Br HeartJ7 1995;74:53-56
`
`53
`
`Concentration dependent cardiotoxicity of
`terodiline in patients treated for urinary
`incontinence
`
`Simon H L Thomas, P Daniel Higham, Kenneth Hartigan-Go, Farhad Kamali,
`Peter Wood, Ronald W F Campbell, Gary A Ford
`
`Abstract
`Objective-Terodiline, an antimuscarinic
`and calcium antagonist drug, was used to
`treat detrusor instability but was with-
`drawn in 1991 after provoking serious
`ventricular arrhythmias associated with
`increases in the corrected QT interval
`(QTc). This research was performed to
`relate drug induced electrocardiographic
`changes in asymptomatic recipients to
`plasma concentrations of the R( +) and
`S(-) terodiline enantiomers.
`Setting-Urological and geriatric clinics
`and wards.
`Subjects-Asymptomatic patients taking
`terodiline in stable dose.
`Methods-Electrocardiograms (50 mm/s)
`were collected from patients while they
`were taking terodiline and compared with
`ECGs obtained before or after terodiline.
`QT interval, heart rate corrected QT
`interval (QTc), and QT dispersion (QTd)
`were measured. Drug induced electro-
`cardiographic changes were related to
`plasma concentrations of R(+) and S(-)
`terodiline.
`Results-During
`terodiline
`treatment
`mean QTc and QTd were prolonged
`(491(43) and 84 (35) ms1l2) compared with
`measurements made off therapy (443 (33)
`and 42 (17) ms'12, paired t tests, P < 0-002
`and P < 0 01
`respectively)
`in the
`12
`patients in sinus rhythm. The mean (95%
`interval)
`confidence
`drug
`induced
`increases were 48 (23 to 74) Ms112 for QTc
`and 42 (13 to 70) ms'12 for QTd. These
`increases correlated with total plasma
`(QTc:
`terodiline
`r = 0-77, P < 0-006,
`QTd: r = 0*68, P < 0.025)
`and with
`plasma concentrations of both terodiline
`enantiomers.
`Conclusions-Terodiline increases QTc
`and QTd in a concentration dependent
`manner. It is not clear whether this is a
`stereoselective effect and, if so, which
`enantiomer is responsible. The results
`suggest that drug induced torsade de
`pointes is a type A (concentration depen-
`dent) adverse drug reaction.
`
`(Br HeartJ7 1995;74:53-56)
`
`Keywords: terodiline;
`graphy
`
`cardiotoxicity;
`
`electrocardio-
`
`Terodiline hydrochloride is an antimuscarinic
`drug with calcium antagonist
`properties'
`which was used for treating urinary inconti-
`nence caused by detrusor instability.2 The
`drug was withdrawn in 1991 after reports of
`cardiac dysrhythmia including bradycardia,
`heart block, ventricular fibrillation, and ven-
`tricular tachycardia, usually of the torsade de
`pointes-type34 and associated with QT pro-
`longation. Plasma terodiline concentrations
`were very high in one affected
`patient.
`Predisposing factors for terodiline associated
`torsade de pointes were old age, coexisting
`ischaemic heart disease, co-prescription of
`other cardioactive drugs, and hypokalaemia.
`Torsade de pointes is
`associated with
`abnormal prolongation of the ventricular
`refractory period which results in a long QT
`interval on the electrocardiogram and is often
`drug induced.5 Increased dispersion of ven-
`tricular recovery may be important in the
`development of this arrhythmia and indirect
`evidence indicates that this is reflected by
`increased dispersion of QT interval durations
`across the standard 12 lead electrocardio-
`gram.67 The relation between torsade de
`pointes and plasma drug concentrations is
`uncertain: while torsade may result from over-
`dose of several drugs,5 many patients develop-
`ing drug induced torsade do not have
`excessive plasma drug concentrations and
`some consider the arrhythmia to be an idio-
`synchratic phenomenon.8
`The effects of terodiline were therefore
`investigated by collecting electrocardiograms
`from asymptomatic patients receiving the
`drug for treatment of urinary incontinence,
`comparing them with those taken before or
`after drug treatment, and relating the terodi-
`line induced electrocardiographic
`changes
`with plasma concentrations of each terodiline
`enantiomer.
`
`Patients and methods
`Electrocardiograms (50 mm/s) and plasma
`samples were collected from patients who were
`taking terodiline in stable dose between 4 and
`24 h after the last dose. This process started
`in June 1991, when reports of dysrhythmia
`first appeared, and ended in September 1991
`when the drug was withdrawn. Copies of elec-
`trocardiograms predating terodiline treatment
`were also collected, when available, and, if
`possible, electrocardiography was repeated at
`
`Wolfson Dept of
`Clinical
`Pharmacology,
`University of
`Newcastle, Newcastle
`upon Tyne
`S H L Thomas
`K Hartigan-Go
`F Kamali
`P Wood
`G A Ford
`Academic
`Department of
`Cardiology,
`University of
`Newcastle, Newcastle
`upon Tyne
`P D Higham
`R W F Campbell
`Correspondence to:
`Dr S H L Thomas, Wolfson
`Department of Clinical
`Pharmacology, Claremont
`Place, Newcastle NE1 7RU.
`Accepted for publication
`11 January 1995
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1008 - Page 1
`
`

`
`54
`
`Thomas, Higham, Hartigan-Go, Kamali, Wood, Campbell, Ford
`
`100- /
`
`*
`
`.
`
`50
`
`*
`
`FO ioo0
`50
`
`0C
`
`0
`
`C'0
`R= 0.78, P < 0.005
`R 0.76, P<0.008
`u -50 -
`-50-
`0 100 200 300 400 500
`0 100 200 300 400 500
`150
`150
`100-
`100
`.C
`50
`50
`D
`CO0
`01
`-5 00. R 0-69, P < 002
`0 100 200 300 400 500
`R(+)-terodiline (ng/ml)
`
`.
`
`*.
`
`0
`
`R 0.67, P < 0.03
`0 100 200 300 400 500
`S(-)-terodiline (ng/ml)
`
`Characteristics ofpatients in sinus rhythm
`Table 1
`taking terodiline
`
`Mean (range)
`
`Age (years)
`Height (cm)
`Weight (kg)
`Daily dose (mg)*
`Duration of treatment (days)
`Sodium (mmol/l)
`Potassium (mmol/l)
`Creatinine (umol/l)
`Ionised calcium (mmol/l)
`Magnesium (mmolIl)
`Albumin (g/l)
`Values are mean (range). *Median daily dose was 25 mg.
`
`73 (46-92)
`161 (150-193)
`61 (44-90)
`38 (12-5-50)
`231 (8-1050)
`139 (136-142)
`4-1 (3 4-4 8)
`110 (89-116)
`1-30 (1-25-1-32)
`0-8 (0 7-0 9)
`41 (37-46)
`
`least 2 months after terodiline had been dis-
`continued. Each patient's medical details
`were recorded and the blood sample analysed
`for plasma drug concentrations, electrolytes,
`and creatinine.
`Electrocardiograms were analysed blind by
`an independent observer. RR, PR, and QT
`intervals were measured using a digitiser
`(Calcomp 9000, Scottsdale, AZ, USA). The
`QT interval was measured from onset of the
`QRS complex to the end of the T wave,
`defined as a return to the TP baseline. In the
`presence of U waves, the end of the T wave
`was taken at the TU nadir. Three representa-
`tive complexes were analysed for those leads
`of the standard 12 lead electrocardiogram
`where the T wave could be clearly defined
`and a mean taken. When the end of the T
`wave could not be reliably identified the lead
`was excluded from analysis. The largest QT
`interval on the 12 lead electrocardiogram
`(QTmax) was used to derive the corrected
`QT interval (QTc), which was calculated for
`each lead using Bazett's formula (QTc = QT/
`V (RR interval)). QT dispersion (QTd) was
`determined as the longest minus the shortest
`QTc on the 12 lead electrocardiogram.
`of R( + )-
`and
`concentrations
`Plasma
`S(-)- terodiline enantiomers were measured
`simultaneously by high performance liquid
`chromatography using a chiral column and an
`ultraviolet detector. The limit of detection of
`the method is 25 ng/ml for each enantiomer
`and coefficients of variation are 5-5% for the
`R(+)-enantiomer at 271 ng/ml and 7-6% for
`173 ng/ml.
`S(-)-enantiomer
`All
`the
`at
`samples were analysed in duplicate and with-
`out knowledge of the electrocardiographic
`changes observed in each patient.
`
`Results
`Nineteen patients taking terodiline took part
`in this study. The electrocardiograms of four
`
`Relation between plasma concentrations of
`Figure 2
`terodiline enantiomers and the extent of drug induced
`prolongation in corrected QT intervals (QTc) and QT
`dispersion (QTd).
`
`patients with atrial fibrillation were not used
`as this condition has major effects on QTd.
`For the 15 patients in sinus rhythm (table 1)
`before
`available
`electrocardiograms
`were
`terodiline was started in two patients and after
`terodiline had been stopped in 11, although
`one of these had developed atrial fibrillation.
`Electrocardiograms in sinus rhythm were
`therefore available during and before or after
`treatment in 12 patients, of whom 11 agreed
`to give a blood sample. Of these, one had
`right bundle branch block and four were taking
`other drugs which might affect QT interval
`(dothiepin, imipramine, thioridazine, sotalol),
`the doses of which were not altered during the
`study, and five had cardiovascular disease
`(three),
`disease
`(cerebrovascular
`coronary
`artery disease (one), and hypertension (one)).
`Electrocardiograms of two patients receiving
`terodiline were collected after only 8 and 16
`days of treatment, possibly before steady state
`concentrations and the maximal electrocar-
`diographic effects of the drug would be
`achieved.
`A total of 17 patients gave a blood sample.
`Plasma concentrations of the two terodiline
`closely
`(r = 0 99,
`correlated
`enantiomers
`P < 0 0001) with a mean (SD) R(+)-/S(-)-
`ratio of 1 03 (0 14). No significant correla-
`tions were observed between daily terodiline
`dose and the plasma concentration of either
`terodiline enantiomer. Apparent terodiline
`clearance, measured as daily dose divided by
`plasma concentration, varied widely between
`patients and did not correlate significantly
`with age in this small group (data not shown).
`Terodiline did not affect the PR interval or
`heart rate but prolonged QTc and QTd
`(fig 1, table 2) compared with measurements
`
`Table 2
`
`Electrocardiographic effect of terodiline in 12 patients in sinus rhythmn
`QTmax
`PR interval
`Heart rate
`(ms)
`(ms)
`(beatslmin)
`405 (49)
`166 (22)
`73 (16)
`456 (64)
`178 (26)
`72 (14)
`51
`12
`-2
`(17 to 85)
`(-3 to 26)
`(-10 to 7)
`NS
`NS
`P < 0 01
`
`Patients not receiving treatment
`Patients receiving treatment
`Mean difference
`(95% CI)
`Paired t test
`Values are mean (SD).
`
`QTc
`(msll2)
`443 (33)
`491 (43)
`48
`(23 to 74)
`P < 0-002
`
`QTd
`(ms)
`42 (17)
`84 (35)
`42
`(13 to 70)
`P < 0 01
`
`p < 0.002
`S
`
`I
`
`7
`
`{
`
`P < 0.01
`
`600_
`^550
`Ch 500 -
`Q450
`C) 400 -
`350 '
`
`150
`
`100
`
`50
`
`Off
`
`0 On
`Corrected QT
`Figure 1
`intervals (QTc) and QT
`dispersion (QTd) in 12
`patients in sinus rhythm on
`and off terodiline, together
`with means (SD). Four
`patients taking other drugs
`that prolong QTc are
`shown as crosses.
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1008 - Page 2
`
`

`
`Concentration dependent cardiotoxicity of terodiline in patients treatedfor urinary incontinence
`
`55
`
`made when patients were not receiving treat-
`ment. There was a
`positive
`correlation
`between absolute values of QTc and QTd in
`patients receiving terodiline
`(r = 0 70, P <
`0 005)
`terodiline
`and
`between
`induced
`increases in QTc and QTd (r = 0-88, P <
`0O001). Increases in QTmax, QTc, and QTd
`correlated significantly with the plasma con-
`centrations of terodiline and each of its enan-
`tiomers (fig 2).
`QTc was increased with terodiline in three
`patients whose electrocardiograms showed
`controlled atrial fibrillation on and off treat-
`ment. QTc was reduced with terodiline in one
`other patient, but this patient's atrial fibrilla-
`tion was uncontrolled (rate 11 0/min) when
`treatment was not given and the QTc is prob-
`ably invalid at this rate.
`
`Discussion
`The QT interval is an important factor in the
`genesis of ventricular arrhythmia. QTc pro-
`of 500 ms!"12 almost
`longation
`in
`excess
`inevitably accompanies torsade de pointes.9
`More modest prolongation is associated with
`an increased risk of sudden death in several
`patient groups.'1-2 Drugs that prolong the QT
`interval can cause ventricular arrhythmia and
`sudden death, for example, antiarrhythmic
`drugs, phenothiazines, and some antihista-
`mines.5 The risk of drug induced arrhythmia,
`however, is not determined by the QT interval
`alone; drugs with class III effects such as
`amiodarone increase QTc but are apparently
`associated with a low risk of torsade."3
`Furthermore,
`of
`evidence
`the
`relation
`between the risk of sudden death and the QTc
`interval in apparently healthy populations is
`conflicting. 14 15
`An important factor in the genesis of
`arrhythmia is the heterogeneity or dispersion
`of the duration of ventricular repolarisation.
`When dispersion is increased some areas of
`the ventricle will be refractory at times when
`others can allow unidirectional or bidirec-
`tional impulse propogation. This may estab-
`lish local re-entry circuits and ventricular
`tachycardia or fibrillation may then be trig-
`gered by critically placed ventricular prema-
`ture contractions.'6 Indirect evidence suggests
`that the interlead variability in QT interval
`durations obtained from the standard 12 lead
`electrocardiogram reflects increased disper-
`sion of ventricular recovery and the risk of
`arrhythmia67 1718 and sudden death.'9 QT
`necessarily
`dispersion
`does
`interval
`not
`increase as the QT interval lengthens: for
`example, amiodarone prolongs QTc without
`increasing QTd9 and this may explain its
`infrequent association with torsade. Early
`afterdepolarisations also seem to be important
`in the genesis of torsade and these might also
`be reflected in the 12 lead electrocardiogram
`as increased QTd.69 It is therefore important
`that QT interval and dispersion are measured
`when investigating the effects of drugs on ven-
`tricular repolarisation.
`Nine of the 10 patients described in the lit-
`erature who developed torsade de pointes
`
`while receiving terodiline had marked prolon-
`gation of the QTc interval,'3 4 20 however, daily
`terodiline doses were only a little higher
`(mean 40 mg) than in our asymptomatic
`group. Our results and those of a small open
`study of the effects of terodiline in elderly
`patients20 show that QTc prolongation is com-
`mon in asymptomatic patients receiving the
`drug, although this is less marked than in the
`patients with torsade de pointes. The observa-
`tion that terodiline also increases the disper-
`sion of ventricular recovery as measured by
`the QTd has not previously been reported.
`These effects correlate closely with plasma
`concentrations of the drug and its enan-
`tiomers confirming that this is a type A con-
`related
`centration
`adverse drug reaction,
`although some patients, for example, those
`with heart disease or hypokalaemia, may be
`particularly susceptible. Consistent with this,
`plasma terodiline concentration was sub-
`stantially higher (2946 ng/ml) in the one
`patient with torsade de pointes who had this
`measured4 than in our asymptomatic patients.
`Why some patients develop high concentra-
`tions of terodiline needs to be clarified. One
`risk factor is increasing age as elderly patients
`metabolise terodiline more slowly, with a
`mean elimination half life of 130-190 h2' 22
`compared with 63 h in younger patients.2'
`Thus it may take several weeks for steady state
`plasma concentrations to be achieved and
`these may be higher than anticipated. In addi-
`tion, there is considerable variability in the
`terodiline elimination half life between elderly
`individuals.2' 22 Variations in clearance proba-
`bly reflect differences in hepatic metabolism
`via p-hydroxyterodiline, the major route of
`elimination. This process may be affected by
`genetic polymorphism as clearance of R(+)-
`terodiline was reduced in a slow hydroxylator
`~~~~~24
`of
`of debrisoquine.4
`The terodiline enantiomers have stereose-
`lective actions. The R( + )-enantiomer is a
`more potent antimuscarinic agent,2526 while
`the S(-)-enantiomer has more marked cal-
`cium antagonist properties.25 In rats hydroxy-
`lation of the two enantiomers occurs at
`different rates, being more rapid for R(+)-
`terodiline.27 If this was also true in humans
`then it would be expected that plasma con-
`centrations of the S(-) enantiomer would be
`higher at steady state. In our patients, how-
`ever, plasma concentrations of each enan-
`therefore
`tiomer were similar, and it
`is
`unlikely that differential clearance occurs in
`humans. This is consistent with a previous
`observation that clearance of R( + )-terodiline
`is similar to that of the racemic drug.24
`This study does not indicate which of the
`enantiomers is most responsible
`for
`the
`observed electrophysiological effects, nor can
`it exclude the possibility that these are caused
`by a metabolite rather than the parent drug.
`Increases in QTc and QTd correlated signifi-
`cantly with both enantiomers, but the concen-
`trations of the enantiomers are closely related
`to each other. The most likely mechanism is
`potassium channel inhibition, a property of
`other QT prolonging drugs such as quinidine,
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1008 - Page 3
`
`

`
`56
`
`Thomas, Higham, Hartigan-Go, Kamali, Wood, Campbell, Ford
`
`amiodarone, and terfenadine.i28 To date the
`effects of terodiline enantiomers on cardiac
`potassium channels have not been studied.
`Important lessons from the terodiline expe-
`rience should be learned. It is clear from this
`and other data that if an effect of the drug on
`cardiac repolarisation had been sought during
`its development it would have been detected.
`This would have limited the use of the drug in
`high risk groups and resulted in closer moni-
`toring of patients while receiving therapy. In
`view of the close structural similarity to the
`proarrhythmic drug prenylamine,29 it is disap-
`pointing that electrocardiographic effects were
`not studied. Nevertheless it is reassuring that
`voluntary organised adverse drug reaction
`reporting by prescribers
`the
`United
`in
`Kingdom detected and characterised
`the
`problem.
`Studies using isolated detrusor muscle
`strips suggest that the beneficial effects of
`terodiline on the bladder are primarily medi-
`by the
`anticholinergic
`R( + )-enan-
`ated
`tiomer.26 If the adverse cardiovascular effects
`are caused by the S(-)-enantiomer then
`treatment with pure R( + )-terodiline might
`have an acceptable risk-benefit ratio. Studies
`to characterise further the electrophysiological
`effects of terodiline enantiomers in animals
`and humans would be useful.
`
`We are grateful to Kabi Pharmacia for supplies of racemic
`terodiline and its enantiomers, and to members of the urology
`department at the Freeman Hospital for their help with the
`study.
`
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`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1008 - Page 4