and Freedman's paradox,” Ann Inst Stat Math 2010;62:117-125). When using the natural mean method (Burnham 2002), parameter estimates for each predictor are averaged over only the models in which that predictor appears and weighted by the total weight of these models. On the other hand, when using the zero method (Burnham 2002), a parameter estimate (and error) of zero is imputed into models in which a given parameter is absent, and the parameter estimate is obtained by averaging over all models in the top model set. Thus, the zero method reduces the effect size (and error) of predictors that appear only in models with small model weights (especially when the predictor has a weak effect), diluting (i.e., shrinking to zero) the parameter estimates for these predictors (Lukacs 2010).

[0059] An IT model averaging approach was used in addition to traditional frequentist statistical forward and backward stepping model selection approaches. The goal was to ensure that results from traditional hypothesis testing were not isolated occurrences. This allowed for robust inferences to be made if findings from model averaging supported results from the forward and backward stepping model selection approaches. Results were reported for model-averaged parameter estimates calculated by the zero method (so-called overall mean coefficients or estimates, (Lukacs 2010)), except when variables needed to be emphasized for biological reasons. In such situations, parameter estimates obtained by the natural mean method (so-called conditional mean coefficients or estimates) were reported. The cutoff criteria used to delineate the "top model set" were the top two AICc and 95% confidence (total weight) of the models. Analyses were performed using the IT approach of model averaging using the AICc and 95% confidence (total weight) criteria as implemented in the R packages AICcmodavg and MuMin.

[0060] The distribution of continuous demographic covariates is in Figure 1. In addition, a statistical summary of the demographic data of the subjects who contributed data to the analysis dataset is contained in Table 2.

[0061] [Table 2]

[0062] The exposure analysis is explained as follows: The concentration distributions of ANAVEX 2-73 and ANAVEX 19-144 are shown in Figure 2A and Figure 2B, respectively. The concentrations of ANAVEX 2-73 ranged from 0.23 to 46.25 ng / mL. The concentrations of ANAVEX 19-144 ranged from 0.18 to 23.96 ng / mL.

[0063] Figure 3 is a plot of QTcF by dose. The QT interval appeared to decrease below baseline at the 10 and 30 mg doses and returned to baseline at the 40 and 60 mg doses (Figure 4). The pattern of heart rate (HR), on average, appeared to be a reversal of the pattern with the QT interval, as shown in Figure 5.

[0064] Graphical analysis of the relationship between paired ANAVEX 2-73 concentrations with QTcF measurements suggests a minimal positive trend due to three points in the concentration range of 35–46 ng / mL (Figure 6A). A similar plot of paired ANAVEX 19-144 concentrations with QTcF measurements suggests a slight, minimal upward trend from baseline followed by a slight negative trend (Figure 6B). The trend returns to baseline values ​​at concentrations of approximately 10 ng / mL for ANAVEX 2-73 and approximately 5 ng / mL for the metabolite. The trend continued in the original positive or downward direction at 25 and 12 ng / mL for the parent compound (Figure 6A) or metabolite (Figure 6B), respectively. Note that the continuous lines are locally weighted regression (smoothed) lines.

[0065] Overall, the QTc interval tended to decrease over time and plateaued over the observation period after ANAVEX2-73 administration (Figure 7). The solid line in Figure 7 is a locally weighted regression (smoothed) line, indicating the general trend in QTcF over time after ANAVEX2-73 administration. This trend is clearly visible for the 30 and 40 mg doses (Figures 8 and 9, respectively). The black dotted line is the mean line, and the gray dotted line is the median line. The horizontal dotted line is the 450 ms cutoff line for outliers. Different colors or symbols represent QTcF values ​​for different subjects who received 30 mg (Figure 8) or 40 mg (Figure 9) of ANAVEX2-73.

[0066] Figure 10 is a similar plot for the 60 mg dose, showing that the QTc interval remained stable over the observation period. The black dotted line is the mean line, and the gray dotted line is the median line. The horizontal dotted line is the 450 ms cutoff line for outliers. Different colors or symbols represent QTcF values ​​for different subjects administered 60 mg of ANAVEX2-73. The pattern seen in the relationship of QTcF with time also holds, as expected, for the relationship of dQTcF with time, as shown in Figure 11.

[0067] Inspection of the data indicated no prolongation of the QTc response with respect to the time of peak ANAVEX2-73 concentration (Figure 12A), and a similar pattern with metabolite ANAVEX19-144 (Figure 12B).

[0068] The final exposure-QTcF model was QTcF ij =407+0.196×parent-0.643×metabolite-0.143×time (In the formula, QTcF ij refers to subject-level QTcF, parent refers to ANAVEX2-73, and metabolite refers to ANAVEX19-144).

[0069] Figure 13B shows the final model (Figure 13A base model) of the linear exposure-QTcF model using all variables (parent, metabolite, and time), which is the preferred model for characterizing the QTcF data. Population predictions from the final model (Figure 14B) show a significant improvement over the base model (Figure 14A) using only baseline QTcF. Variability in the dataset is explained by including all three variables (parent, metabolite, and time) in the model (Figures 15A-F).

[0070] The estimated values ​​were used to apply the exposure-QTcF relationship using observed and unlikely concentrations of the parent drug, and the metabolite QTc interval was predicted, taking into account the parameter estimates obtained using the constructed exposure-QTcF model. Assuming a maximum Cmax of 91.36 ng / mL for ANAVEX 2-73 observed in subjects in the Phase 2a study for the 50 mg dose (Table 3) and a dose-proportionality coefficient of 0.085 for Cmax, the predicted Cmax for the 200 mg dose is 102.78 ng / mL. Assuming the corresponding Cmax for ANAVEX 19-144 is 22.12 ng / mL, a doubling from 11.06 ng / mL was observed for subjects with an ANAVEX 2-73 concentration of 91.36 ng / mL, and the predicted QTcF is 412.77 ms at the 200 mg dose. Similarly, assuming a Cmax of 131.0 ng / mL is achieved for a subject at a dose of 60 mg and the dose is increased 3.3-fold to 200 mg, the subject is predicted to have a Cmax of 145.10 ng / mL. The predicted QTcF for that subject is 410.67 ms, taking into account the corresponding concentration of ANAVEX 19-144, which is 38.3 ng / mL (Table 3). Therefore, the QT corrected interval with treatment with ANAVEX 2-73 is predicted to be less than 420 ms.

[0071] [Table 3]

[0072] Further modeling characterized the exposure-heart rate relationship. The dependent variables in the model were ANAVEX 2-73 and ANAVEX 19-144 concentrations and time. Baseline heart rate was also estimated. The best model constructed to explain the exposure-heart rate relationship included all three variables. Again, ANAVEX 2-73 concentrations themselves were not initially biologically active in the QT but became active as they were metabolized to A19-144 in the model. The results of the constructed model are summarized in Table 4 and Figure 16. A19-144 peaked approximately 4 to 8 hours post-dose and surpassed A2-73 at approximately 8 hours post-dose. The results show that ANAVEX 2-73 and ANAVEX 19-144 had opposing initial effects on heart rate. Metabolism of A2-73 to A19-144 modifies this effect. The goodness-of-fit plot in Figure 17 demonstrates the validity of the model in characterizing the exposure-heart rate relationship. It is important to note that the upward and negative inflections for the parent compound and active metabolite, respectively, in the final model do not indicate model misdesign, but are due to the sensitivity of the smoothed Lowess regression (red line in Figure 17) to outlying observations on the y-axis. The final model is given below: HR ij =56.5-0.106×parent+0.369×metabolite+0.153×time (In the formula, HR ij is subject-specific heart rate, the parent refers to ANAVEX2-73, and the metabolite is ANAVEX19-144).

[0073] [Table 4]

[0074] Considering the parameter estimates obtained using the constructed exposure-heart rate model, heart rate is predicted using observed and unlikely concentrations of parent drug and metabolites. Assuming a maximum Cmax of 91.36 ng / mL for ANAVEX 2-73 observed in subjects in a Phase 2a study for the 50 mg dose and a dose-proportionality coefficient of 0.085 for Cmax, the predicted Cmax for the 200 mg dose is 102.78 ng / mL. Assuming a Cmax of 22.12 ng / mL for ANAVEX 19-144, a doubling from the 11.06 ng / mL observed in subjects with an ANAVEX 2-73 concentration of 91.36 ng / mL (Table 5), the predicted heart rate is 54.00 beats / min at the 200 mg dose. Similarly, assuming that a Cmax of 131 ng / mL is obtained for a subject at a dose of 60 mg and the dose is increased 3.3 times to 200 mg, the subject is predicted to have a Cmax of 145.10 ng / mL.The predicted heart rate for the subject is 54.74 beats / min when the corresponding concentration of ANAVEX19-144 is 36.5 ng / mL (Table 5).Therefore, the heart rate of treatment with ANAVEX2-73 is predicted to be lower than 75 beats / min.

[0075] [Table 5]

[0076] Exposure-dQTcF was calculated based on the model described above, with ANAVEX2-73 and ANAVEX19-144 concentrations and time as variables tested in the model. Baseline dQTcF is fixed at 0. Only time is retained in the final model. A linear model of time is used, using goodness-of-fit diagnostics. Model validity is demonstrated in Figure 18. The upward trend of the smoothed lowess regression line is driven by the density of points in the positive y-axis direction at 48 hours.

[0077] Daily to weekly antiarrhythmic doses of A2-73 are described, with specific reference to every two days to every three days. Doses of about 10 to about 80 mg are described, with specific reference to about 30 mg, about 40 mg, and about 60 mg. Lower doses of A2-73 and A19-144 are contemplated when combined with other antiarrhythmic drugs. Such reductions may, in certain embodiments, be about half to about a quarter of the above dosages. [Example]

[0078] Example 1 [Treatment of atrial fibrillation using A2-73] The safety, tolerability, and short-term efficacy of ANAVEX2-73 in human subjects with persistent atrial fibrillation (AF) will be demonstrated as follows: A 57-year-old male subject with symptomatic AF (72 hours duration) will receive 30 mg of A2-73 orally daily. Administration will begin in the hospital and continue at weekly follow-up outpatient visits. Efficacy will be assessed as the absence of AF recurrence on weekly 12-lead ECGs and daily telephone monitoring during the study.

[0079] From the start of administration to the end of the 30-day follow-up period, no serious adverse events occurred, and AF stopped within 12 hours and did not recur.

[0080] <Example 2> [Treatment of atrial flutter using A2-73] The safety, tolerability, and short-term efficacy of ANAVEX 2-73 in human subjects with persistent atrial flutter are as follows: A 48-year-old female subject with atrial flutter (72 hours duration) is given 60 mg of A2-73 orally daily. Administration begins in the hospital and continues at weekly follow-up outpatient visits. Efficacy is assessed as the absence of atrial flutter recurrence on weekly 12-lead ECGs and daily telephone monitoring during the study.

[0081] From the start of administration to the end of the 30-day follow-up period, no serious adverse events occurred, and AF stopped within 12 hours and did not recur.

[0082] Example 3 [Treatment of ventricular fibrillation with A19-144] The safety, tolerability, and short-term efficacy of ANAVEX2-73 in human subjects with persistent ventricular fibrillation will be demonstrated as follows: A 57-year-old male subject with symptomatic ventricular fibrillation (72-hour duration) will receive 40 mg of A19-144 orally at a dose of 20 mg twice daily. Administration will begin in the hospital and continue at weekly follow-up outpatient visits. Efficacy will be assessed as the absence of ventricular fibrillation recurrence on weekly 12-lead ECGs and daily telephone monitoring during the study.

[0083] From the start of administration to the end of the 30-day follow-up period, no serious adverse events occurred, and ventricular fibrillation stopped within 12 hours and did not recur.

[0084] Example 4 [Treatment of atrial fibrillation using A2-73] The safety, tolerability, and short-term efficacy of ANAVEX2-73 in human subjects with persistent atrial fibrillation (AF) will be demonstrated as follows: A 60-year-old male subject with symptomatic AF (72 hours duration) will receive 30 mg of A2-73 intravenously daily. Administration will begin in the hospital and continue at weekly follow-up outpatient visits. Efficacy will be assessed as the absence of AF recurrence on weekly 12-lead ECGs and daily telephone monitoring during the study.

[0085] From the start of administration to the end of the 30-day follow-up period, no serious adverse events occurred, and AF stopped within 12 hours and did not recur.

[0086] Intravenous administration of A2-73 and A19-144 is a specifically mentioned treatment option. The specific intravenous (iv) dose is arrived at empirically and under the supervision of a medical professional. The dose is determined based on the specific subject It fluctuates about.

[0087] Empirically, a therapeutically effective IV dose is approximately 30% by weight of the oral dose. Data suggest that an oral dose of 20 mg correlates with an IV dose of approximately 6 mg, and an oral dose of 60 mg correlates with an IV dose of approximately 17 mg. Notably, a therapeutically effective IV dose can vary by ±40% or more.

[0088] The pharmacologically active compositions of the disclosure can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to a patient, eg, a mammal, including a human.

[0089] The compositions of the present disclosure may be used in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral (e.g., oral or inhalation) use that do not adversely react with the active composition. Suitable pharmaceutically acceptable carriers include, but are not limited to, water and saline solutions. The pharmaceuticals may be sterilized and, if desired, mixed with auxiliary agents, such as salts for affecting osmolality, buffers, and the like, that do not adversely react with the active composition. They may also be combined, if desired, with other active agents, such as cardiac agents for reducing or controlling long QT syndrome. Beta-blockers are a described class of drugs for such therapy, such as nadolol (Corgard) and propranolol (Inderal LA, InnoPran XL). Mexiletine, rufinamide, and spironolactone are also described. It is further anticipated that additional pharmaceuticals for reducing or controlling long QT syndrome will be developed and similarly applicable.

[0090] In some embodiments, the dosage form comprises instructions for use of such a composition.

[0091] For parenteral application, particularly suitable are injectable (including intravenous) substances, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampoules are convenient unit doses.

[0092] Sustained or specific release compositions can be formulated, e.g., liposomes, or those in which the active ingredient is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc. It is also possible to lyophilize the new composition and use the resulting lyophilizate, e.g., for the preparation of an injectable product.

[0093] Generally, the composition is dispensed in a unit dosage form containing from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.

[0094] The dosage of compositions according to the present disclosure is generally 0.4 to 1 mg / kg / day, preferably 0.4 to 0.8 mg / kg / day. Doses of about 20 mg to about 60 mg per day are specifically mentioned. Unit dosage forms of about 25 mg to about 1 gram are described, with specific reference to dosage forms of about 20 mg to about 60 mg.

[0095] It will be understood that the actual preferred amount of active composition in any particular case will vary according to the particular composition being utilized, the particular composition formulated, the mode of application, and the particular location and organism being treated. The dosage for a given host can be determined using conventional considerations, for example, by an appropriate, conventional pharmacological protocol, for example, by routine comparison of the differential activities of the subject composition and known agents.

[0096] As used herein, the term "effective amount" or "therapeutically effective amount" is broadly understood to encompass both a sufficient amount of at least one agent being administered to achieve a desired result, e.g., to some extent alleviate one or more symptoms of the disease or condition being treated, as well as a sufficient amount of at least one agent being administered to prevent the onset of one or more symptoms of the disease or condition being treated (a prophylactically effective amount). In certain cases, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In certain cases, an "effective amount" for therapeutic use is the amount of a composition comprising an agent as described herein required to provide a clinically significant reduction in disease. The appropriate "effective" amount in any individual case will be determined using any suitable technique, such as a dose escalation study. The term "prophylactic" or "prevention" means preventing or reducing the likelihood of a disease, condition, or event occurring. A treatment is considered therapeutically prophylactic if the subject is asymptomatic for at least about 30 days or there is at least about a 50% reduction in incidence over a 30-day period compared to the incidence before treatment. <Additional Notes> Aspects of the present invention include the following. <Section 1> A method for treating cardiac dysfunction, comprising administering to a subject in need thereof a therapeutically effective amount of at least one of ANAVEX 2-73 or ANAVEX 19-144, or a pharmaceutically acceptable salt thereof, or a combination thereof. <Section 2> Item 1. The method according to item 1, wherein the cardiac dysfunction is selected from the group comprising cardiac arrest-related dysfunction including cardiac arrhythmia, premature ventricular contraction (PVC)-induced left ventricular dysfunction, atrial fibrillation, atrial flutter, inducible left ventricular dysfunction, ventricular arrhythmia including ventricular tachycardia and fibrillation, and combinations thereof. <Section 3> Item 10. The method according to Item 1, wherein the cardiac dysfunction is ventricular arrhythmia. <Section 4> Item 10. The method according to Item 1, wherein the cardiac dysfunction is atrial arrhythmia. <Section 5> Item 10. The method according to item 1, wherein the administration to the subject is a daily therapeutically effective amount of ANAVEX 2-73. <Section 6> Item 6. The method according to Item 5, wherein the therapeutically effective amount is about 20 to about 60 mg when administered orally. <Section 7> Item 7. The method of item 6, wherein the therapeutically effective amount is a dose of about 20 mg twice a day. <Section 8> Item 7. The method according to Item 6, wherein the therapeutically effective amount is a dose of about 30 mg twice a day. <Section 9> Item 7. The method of item 6, wherein the therapeutically effective amount is administered as a single daily dose of about 60 ml. <Section 10> Item 6. The method according to Item 5, wherein the therapeutically effective amount is about 6 to about 17 mg when administered intravenously. <Section 11> Item 1, wherein the amount administered to the subject is a therapeutically effective amount of ANAVEX19-144. <Section 12> Item 12. The method according to Item 11, wherein the therapeutically effective amount is about 20 to about 60 mg when administered orally. <Section 13> Item 13. The method of item 12, wherein the therapeutically effective amount is a dose of 20 mg twice daily. <Section 14> Item 13. The method of item 12, wherein the therapeutically effective amount is a dose of 30 mg twice a day. <Section 15> 13. The method of claim 12, wherein the therapeutically effective amount is administered as a once-daily dose of about 60 mg. <Section 16> Item 12. The method according to Item 11, wherein the therapeutically effective amount is about 6 to about 17 mg when administered intravenously.

Claims

1. 1. A unit dosage form for use in shortening the QT interval, comprising a therapeutically effective amount of 1 mg to 100 mg of an active substance comprising 1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine hydrochloride (ANAVEX2-73) or 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (ANAVEX19-144) or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier, The unit dosage form, wherein the QT interval is shortened by about 10 ms or about 2% to about 3% after administration of the unit dosage form relative to the QT interval before administration.

2. 10. The unit dosage form of claim 1, wherein the QT interval is associated with cardiac arrhythmia, ventricular arrhythmia, ventricular tachycardia, torsades de pointes, ventricular fibrillation, or any combination thereof.

3. 3. The unit dosage form of claim 2, wherein the QT interval is associated with ventricular arrhythmia.

4. 3. The unit dosage form of claim 2, wherein the QT interval is associated with ventricular tachycardia.

5. 3. The unit dosage form of claim 2, wherein the QT interval is associated with ventricular fibrillation.

6. 2. The unit dosage form of claim 1, wherein the amount of ANAVEX 2-73 for oral administration is 20 mg to 60 mg.

7. 7. The unit dosage form of claim 6, wherein the oral administration is oral administration at a dose of 20 mg twice daily.

8. 7. The unit dosage form of claim 6, wherein the oral administration is oral administration at a dose of 30 mg twice daily.

9. 7. The unit dosage form of claim 6, wherein the oral dose is 60 mg once daily orally.

10. 2. The unit dosage form of claim 1, wherein the amount of ANAVEX 2-73 for intravenous administration is 6 mg to 17 mg.

11. 2. The unit dosage form of claim 1, wherein the amount of ANAVEX 19-144 for oral administration is 20 mg to 60 mg.

12. 12. The unit dosage form of claim 11, wherein the oral administration is oral administration at a dose of 20 mg twice daily.

13. 12. The unit dosage form of claim 11, wherein the oral administration is oral administration at a dose of 30 mg twice daily.

14. 12. The unit dosage form of claim 11, wherein the oral dose is 60 mg once daily orally.

15. 2. The unit dosage form of claim 1, wherein the amount of ANAVEX 19-144 for intravenous administration is 6 mg to 17 mg.

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