International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 - No. 612011 (353-365)

The influence of propiverine hydrochloride on cardiac repolarization in healthy women and cardiac male patients

Original F. Donathl, M. Braeter2 and C. Feustel2

©2011 Dusbi-Vertag Dr. K. Feistle ISSN 0946-1965 1 Socra Tee R & D GmbH, Erfurt, and 2APOGEPHA Arzneimittel GmbH, Dresden, DOI10.5414/CP201443 Germany

Keywords Abstract. Objective: Two comprehen­ gation of QTc as a sign of delayed ventricular propiverine - cardiac sively designed mono-centric ECG studies repolarization; it is thus potentially associated repolarization - torsades were performed to investigate the influence de pointes - drug safety with increased risk of cardiac rhythm distur­ of propiverine hydrochloride and its main me­ - QTc-prolongation tabolite propiverine-N-oxide on cardiac func­ bances such as "torsades de pointes". tion with regard to QTc prolongation, QTc dis­ Examples of drugs which pose a sub­ persion and T-wave shape. Methods: The first stantial clinical risk to provoke ventricular study was conducted on 24 healthy females, arrhythmias arise independently on pharma­ followed by a second study on 24 male pa­ cological classes: sertindole, pimozide, halo­ tients with coronary heart disease (CHD)and a peridole, terfenadine, astemizole, cisapride, pathological Pardee-Q-wave in the ECG. Both studies were placebo-controlled and compared halofantrine, erythromycin, sparftoxacin and the effects of single (30 mg s.i.d.) and multiple some other non-cardiac drugs have been cor­ dosing (15 mg t.i.d.) of pro piverine hydrochlo­ related with the ability to prolong ventricu­ ride in a crossover design over 6 and 13 days, lar repolarization [1]. In 1997 the European respectively. In CHD patients, the ECG was Age Y for the Evaluation of Medicinal recorded under standardized exercise stress nii conditions. Results: An effect of propiverine Products (EMEA) consequently issued a on cardiac safety in healthy women and male "Points to Consider" document addressing patients with CHD could not be determined rigorous preclinical and clinical testing of by the evaluation of QTc intervals derived new chemical entities to identify cardiac re­ from ECG under the following conditions: polarization delay and to ensure safe clinical (1) single dosage; (2) steady-state and el­ usage [2]. In 2001 the Health Canada pub­ evated dosage; (3) healthy female volun­ teers and male CHD patients; (4) resting and lished the "Therapeutic Products Director­ stress conditions in CHD patients. Moreover, ate Guidance Document for assessment of other ECG parameters like QT dispersion, the QT prolongation potential of non-anti­ T-wave shape, and U-wave occurrence were arrhythmic drugs" [3] which served as the not affected by propiverine compared to pla­ basis for the ICH guideline E14 [4]. cebo after single or repeated dosing to reach steady-state conditions. Conclusion: These Propiverine hydrochloride (in the follow­ results reflect and confirm preclinical data as ing referred to as propiverine) is an anticho­ well as clinical observations on hundreds of linergic and spasmolytic drug for the symp­ volunteers and numberless patients suffer­ tomatic treatment of urinary incontinence ing from overactive bladder syndrome and when accompanied by symptoms of urgency neurogenic detrusor overactivity who were Received and frequency as may occur in patients with April 19, 2010; treated with propiverine hydrochloride over overactive bladder or neurogenic detrusor accepted nearly three decades in Europe and Japan. January 22,2011 overactivity. It has been used in this indi­ cation for nearly three decades [5]. Among Correspondence to others, anticholinergic drugs are thought to Dr. C. Feustel Introduction APOGEPHAArznei­ cause arrhythmic events in humans. In the mittel GmbH, Clinical QT prolongation is a risk factor for ven­ early 1990s, Terodiline, a drug of this class, Research & Develop­ tricular arrhythmias not only in patients suf­ was withdrawn from the market after only ment, KyffhauserstraP..e fering from cardiovascular conditions, but 5 years because of reported conduction dis­ 27,01309 Dresden, Germany also in otherwise healthy individuals. For turbances, QT prolongation and "torsades de [email protected] years much attention was given to the pro lon- pointes" [6, 7]. Donath, Braeter and Feustel 354

Although propiverine has never been Study 11 directly associated with cases of cardiac ar­ rhythmia [5],propiverine blocks the human Double blind,randomized, placebo-con­ ether-a-go-go-related gene (hERG) channels trolled,two-way crossover study in high-risk in vitro that conduct the rapid component of cardiac male patients to assess the effects of the delayed rectifier K+ current IKr [8]. De­ propiverine and its main metabolite propiv­ spite the action potential duration in several erine-N-oxide on cardiac safety after single in-vitro models is rather shortened by propiv­ and multiple dosing under resting and stress erine, an influence on action potential dura­ conditions tion and on the refractory period of the human Both study protocols were approved by myocardium under clinical conditions can the Ethics Committee of the State Pharmaco­ thus not be excluded. In accordance with the logical Center of the Ukrainian Ministry of "Therapeutic Products Directorate Guidance Health in Kiev,Ukraine. Document" [3] and before the guideline E14 [4] came into operation,two comprehensive ECG studies were conducted consecutively Methods to determine the influence of propiverine on human cardiac function and to answer the Study I question of whether propiverine influences The single center 2-way crossover study repolarization processes in humans. was conducted on healthy females,the most Gender-specific differences in the cor­ susceptible population for developing ar­ rected QT interval have been reported since rhythmias [15]. 24 Caucasians aged 40 - 65 Bazett's initial description in the 1920s [9]. years were informed in detail about the study Several studies suggest that women are and signed a written consent before starting more susceptible than men to develop "tor­ study procedures. Females suffering from sades de pointes" during the administration relevant diseases,particularly of the cardiac of drugs that prolong cardiac repolarization system, or from congenital long QT syn­ (for review see: [10]). Based on these stud­ drome, or demonstrating QTc time above ies and following the recommendations of 450 ms at screening (corrected with Bazett the "Therapeutic Products Directorate Guid­ formula), or with pathological potassium ance Document for assessment of the QT levels were not included in the study. prolongation potential of non-anti arrhythmic Since no reliable information on variabil­ drugs" [3] the first of the two studies was ity was available at time of trial planning,the conducted on healthy women. standard deviation for the intra-subject dif­ One of the predisposing factors for sec­ ference between drug and placebo (SDdiff) of ondary forms of QT prolongation can be at­ the maximum increase of QTc was assumed tributed to coronary heart disease manifested to be in the range of 2D - 30 ms as a conser­ by myocardial ischemia or infarction [11, vative approach. 24 subjects were chosen as 12]. A consecutive study was thus planned sample size in order to be able to detect a dif­ in male cardiac post-infarct patients with in­ ference of about 15 ms (with an SDdiffOf 25 creased risk for the development of rhythm ms) with significance level a = 5% (2-sided) disturbances [3,13, 14]. and a power of 80%.

Study objectives Study conduct

Study I After thorough screening procedures and confirmation of eligibility, volunteers were Double blind,randomized, placebo-con­ placed randomly into one of two treatment trolled, 2-way crossover study on healthy groups,starting either with placebo or with women to assess the effects of propiverine propiverine in the first treatment period and (P4) and its main metabolite propiverine-N­ vice versa in the second treatment period. oxide (P4NO) on cardiac safety after single The evening before treatment (Day -1) and and multiple dosing under resting conditions on Days 5 and 12 of both periods,the volun- Propiverine hydrochloride and cardiac safety in humans 355 teers were admitted to the clinical pharma­ QT. The QT interval was corrected for heart cology unit (CPU) for 36 consecutive hours. rate according to Bazett [9]: The wash-out period between treatments lasted 2 weeks and the follow-up phase after QTobserved (sec) QTcorrected = -r::3��7=::::::=-";" the second treatment period was 7 days. .j60jRR(sec) . After overnight fasting. volunteers were administered 2 tablets orally next morning The positions of the electrodes on the skin which corresponded to either a single dose were marked to ensure identical placement of 30 mg propiverine or to placebo. Pharma­ in both study periods. During the 24 h post­ cokinetic blood samples (PK sampling) were dose interval, the ECG was recorded while taken at regular intervals over the next 24 h. subjects remained in supine position. ECGs On the following 4 consecutive days, all were evaluated twice by two independent 15 volunteers received mg propiverine t.i.d. cardiologists in a blinded manner. The first 2 - 5 The morning doses of Days were ad­ assessor and co-investigator also screened ministered in the CPU. The noon and eve­ and assessed the ECG from a clinical point ning doses of these days were taken by the of view in a blinded manner. subject at home. Intake was monitored by phone. Afterreadmission and overnight fast­ 30 ing, the volunteers received mg propiv­ Blood sampling erine the morning of Day 6. Plasma concen­ trations were recorded for the next 24 h by Pharmacokinetic blood samples for deter­ PK-sampling. mination of propiveri ne (P4) and its main me­ tabolite propiverine-N-oxide (P4NO) were collected in parallel with blood samples for Selection of doses determination of potassium concentration immediately following each ECG record. Se­ The recommended daily dose for adults rum levels of P4 and P4NO were determined is 15 mg propiverine immediate release (IR) using a validated HPLC method [19]. 2 times daily, which can be increased to 3 times daily (t.i.d.), or 30 mg extended release (ER) once a day [16, 1 7]. In order to follow Safety assessments the most sensitive approach for investigating cardiac safety of propiverine in this study, All adverse events (AE) during the study the volunteers received the highest recom­ were rated regarding onset, end, severity, seri­ mended dose: 30 mg (2 tablets propiverine ousness, relationship to the study medication, IR) as single dose when starting treatment outcome and actions taken. Safety laboratory and, for repeated dosing, 15 mg t.i.d. over 4 examinations were performed before, during days. and after the end of study conduct.

ECG measurement Statistical analysis

For pharmacodynamic assessments the The following descriptive statistics were ECG was performed on Days 1, 6 and 13 of calculated for ECG intervals, PQ, QRS, each period, starting before daily treatment. QT, QTc for heart rate and QT dispersion: Additionally, 2, 4, 6, 8, 10, 12, 16 and 24 h n (number of non-missing values), arithme­ after the morning dose of propiverine or pla­ tic mean, standard deviation and minimum, cebo (Days 1 and 6) or for equivalent time maximum, median. Additionally, differences points on Day 13, ECGs were recorded us­ to baseline were considered. Baseline was ing the internationally recognized 12 leads defined as mean of measurements on Day -1 [18]. Standard ECGs were printed at 25 and Day 1 (pre-dose) in each period. mmls using the Vetter-PC-ECG-ergo-system The following parameters were derived (Dr. Vetter GmbH, Baden-Baden, Germany). for QTc interval: Heart rate (HR) and the following ECG in­ Maximum increase: post-dose maximum tervals were determined: RR, PQ, QRS and (2 - 12 h) value minus baseline Donath, Braeter and Feustel 356

Maximum value: post-dose maxImum Table 1. Ratings of OTc post dose values. value during ECG profile (2 12 h) - Mean value: mean QTc interval of ECG Maximum value Maximum increase profile on therapy (2 - 12 h) Normal <450 msec < 30 msec Baseline: mean measurements on Day -l Borderline 450 - 470 msec 30-60 msec

and Day 1 (pre-dose) Prolonged >470 msec > 60 msec

Two separate ratings of QTc post-dose The primary aim of this study was to maximum value and maximum increase dur­ demonstrate that compared to placebo, re­ ing ECG profile were determined as shown peated dosing of pro piverine does not signif­ in Table 1. icantly increase the QTc interval in patients Frequency tables for the rating of QTc with high cardiac risk. For study inclusion maximum and maximum increase and for patients had to meet all of the following re­ T-wave shape and V-wave occurrence were quirements: provided. The QTc parameters maximum in­ Male Caucasians aged;::: 45 years crease, AVCo_1b maximum and mean value - Written informed consent were submitted to separate analysis of vari­ - Pathological Q wave in at least 1 of the ance including sequence, subject (sequence), 12 standard ECG leads period and treatment as class effects. Point - Ability to perform a standard exercise estimates and 95% confidenceintervals were test on a bicycle constructed for the difference "propiverine minus placebo" using the residual variance. In Study I in healthy women the stan­ Distributional assumptions of analysis-of­ dard deviation for the intra-subject differ­ variance were checked by inspection of re­ ence between drug and placebo (SDdiff) of sidual plots of studentized residuals versus the maximum increase in QTc was found as normal order scores to check normality and about 15 ms after repeated dosing (and only studentized residuals versus predicted values 7 ms after single dosing). But since patients to check homogeneity of variance. with an increased cardiac risk were to be The following parameters were derived included, the SDdiff was assumed to be up to about 30 ms as a conservative approach. from QT-dispersion: From the clinical point of view, differences Maximum increase: post-dose maximum between the drug and placebo below 30 ms (2 - 12 h) value minus pre-dose were considered as equivalent. Taking into Maximum decrease: pre-dose minus account that the true difference could be up post-dose minimum value (2 - 12 h) to 5 ms, sample size calculation yielded a number of 18 patients with significance lev­ el a = 2.5% (l-sided).and a power of 90%. Study // 24 patients were included in the trial to take After finishing and reporting Study I account for dropouts. the following single center 2-way crossover study was performed in 24 male patients Study conduct with coronary heart disease (CHD) and with a pathological Pardee wave in the ECG indi­ The patients were confined from the cating a previous myocardial infarction. morning of Day -1 until the afternoon of As a QTc prolongation induced by pro­ Day 2, from the evening of Day 13 until the piverine or its metabolites may only be ob­ afternoon of Day 15, and additionally from served at higher heart rates and/or in patients the evening of Day .20 until the afternoon suffering from CHD, the study was per­ of Day 22 of each period. A follow-up visit formed on post-infarct patients with CHD took place on Day 22 of the second treat­ and pathological Q-wave (Pardee wave at ment period. least in one of the ECG leads) under resting In the morning of Days 1 and 14 patients as well as under standardized exercise stress received 30 mg propiverine or placebo, and conditions. from Days 2 - 13 three times daily 15 mg Propiverine hydrochloride and cardiac safety in humans 357 propiverine or placebo. Basic medication and placebo administration, respectively, as for the treatment of CHD or associated risk defined above. Increases in QTc intervals up factors (e.g. hyperlipoproteinemia, diabetes to 30 msec were generaily considered as nor­ mellitus, and hypertension) was continued mal [14]. throughout the study. Drugs which could Secondary endpoints were: maximum in­ prolong the QT interval were not permitted. crease in QTc interval (0 - 12 h post dosing) ECG recording under resting conditions on Day 1 at rest; AUCO-I2, maximum value, and blood sampling were performed at Days mean value in QTc interval on Days 1, 14 1, 14 and 21 ( during washout) of each study and 21 at rest; QTc minimum value at rest; period in the same manner as in the first QTc maximum value at rest; QTc interval study. Additionally, on these days an ECG at the maximum workload (exercise ECG); under stress conditions was performed 8 h plasma concentrations of propiverine and after the administration of study medication. propiverine-N-oxide; plasma concentrations On Days 7, 9, 11 and 13 of each treatment for potassium; shape of T-wave; occurrence period trough levels of pro piverine were col­ of U-wave. lected to verify the correct intake of study The handling of samples and the record­ medication. ing of adverse events were comparable to the procedures as described above for Study 1.

Exercise ECG Statistical analysis A 12-lead ECG was recorded under stan­ dardized stress conditions with the patients For statistical analysis, nearly the same on an ergometric bicycle. The procedure methods were applied as described for Study started with an ECG under resting conditions 1. The QTc interval at the maximum work­ after at least 5 min in sitting position. After­ load on Days 1, 14 and 21 was submitted to wards, load steps were increased every 3 min separ�te analysis of variance in order to as­ in intervals of 25 Watt starting with 50 Watt sess the effect of propiverine under exercise until an individual maximum heart rate was conditions. achieved. The individual maximum heart rate was defined in beats per minute (bpm) as 200 minus the age of the patient. ECG and Results blood pressure were recorded during the last minute of each load step. 2 and 3 min after 24 female subjects took part in Study I termination of maximum load, an ECG un­ and finished the study according to protocol. der resting conditions was recorded to docu­ 24 male post-infarct patients with CHD ment the patient's recovery. For the ECG took part in Study 11, 23 of them completed under stress conditions, pre-defined criteria the study according to protocol. One patient for termination included reaching maximum terminated the study prematurely due to a pulse rate, exhaustion or angina pectoris. serious adverse event (placebo arm). Demo­ graphic data of all volunteers are displayed in Table 2.. Primary endpoint

The primary endpoint of this study was Maximum increase of QTc (msec) defined as the maximum increase in QTc in­ terval: post-dose maximum of QTc on Day Table 3 shows descriptive statistics con­ 14 minus baseline (mean of Day -1 and Day cerning the maximum increase of QTc up to 1 with regard to 12-lead ECG at rest). 12 h after dosing in comparison with placebo The following hypotheses were tested: in healthy women. Over the whole observa­ Ho: Ilprop - /lplac :::::: 30 msec versus HI: tional period, and independently from the Ilprop - /lplac < 30 msec, mode of study medication administration, where Ilprop and /lplac corresponded to the maximum increase of QTc differed sta­ the true maximum increase in QTc interval tistically not significant between treatments. at rest between 0 and 12 h after propiverine In contrast, a slight tendency for decrease of Donath, Braeter and Feustel 358

< Occurrence of U-waves t�ble2.>Main dem�graphic data for both studies (AM/SD*(range». No V-waves occurred in the ECG in healthy women. At screening, 19 cardiac patients showed a V-wave in the ECG under resting condi­ tions, 9 patients showed a V-wave at all time *AM:;; arithmetic mean; SD = standard deviation. points for the duration of study. V-waves occurred at several time points with compa­ rable frequencies under propiverine and pla­ maximum increase of QTc under propiverine cebo treatment in 11 patients. could be observed. This tendency increased after single-dose administration of propiver­ ine in cardiac patients (Table 4) and tapered QT dispersion maximum increase off aftermultiple dosing of propiverine. Nev­ ertheless, a statistically significantdifference QT dispersion was assessed in healthy between treatments could not be observed. women only (Study I). Table 7 shows descrip­ Based on this exploratory analysis it can tive statistics for the QT dispersion maximum be concluded that propiverine neither af­ increase from2 to 12 h after dosing. ter single nor after repeated administration An effect of propiverine on the maximum leads to a prolongation of the QTc interval increase of QT dispersion was not indicated in healthy women and male cardiac patients. by statistical analysis. A further analysis of the maximum decrease of QT dispersion also revealed no differences between treatments. QTc maximum value

Table 5 and Table 6 show descriptive sta­ Exercise ECG tistics for the QTc maximum values during the post-dose interval 2 - 12 h aftertreatment Table 8 displays the effects of propiver­ with propiverine or placebo in healthy wom­ ine or placebo on QTc interval at maximum en and in male cardiac patients respectively. workload in cardiac patients under stress con­ A relevant effect of propiverine on the ditions (Study n only). Maximum workload maximum value of QTc interval in healthy fe­ was reached 8 h after single dose of 30 mg males as well as in cardiac patients was not de­ propiverine after 125 W (4 patients), 100 W termined by the descriptive statistical analysis. (7 patients), 75 W (9 patients) or 50 W (3 pa­ tients). Similar responses were observed in all other exercises. Shape of T-wave An effect of propiverine on QTc interval at maximum workload was not determined In all healthy female volunteers no ab­ by statistical analysis. normal T-waves were detected at any point of assessment. In Study n, except for 1 subject, all ECGs Central QTc tendency showed abnormal T-waves at every point of measurement during study including screen­ Figure 1 displays the central tendency of ing. At screening and pre-dose in the ECG QTc development over time in healthy wom­ negative, isoelectric, diphasic and coronaric en after administration of propiverine and T-waves occurred. The frequencies of change placebo respectively. In healthy women the in T-wave shapes related to the screening baseline before single dose administration and pre-dose findings appear comparable af­ of placebo as well as of propiverine seems ter the different treatments with placebo or to be lower compared to baselines at mul­ propiverine. tiple dose and washout. No difference could be determined when comparing placebo to propiverine under the respective administra­ tion conditions. Propiverine hydrochloride and cardiac safety in humans 359

3. Table Maximum increase of OTc (msec) in healthy women (AM/SD.(range)) and mean differe!lc��·. propiverine minus placebo (AM (2-sided CI))*.

*AM =arithmetic mean; SO =stand ard deviation; Cl = confidence interval.

Table 4. Maximum increase of OTc (msec) in male cardiac patients (AM/SO (range)) and mean differ­ ences propiverine minus placebo (AM (1-sided CI))*.

*AM = arithmetic mean; SO = standard deviation; Cl = confidence interval.

Table 5. Maximum values of OTc·(msec) in healthy women (AM/SO (range)) and mean differences propiverine minus placebo (AM (2-sided CI))*.

*AM =arithmetic mean; SO =standard deviation; Cl = confidence interval.

Table 6. Maximum values of OTc (msec) in male cardiac patients (AM/SO (range)) and mean differ­ ences propiverine minus placebo (AM (one-sided CI))*.

*AM =arithmetic mean; SO = standard deviation; Cl = confidence interval.

Table7. OT dispersion (m sec) in healthy women (AM/SO (range)) and mean differences propiverine minus placebo (AM (2-sided CI))*.

*AM =.arithmetic mean; SO �=standard d€lviation; Cl =confidence interval.

Table 8. OTc intervals (msec) at maximum workload in male cardiac patients (AM/SO (range)) and mean differences propiverine minus placebo (AM (1-sided CI))*.

*AM = arithmetic mean; SO =standard deviation; Cl = confidence interval. Donath, Braeter and Feustel 360

460 -- PRO - single dose 460 -- PRO - repeated dose 'go 'go U) 455 U) 455 ....., .... PRO - washout .§. .§.450 450 C,) �C,) 445 � 445 -- PRO - Single dose c 440 m 440 III -- PRO - repeated dose E E 435 435 ....., .... PRO - washout 430 430 j j j j j I I j j j j j I I o 2 4 6 8 10 12 o 2 4 6 8 10 12 time afteradministration [hours] time afteradministration [hours] 460 460 -0- PLA - single dose 'go -&- PLA - repeated dose I455 U) 455 .§. ....,.,. ... PLA - washout .§.450 450 C,) �C,) 445 � 445

______-0- PLA - single dose c �------t-:.-_ !-_ .PJ::__� III 440 � m 440 -&- PLA - repeated dose E E 435 435 ....,.,. ... PLA - washout 430 430 j j j j j I I j j j j j I I o 2 4 6 8 10 12 o 2 4 6 8 10 12 time after administration [hours] time afteradministration [hours]

Figure 1. Central tendency of QTc after adminis­ Figure 2. Central tendency of QTc after adminis­ tration of propiverine (upper diagram, PRO) or pla­ tration of propiverine (upper diagram, PRO) or pla­ cebo (lower diagram, PLA) in male cardiac pa­ cebo (lower diagram, PLA) in healthy women. tients.

Figure 2 displays the central tendency for [20, 21]. Mean terminal half-life after single QTc development over time in male cardiac dose were found to be 18.0 h for propiverine patients after administration of propiverine and 9.1 h for P4NO, after repeated dosing and placebo respectively. Summarizing the 18.6 h for propiverine and 12.1 h for P4NO, data, differences in QTc tendency between respectively. propiverine and placebo could not be deter­ The maximum plasma concentration of mined. propiverine and P4NO after administration of a single dose of 30 mg propiverine in male cardiac patients were slightly increased Potassium serum concentration compared to healthy females. Mean terminal half life after single dose was found to be In both studies the concentration-time 13.8 h for propiverine.and 9.0 h for P4NO, curves for potassium were similar after the after repeated dosing 17.4 h for propiverine different treatments. All measured values and 13.3 h for P4NO, respectively. were within normal ranges. No effect of The corresponding PK parameters and propiverine on the potassium concentration descriptive statistics are listed in Table 9. in healthy women or in male cardiac patients could be determined. Adverseevents

Pharmacokinetic parameters In total, 11124 female subjects reported 29 adverse events (10 with propiverine, 1 with The maximum plasma concentration of placebo). All of them were treatment emer­ both propiverine and propiverine-N-oxide gent and non-serious (25 of mild intensity, (P4NO) in healthy women after administra­ 4 of moderate intensity). Blurred vision, dry tion of a single dose of 30 mg propiverine mouth or nausea were most frequently re­ as well as after repeated dosing of 15 mg ported. propiverine t.i.d. was comparable to those During the study on male cardiac pa­ found in other studies on healthy volunteers tients 88 adverse events (56 with propiver- Propiverine hydrochloride and cardiac safety in humans 361

Table 9. Descriptive statistics for PK parameters obtained from Study I and Study 11 (extract).

ine, 23 with placebo, 9 prior to medication) linergics like terodiline [6, 7, 27] can cause were reported. Except for 1 case of angina polymorphic ventricular arrhythmias like pectoris, all AEs were non-serious. This "torsades de pointes" by blocking IKr. In a SAE in a placebo-treated patient was judged previously performed multicenter study, el­ as "unlikely related" to study medication. 21 derly patients with detrusor overactivity but adverse events were of severe intensity, but no signs for cardiac dysfunction were given all of them were assessed as "unrelated" to 45 nfg propiverine daily for 4 weeks. At the the study medication. The most frequent AE end of treatment no evidence for the develop­ was dry mouth, complained in 70% under ment of QT prolongation was detected [28]. propiverine and 33% under placebo. Compared to placebo, differences in heart rate or in parameters characterizing conduc­ tion processes were not observed. In another Discussion previously performed study, patients with symptoms of overactive bladder were treated Nowadays the regulatory authorities ex­ over 4 weeks with 30 mg propiverine (im­ pect in almost all drugs at least one clinical mediate- or extended-release) daily, or with pharmacology study assessing a medica­ placebo (395, 391 and 202 patients) [29]. tion's effect on the ECG, even when non­ The study demonstrated neither evidence for clinical safety pharmacology studies, which QTc-prolongation nor for significant changes also assess the potential for delayed ventric­ from baseline in the QTc (Bazett) interval in ular repolarization, do not provide cause for all three treatment groups (mean (SD): 0.3 concern [22]. (23.3), -0.8 (22.5) and 0.1 (22.4) ms; cor­ The main mechanism of propiverine ef­ responding p-values: 0.80, 0.49 and 0.95 fects on the bladder is based on muscarinic (paired t-test)). acetylcholine receptor antagonism which Anticholinergics, however, have been may involve calcium and potassium chan­ proven to increase heart rate by blocking the nels in smooth muscle cells. Furthermore, parasympathetic innervation of the heart. In­ direct inhibition of L-Type Ca2+ currents creased heart rate seems to be correlated with in the urinary bladder may occur [23, 24, an increased risk of morbidity and mortality 25, 26] and thereby relax smooth muscles. [30, 31]. Terodiline is the only anticholin­ As a consequence of the channel-blocking ergic substance with a "torsade de points" properties of propiverine, an influence on potential reported so far [32, 33, 34, 35]. the cardiac repolarization may be expected. In a recently published study, Japanese pa­ Moreover, it has been suggested that anticho- tients suffering from overactive bladder were Donath, Braeter and Feustel 362 treated over 12 weeks with propiverine, imi­ (over post-dose assessment up to 12 h), rat­ dafenacin or placebo. A significant increase ing of QTc maximum interval, T-wave shape, in the mean QTc by 7.56 ± 20.08 ms under U-wave occurrence under resting conditions propiverine (20 mg s.i.d.) and -l.35 ± 19.29 or QTc interval at the maximum workload in ms in the placebo group was reported, but no CHD patients. clinical signs of arrhythmia or arrhythmic In both study populations the actual events [36]. Maximal value in the QTc inter­ standard deviation for the intra-subject dif­ val in the propiverine group was 486.6 ms. ference between drug and placebo (SDdiff) Since the heart rate was slightly increased by of the maximum increase in QTc was found propiverine (4.4 ± 9.2 bpm, placebo: -1.0 ± much smaller than anticipated at the plan­ 9.2 bpm), this result may rather be attributed ning stages with SDdiff of about 7 ms after to the QTc correction procedure as discussed single dosing in both trials, and SDdiff of 12 below. 15 ms after repeated dosing. In 2002, the two ECG studies were per­ According to the current ICH guideline formed to investigate the influence of propiv­ E14 the upper bound of the 95% I-sided con­ erine and its main metabolite propiverine-N­ fidence interval for the difference between oxide on cardiac functionwith special regard drug and placebo should exclude 10 ms in to QTc prolongation, QTc dispersion and T­ order to allow for concluding that the drug wave shape. has no relevant effect. Thus, 10 ms may also In the first study, female volunteers re­ be considered as the acceptable equivalence ceived in each of the two treatment periods boundary to be applied for these trials. A-pos­ propiverine or placebo as previously de­ teriori power considerations based on the ob­ scribed in detail. The resulting plasma con­ served maximum SDdiff of 15 ms resulted in centrations of pro piverine and P4NO and the 22 subjects that would have been required for extent of exposure were comparable with the cross-over trialto demonstrate "no effect" other existing data for young healthy volun­ even with 90% power. In consequence, since teers receiving propiverine as single dose or at least 22 subjects were included in each of under steady-state conditions [20, 21]. the QTc analyses, both trials can be consid­ In the second study, male. cardiac patients ered as sufficiently powered and the results received in each of the two treatment peri­ can be regarded as highly reliable and cred­ ods propiverine or placebo in the previous ible also in context of the requirements of the described manner. The resulting plasma con­ current guideline. centrations of propiveri ne, P4NO and the ex­ Despite the fact that these studies were tent of exposure were slightly increased when planned and conducted before the ICH compared to those of healthy women after a guideline E 14 came into operation, the stud­ single dose of 30 mg propiverine as well as ies were performed according to recommen­ under steady-state conditions (15 mg propiv­ dations existing at this time. Moreover, some erine t.i.d.). The concentrations were found to criteria, differing from the actual recom­ be in the range of exposure for patients with mendations described by ICHEI4, tend to impaired hepatic or renal function [37, 38]. overestimate the potential risk of QTc pro­ Furthermore, in both studies concentra­ longation caused by drug treatment. First, tion-time curves for potassium were similar it is currently recommended to assess the after propiverine or placebo treatment. As ECG automatically rather than manually or changes in electrolytes can be a confounder by both methods. Depending on the condi­ for development of torsades de points the in­ tions of the particular investigation, each fluence on drugs on these parameters may be procedure has advantages. In the cardiac a predictor for the drug-related potential to patient population displaying a pathological provoke such hazardous sensations [39]. ECG pattern with altered T-wave morphol­ Neither the study on healthy women nor the ogy the manual assessment of ECG has clear study on CHD-patients provided any evidence advantages [40]. In addition, the application for effects of propiverine on the ECG. There of different automated measurement devices were no differences apparent between propiv­ requires careful standardization [41]. erine and placebo with regard to post-dose Second, the application of any procedure maximum of QTc, QTcAUCO-I2, average QTc which corrects the frequency-dependent Propiverine hydrochloride and cardiac safety in humans 363 changes of QT may lead to overcorrection. ditions when compared to placebo. Repeated In particular, Bazett's formulafor frequency­ high doses of propiverine neither prolonged based correction of QT leads to an overcor­ the QTc interval nor affected other ECG pa­ rection at elevated heart rates resulting in rameters like QT dispersion, T-wave shape, longer QTc intervals [42, 43, 44, 45]. Hence, and U-wave occurrence. Potassium levels the applicatioI1QLth�Ba:(:ett's formllla in appeared unaffected by treatment. such cases produces rather false positive than Propiverine was tolerated well with re­ false negative results [46]. To avoid inciden­ spect to adverse events, clinical laboratory, tal findings, the two studies were designed in and vital signs. a cross-over manner and the QT/QTc inter­ These results confirm nearly three de­ vals were compared intra-individually. cades of clinical observations on the effects Another aspect, described in the above of propiverine hydrochloride in tht; treat­ mentioned guideline, which has not been ment of patients of both genders and of all considered for these studies, was a positive age groups suffering from overactive blad­ control group. The disadvantage due to the der and urinary incontinence in Europe and absence of a positive control like moxifloxa­ Japan. cine is partly compensated by the cross-over design of these two studies and the placebo controlled mono-centric setting. Addition­ Acknowledgments ally, in the study on cardiac patients physical exercise under tightly controlled conditions S. Biletsky, K. Eckl, N. Tsvitbaum and L.P. Sydorchuk (Chemivtsi, Ukraine) are can serve as a positive control for QT-prolon­ highly acknowledged for their contribution gation [47, 48]. to plan and conduct the clinical trials. The results of these two studies reflect F. Schnabel (Dresden, Germany) provid­ recent preclinical findings: even though ed additional data analysis and graphics. propiverine and some of its metabolites Jhe authors also thank T. Christ (Dres­ block in a concentration-dependent manner den; Germany) for helpful discussions dur­ hERG channels expressed in HEK293 cells ing the evaluation of the studies and prepara­ and native IK current in ventricular myo­ tion of the manuscript. cytes of guinea pigs and Ica,L in human atrial myocytes, the action potential duration was not prolonged in guinea-pig and human ven­ tricular tissue [8]. Similar effects were ob­ References served in dog Purkinje fibres. Obviously, the [I] Carlsson L. 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