N494
`
`@733-E467
`
`v.
`
`14
`
`no. 6
`1995
`
`Received on: @6~@3—E@
`
`Neurournlogy and
`urodynamics.
`
`WILEY-LISS
`
`ISSN 0733-2457
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0001
`
`

`
`NEUROUROLOGY
`
`AND
`
`URODYNAMICS
`
`EDITOR-IN-CHIEF
`
`Jerry G. Blaivas, M.D.
`Clinical Professor of Urology
`
`Cornell University Medical School
`
`Addressjournal correspondence to:
`400 East 56th Street - New York. NY. USA
`
`DEPUTY EDITORS
`
`Paul Abrams, M.D., F.R.C.S.
`
`Alan J. Wein, M.D.
`
`Bristol Urological Institute
`Southrnead Hospital
`Bristol, UK
`
`Professor and Chairman
`Division of Urology
`University of Pennsylvania
`Medical Center
`
`Philadelphia. PA. USA
`
`International Continence
`Society
`
`The Official Journal of
`Urodynamics Society
`
`International Society for
`Dynamics of the Upper
`Urinary Tract
`
`©l995 Wiley-Liss. Inc. All rights reserved. No part of this publication may be reproduced in any form or by any means. except as
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`Medica - ISI-Soviet Union - MEDLINE- Scisearch. Printed in the United States of America. Copyright © 1995 ‘Wiley-Llss,
`Inc.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0002
`
`

`
`Neurourology and Urodynamics 14: 647-655 (1995)
`
`Urodynamic and Other Effects of
`Tolterodinet A Novel Antimuscarinic Drug
`for the Treatment of Detrusor Overactivity
`
`M.M.S. Stahl, B. Ekstrom, B. Sparf, A. Mattiasson, and K.-E. Andersson
`
`Departments of Clinical Pharmacology (M.M.S.S., K.-EA.) and Urology (B.E., A.M.),
`Lund University Hospital, Lund, and Department of Research and Development,
`Pharmacia AB, Uppsala (B.S.), Sweden
`
`Tolterodine, a novel compound intended for u-eatrnent of urgency and urge incontinence,
`has been characterized as a potent muscarinic receptor antagonist in pharmacological in
`vitro and in vivo studies. In cats, tolerodine was shown to reduce bladder pressure at doses
`significantly lower than those affecting salivation. To predict clinical effectiveness, an open
`pilot study was performed in healthy male volunteers. Efficacy was measured by cystom-
`etry and by spontaneously reported effects after administration of a single oral dose of
`tolterodine, 6.4 mg, given as a water solution. Toltcrodine had distinct inhibitory effects on
`urinary bladder function. both at l and 5 hours post-dose. At 1 hour, but not at 5 hours
`post-dose tclterodine also significantly reduced stimulated salivation. In addition to the
`objectively demonstrated changes in urodynamic parameters, most volunteers experienced
`voiding difficulties. No significant changes in blood pressure. heart rate, or near point of
`accommodation were registered. Tolterodine, in the dosage used, was both objectively and
`subjectively shown to exert a marked inhibitory effect on micturition in healthy subjects,
`and the data suggest a more pronounced effect on bladder function than on salivation.
`0 I995 Wiley-Liss. Inc.
`
`Key words: antimuscarlnics, urodynamics, snlivatlon, healthy volunteers
`
`INTRODUCTION
`
`Available evidence suggests that muscatinic receptors mediate not only the
`dctrusor contraction of normal voiding, but also the main part of contraction in
`bladder overactivity associated with urge and urge incontinence [Andcrsson, 1993].
`Anticholinergic treatment would therefore seem to be the logical choice for treatment
`of detrusor overactivity, but the results of such treatment are often disappointing
`[Andcrsson, 1988; Wein et al., 1994]. Contributing to this may be low bioavailabil-
`ity, particularly with quarternary compounds, and side effects, such as dryness of the
`mouth, accommodation difficulties, and increased heart rate. Anticholinergics with
`
`Received for publication June 25, I995; accepted July 20. 1995.
`
`Address reprint requests to K.-E. Andersson, M.D., Ph.D., Department of Clinical Pharmacology. Lund
`University Hospital, S-221 85 Lund, Sweden.
`
`© 1995 Wiley-Llss, Inc.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0003
`
`

`
`648
`
`Stahl et al.
`
`selectivity for the urinary bladder are desirable, but none of the drugs currently in
`clinical use has any such preference.
`In the development of new drugs for treatment of detrusor hyperactivity. the
`intention has been to find substances with a selective action on the detrusor muscle.
`thereby avoiding the systemic side effects. Tolterodine is a new muscarinic receptor
`antagonist intended for treatment of urgency and urge incontinence. It is a potent and
`competitive antagonist at muscarinic receptors in guinea pig as well as human detru-
`sor muscle {Nilvebrant et al., 1994, 1995], and in cats, the drug was shown to reduce
`bladder pressure at doses significantly lower than those affecting salivation [Gillberg
`et al.. 1994].
`The present study was undertaken to investigate the urodynamic effects of
`tolterodine administered to healthy male volunteers as a single oral dose. In addition,
`changes in blood pressure, heart rate, stimulated salivation, and near point of ac-
`commodation were registered, and serum concentrations were measured.
`
`MATERIALS AND METHODS
`
`Twelve male subjects were recruited for the study. Their mean age was 24 years
`(range 21-29 years) and their mean body weight 77 kg (range 68-87 kg). They were
`all judged to be healthy by clinical examination,
`l2—lead ECG, routine laboratory
`tests and a urine culture and were without any previous history of significant illness.
`Each subject gave his written infonned consent to participation, and the study pro-
`tocol was approved by the Ethics Committee of the University of Lund, Sweden.
`The subjects were fasting from l0 pm on the preceding evening and abstained
`from food on the trial day until lunch was served (4 hours after the administration of
`tolterodine). However, coffee and tea without sugar and cream were allowed in the
`morning of the study day. The subjects received 6.4 mg of tolterodine (Pharmacia,
`Uppsala, Sweden) orally as an aqueous solution (6.4 mg/150 111]), a dose that in
`previous phase I studies had been shown to produce a clear—cut reduction of stimu-
`lated salivary secretion. This dose was assumed to be too high for clinical use, but
`was deliberately chosen to secure effects on the bladder. No other drugs or alcohol
`were allowed during 48 hours prior to and 24 hours after drug intake.
`
`Urodynamlc Investigation
`
`The urodynarnic measurements were performed according to the routines at the
`Department of Urology, University of Lund, Sweden, using a Life-Tech 1106 Urolab
`equipment. Two 8 Fr baby-feeding catheters were inserted into the bladder for infu-
`sion and pressure recording. The rectal pressure, considered approximately equal to
`the intraabdominal pressure, was recorded simultaneously to correct for an increase
`in intravesical pressure as caused by an increase in intraabdominal pressure. For this
`purpose a balloon catheter applied to an external pressure transducer was used and
`placed 5-10 cm into the rectum. Saline of body temperature was infused into the
`bladder at a rate of approximately 50 ml/min. The volumes at which the subject
`experienced the first sensation of bladder filling (FS) and the normal desire to void
`(ND) were noted. The maximum detrusor pressure (pdc,_,,,,,,,) was recorded during
`micturition alongside the catheters. Each time this procedure was executed twice
`consecutively. Finally, the bladder was filled until ND, the catheters were removed
`
`5
`
`1
`
`I
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0004
`
`

`
`Toltero-dine and Bladder Function
`
`549
`
`and the maximum flow rate (Q,,,_,,) was registered during natural micturition. The
`volume of residual urine (Vm) was measured prior to the urodynamic investigations
`(true residual urine) and during the second cystometry in each session (that is, after
`micturition with the catheters present). The above mentioned investigations were
`performed thrice on the trial day, that is, prior to and 1 and 5 hours following the
`administration of tolterodine.
`
`Measurements of Other Pharmaeologic Effects
`
`Heart rate and supine blood pressure (both simultaneously recorded by an au-
`tomatic, non-invasive, digital blood pressure meter, Model UA-751, A&D Company
`Ltd. , Japan), near point of accommodation (R.A.F. Near point rule, Clement Clarke,
`Ltd., England) and stimulated salivation (see below) were measured before (prior to
`the baseline cystometry) and 15 and 45 minutes and 1 h 45 min, 2 h 15 min, 2 h 45
`min, 3h 15 min, 3h45 min,4h45 min, 5h45 min,6h 15 min, 6h45 min,7h
`15 min and 7 h 45 min after drug intake. The ability to accommodate for near vision
`was measured binocularly by moving a block of fine print along the above mle
`balanced on the subject's nose and recording the nearest point (distance in mm) at
`which the letters were still clearly distinguishable. For this test the subjects were told
`to retain their visual correction. All baseline measurements were done after 10-20
`minutes’ rest in the supine position. For heart rate, blood pressure, and stimulated
`salivation, the baseline values consisted of one measurement only, but for accom-
`modation, the baseline values were the means of two recordings. The baseline mea-
`surements were performed on average 70-90 minutes prior to drug intake, and the
`interval between the first and second near point recording was approximately 10
`minutes. At each of the time points,
`the recordings of the physiologic variables
`occurred in the following order: heart rate and blood pressure simultaneously, ac-
`commodation for near vision and finally, salivation. In addition, a one-lead ECG strip
`was obtained in conjunction with each heart rate and blood pressure recording. For
`the salivation test,
`the subject was asked to swallow all saliva, whereupon one
`paraffin tablet (Orion Diagnostica. Espoo, Finland) was chewed for 5 minutes alter-
`nately on the left and right side. All saliva was continuously spat out into a plastic cup
`and the salivation flow was calculated as weight of saliva collected during 5 minutes
`
`(gl5 min).
`
`Blood Sampling
`
`Blood samples of 10 ml were drawn from an antecubital vein via an indwelling
`catheter (Venflon) into Vacutainer tubes (Becton Dickinson) without additives, prior
`to and 20 and 40 minutes and 1, 2, 3, 4, 6 and 8 hours after drug administration. The
`samples were kept at room temperature for 1 hour, followed by centrifugation (10003
`for 10 min). Serum was then immediately separated and frozen. These samples were
`stored at —20°C until analysis.
`
`Analysis of Tolterodine
`
`Tolterodine was analyzed by capillary gas chromatography and mass spectrom-
`etry [Palmér and Stenberg, to be published].
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0005
`
`

`
`650
`
`Stahl et al.
`
`TABLE I. Effects on Urodynamic Parameters of a Single Dose of 6.4 mg of Tolterodine Given
`Orally as an Aqueous Solution to Healthy Male Volunteers
`
`0 h cystornetry
`Before
`At
`
`I h cystometry
`Before
`At
`
`5 h cystometry
`Before
`At
`
`V,“ ml
`P,,,,_,,_, crn H20
`QM ml/s
`FS ml
`ND ml
`
`20 (22)
`
`13 (24)
`56 (17)
`25 ('7)
`218 (‘Ill
`395 (I00)
`
`I24 H28)‘
`
`'
`
`234 (l3l)
`41 (13)*
`I8 ('I)*
`282 (80)*
`42] (76)
`
`208 (14-8)“
`
`202 (159)
`43 (9l"
`20 (S)"
`232 (76)‘
`490 (98)*
`
`I and 5 hours after adrninistration. Mean values are
`Measurements were performed at baseline (0 hour),
`given with 1 SD within parentheses. The results from the second cystometry in each investigation was
`used for calculations. The number of subjects is twelve. except for P,,_,_m__ (n= 10).
`*P<0.05 vs. baseline. For ND the difference between I and 5 hours was also statistically significant
`{.P<0.05).
`
`Adverse Ettects
`
`Each subject was questioned in a non-leading way about any symptoms that
`deviated from his normal status. Approximately 1 week after each subject had com-
`pleted the study he was subjected to routine laboratory testing, a 12-lead ECG-
`recording, urine culture and a physical examination.
`
`Data Analysis and Statistics
`
`1 and 5 hours
`Comparisons between the three different occasions (baseline,
`after drug intake) were made for the following urodynamic variables: 1) V,“ prior to
`each of these time points, 2) V,“ during cystometry, 3) volume at FS, 4) volume of
`ND, 5) pdehmu, and 6) Qmu. The second cystometry at each of the mentioned three
`time points was regarded as the valid one, since the subjects had no previous expe-
`rience of urodynamic investigations. Statistics thus consistently refer to the second
`investigation (variables 2-5 above). For the variables, an ANOVA, including mul-
`tiple comparisons with the Ryan—Einot-Gabriel-Welsh Multiple Range Test [Rarnsey,
`1978], was executed on the 0.05 level of statistical significance. Values of the effect
`variables are given as means 1 standard deviations (mean 1 1 SD) and are presented
`vs. time together with the corresponding 95% confidence intervals of the means.
`From the serum concentrations of tolterodine the following pharmacokinetic data
`were derived: maximum concentration (Cmu), its corresponding time point (tum). the
`elimination rate constant (k,) and elimination half-life (tm). All pharmacokinetic data
`are presented as mean :t
`1 SD, except for tmu, which is expressed as median and
`range.
`
`RESULTS
`
`Urodynamlc Eflects
`
`The mean values of the urodynamic effect variables are given in Table I. For
`each of them, there was a statistically significant difference between investigations
`before and after tolterodine intake (P < 0.05).
`The mean V,“ was higher during the second cystometry compared to the first
`
`l
`
`,
`'
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0006
`
`

`
`Tolterodine and Bladder Function
`
`651
`
`one both at 1 and 5 hours after the administration of tolterodine (234 vs. 181 ml, and
`202 ml vs. 175, at 1 and 5 hours, respectively). The same was true for FS (282 vs.
`235 ml, and 282 ml vs. 243 ml, respectively), but for ND only at 5 hours (490 vs.
`435 ml). This tendency was not seen for the corresponding baseline measurements.
`For p,,,,_,,,,,,, the difference between the first and the second cystometry at l and 5
`hours was not obvious.
`Four subjects were unable to void at baseline, probably because too short a time
`had elapsed since the previous micturition. These subjects had the largest initial
`residual volumes (32-75 ml). Further, three and four subjects, respectively, could not
`void prior to the investigations at l and 5 hours, most likely due to a pharmacologic
`effect. Two subjects were excluded from the mean calculations of p,,,,_,,,,,,, because of
`their inability to void at
`1 hour. Hence, the detmsor pressures (9 and 0 cm H20,
`respectively) measured in these cases are not comparable to those of the others.
`Since the subjects were undergoing several catheterizations during the study
`it was difficult to evaluate the micturition problems reported. However,
`the
`day,
`subjects seemed able to separate actual voiding problems and the burning sensation
`from the urethra seen as a result of the manipulations. Taking this uncertainty into
`account, at least eight subjects had voiding difficulties, seven of them also in the
`afternoon during the last urodynamic procedure, approximately 5 hours after drug
`intake. One subject experienced micturition problems 10 hours following drug ad~
`ministration. Before the 1 hour cystometry. another subject felt that the bladder had
`been not completely emptied, and in accordance with this, the volume of residual
`urine was considerable (175 ml). Before the 5 hour cystometry, however, voiding
`was experienced as normal, yet the volume of urine remaining in the bladder fol-
`lowing micturition was now 375 ml.
`For one subject (No. 7), whose pharmacokinetics differed from that of the
`others (see below), V,,,, prior to each investigation amounted to 35, 10 and 4 ml (at
`baseline, 1, and 5 hours, respectively). The initial residual volume (35 ml) was
`probably an overestimation of the true Vm, since this subject was unable to micturate
`before the investigation. The residual volume of urine during cystometry was 0, 30
`and I0 ml for baseline, 1 and 5 hours, respectively. FS was 280, 290 and 300 ml at
`the same time points, ND 430, 425 and 505 ml, p,,,,,.,,,,,, 74, 54 and 50 cm H20, and
`Q“, 18, 25 and 18 ml/s.
`
`Other Pharrnacologie Effects
`
`Tolterodine caused a significant mean maximum decrease (72%, related to the
`basal value) of stimulated salivation, 45 min after drug intake (Fig. 1). At approxi-
`mately 5 hours after dose, salivation was normalised.
`Tolterodine had no effect on the diastolic and systolic blood pressures. In
`relation to the basal value, there was a non-significant increase in heart rate (Fig. 2),
`and in the near point of vision (data not shown).
`
`Pharrnacoklnetics
`
`I The mean Cm“ was 5.6 t 2.8 |.l.g/L, excluding subject No. 7 whose Cm, was
`21.4 p.g/L (Fig. 3). In seven subjects Cm, occurred at 0.67 hours, in four (including
`subject No. 7) at 1 hour and in one at 0.33 hours after the intake of tolterodine. Mean
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0007
`
`

`
`652
`
`Stahl et al.
`
`15
`
`_;‘ 10
`E
`in
`‘-6,
`1:.9
`.6
`Q
`
`
`
`_
`
`‘l
`
`_ ’-
`
`i
`
`_x'
`
`’_.
`
`—’
`
`_,.
`
`I
`t
`0
`0
`2
`4
`E
`3
`
`Time ( h )
`
`Fig. I. Mean stimulated salivation vs. time after 6.4 mg tolterodine given orally as an aqueous solution
`to I2 healthy male volunteers. Solid lines are standard deviations and broken lines are 95% confidence
`limits.
`
`100
`
`Q,
`
`E
`D
`
`1%an
`I 25
`
`r
`
`"’---.---- ‘f-_%" ‘.-‘£—.--—-$-H‘-H-“{
`-
`_
`
`'
`
`‘
`
`. ___ __ -_
`
`i § £ ¥
`
`D
`
`I
`0
`2
`4
`6
`8
`
`Time { h )
`
`Fig. 2. Mean resting heart rate vs. time after 6.4 mg tolterodine given orally as an aqueous solution to
`12 healthy male volunteers. Solid lines are standard deviations and broken lines are 95% confidence
`limits.
`
`rm was 2.5 1 0.4 hours, again excluding subject No 7 (t.,2 15.0 hours), and mean
`k, was 0.23 i 0.046 h".
`
`Adverse Effects
`
`All subjects reported dry mouth, commencing 8-72 minutes (mean 37 minutes)
`following the administration of tolterodine. The duration ranged between 69 minutes
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0008
`
`

`
`Tolterodine and Bladder Function
`
`553
`
`-.‘.'-"*0.
`
`‘‘‘°
`
`25
`
`E 20
`E
`L‘ 15
`3
`3 10
`3
`5
`D
`to
`
`5
`
`0
`
`l.'"°‘~‘
`:
`-'
`.'
`5
`:
`:
`
`r--r"-—1-:-r'—-—t--
`0
`2
`4
`B
`8
`
`'Frne(h)
`
`Fig. 3. Mean (1 SD.) serum tolterodine concentrations in it healthy male subjects after an oral dose
`of 6.4 mg as an aqueous solution (solid line). The data from subject No. 7 are shown separately (broken
`line).
`
`and 9 hours (mean 4 hours). Two individuals also reported dry throat. Five of the
`volunteers reported dry hands, and in two of them, the symptom was accompanied by
`a sensation of dry feet.
`Other symptoms reported were change of taste, increased sensitivity to light,
`problems focusing, hoarseness, hazy vision, and nasal congestion.
`All post study physical and laboratory examinations including 12-lead ECG and
`urine culture were found to be normal.
`
`DISCUSSION
`
`In the normal human detmsor, the emptying contraction in vivo and the con-
`traction evoked by electrical stimulation of nerves in vitro has been suggested to be
`mediated mainly, if not exclusively, through muscarinic receptor stimulation [Sjégren
`et al., 1982; Sibley, I984; Kinder and Mundy, I985; Craggs et al.. 1986], because
`these responses can be more or less completely blocked by atropine. In support of this
`suggestion, atropine [Cullumbine et a1., 1955] and other anticholinergic drugs can
`produce an almost complete paralysis of the bladder when injected intravenously in
`nonnal humans.
`
`Tolterodine is a potent and competitive antagonist at human bladder muscarinic
`receptors. In electrically stimulated bladder strips, tolterodine effectively and con-
`centration-dependently reduced the contractile responses, and the receptor specific
`binding of (-)3H-QNB in homogenates of urinary bladder from humans was effec-
`tively inhibited by tolterodine in a concentration-dependent manner [Nilvebrant et al. ,
`I994, I995]. Intravenous infusion of tolterodine (0.0l—l mg/kg) to anaesthetised cats
`resulted in a dose-dependent inhibition of urinary bladder contractions induced by
`acetylcyholine and of salivation evoked by electrical nerve stimulation [Gillberg et al.,
`1994]. The effect of urinary bladder contractions occuned at significantly lower doses
`than the effect on salivary secretion. In contrast, oxybutynin was significantly more
`potent in inhibiting salivary secretion than urinary bladder contractions; atropine was
`equally effective on both parameters.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0009
`
`

`
`654
`
`Stahl et al.
`
`In the present study, tolterodine had a pronounced effect on bladder function in
`healthy volunteers when given orally. The main urodynamic effects of tolterodine
`consisted of an increase in Vm, reflecting an incomplete emptying of the urinary
`bladder, and a decreased pd,,_,,,,,,,. These findings are consistent with a potent anti-
`muscarinic action on the lower urinary tract. The mean baseline Vm prior to the
`urodynamic investigation was probably an overestimation of the true baseline Vm,
`since four of the subjects included in the mean calculations were unable to void at
`baseline. Thus, although three and four subjects, respectively, were unable to mic-
`turate prior to the urodynamic procedure at 1 and 5 hours, the difference in mean V,“
`prior to cystometry (that is, the “tn.1e" Vm), and therefore the drug effect, is likely
`to be underestimated. The V,“ during each cystometry disclosed a similar increase.
`However this volume does not constitute a true V,“ since it was assessed following
`micturition with indwelling catheters in position.
`Tolterodine also influenced the other urodynamic variables investigated. A
`decreased urinary flow rate was found. However, the rates were still within the normal
`range. There was an increase in ND which coincides well with an assumed decrease
`in detrusor contractility, and also in the volume of FS. Even if significant, the changes
`in FS should be interpreted with caution because of its large interindividual variability.
`As expected, tolterodine in the dose used (6.4 mg), caused a distinct decrease
`in stimulated salivation. The effect was, however, shorter-lasting than the effect on
`bladder function, and at 5 hours, when the effects on the bladder were still as
`pronounced as at 1 hour post close, stimulated salivation was normalised. No signif-
`icant effects on heart rate, blood pressure, or near point of accommodation were
`found, despite the high tolterodine dose that was used. This suggests that if any side
`effect will be dose-limiting in clinical practice, it is likely to be reduced salivation,
`rather than effects on the heart or the eye.
`The pharmacokinetics of tolterodine, as found in this pilot study, revealed a
`rapid absorption with a mean time for maximal serum concentration of less than 1
`hour, and a serum half life of about 2.5 hours.
`In_one of the 12 subjects,
`the
`pharmacokinetics of the drug differed markedly from that of the others. This subject
`had a maximal serum tolterodine concentration almost four times higher than the
`mean, and a serum half-life of 15 hours. Despite this, the urodynamic effects were not
`conspicuous. These findings suggest that tolterodine is metabolised to active metab-
`olities, and that the subject was a slow metabolizer.
`Thus, tolterodine,
`in the dosage used, was both objectively and subjectively
`shown to exert a powerful inhibitory effect on micturition in healthy subjects. Even
`if the drug reduced stimulated salivation, the results suggest that a selective effect on
`the bladder, as demonstrated in an animal model [Gillberg et al., 1994], and be
`obtained also in humans. Overall the drug had an acceptable adverse effect profile.
`Taking into account the relatively large residual volumes produced in this study on
`healthy volunteers, and the distinct effects on stimulated saliva secretion, a dose of
`6.4 mg of tolterodine seems too high a dose for future patients.
`
`REFERENCES
`
`Andersson KE (1988): Current concepts in the treatment of disorders of micturition. Drugs 35:477-494.
`Andersson KE (1993): The pharmacology of lower urinary tract smooth muscles and penile erectile
`tissues. Pharmacol Rev 45:253-308.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0010
`
`

`
`Tolterodine and Bladder Function
`
`655
`
`Craggs MD. Rushton DN. Stephenson JD (I986): A putative nomcholinergic mechanism in urinary
`bladder of new but not old world primates. J Urol l36:l348—l350.
`Cullumbinc H, Mckee W, Creasey NH (1955): The effects of atropine sulphate upon healthy male
`subjects. Q J Exp Physiol 30:309-319.
`Gillberg P-G, Modiri A-R. Spain’ 8 (1994): Tolterodine—A new agent with tissue effect selectivity for
`urinary bladder. Neurourol Urodyn 13:435-436.
`Kinder RB. Mundy AR ( 1985): Atropine blockade of nerve-mediated stimulation of the human detrusor.
`Br J Urol 57:4l8-42l.
`
`Nilvebrant L, Glas G. Jénsson A, Sparf B (1994): The in vitro phannacological profile of tolterodine—a
`new agent for the treatment of urinary urge incontinence. Neurourol Urodyn l3:433—43S.
`u_’u5u.u u.., 1 uiuunaarusu l\ n.., Lluaevu u, nuuu.un..-nun :1, uupuun-ugnuouu u \ lzuag.‘ riuvpiuu n.-.1e.na.|u..I.. ua nu.
`
`transmurally stimulated isolated human bladder. J Urol l28:I368-1371.
`Wein AJ, Longhurst PA, Levin RM (1994): Pharmacologic treatment of voiding dysfunction. In Mundy
`AR, Stephenson TP, Wein A] (eds): "Urodynamics. Principles. Practice and Application." 2nd ed.
`New York: Churchill Livingstone, pp 43-70.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2069 - 0011