ELSEVIER
`
`PII SOO24-320S(97)OOOS7-X
`
`Ufe Sciences, Vol. 60, Nos. 13/14, pp. 1129-1136, 1997
`Copyright C> 1997 Elsevier Science Inc.
`Printed in the USA. All rights reserved
`0024-3205/97 $17.00 + .00
`
`TOLTERODINE - A NEW BLADDER SELECTIVE MUSCARINIC RECEPTOR
`ANTAGONIST: PRECLINICAL PHARMACOLOGICAL AND CLINICAL DATA
`
`L. NIL VEBRANT, B. HALLEN*, G. LARSSON
`
`Medical Dept. Urology and *Dept. of Clinical Pharmacology
`Pharmacia & Upjohn, S-751 82 Uppsala, Sweden
`
`Summary
`
`Tolterodine is a new, potent and competitive muscarinic receptor antagonist in
`clinical development for the treatment of urge incontinence and other symptoms of
`unstable bladder. Tolterodine has a high affinity and specificity for muscarinic
`receptors in vitro and it exhibits a selectivity for the urinary bladder over salivary
`glands in vivo. A major active metabolite, (PNU-200577) the 5-hydroxymethyl
`derivative of tolterodine, has a similar pharmacological profile. Based on
`pharmacological and pharmacokinetic data, it has been concluded that this
`metabolite contributes significantly to the therapeutic effect of tolterodine. The
`bladder selectivity demonstrated by tolterodine and PNU-200577 in vivo cannot be
`attributed to selectivity for a single muscarinic receptor sUbtype. Moreover, this
`favourable tissue-selectivity seems to occur also in humans. Tolterodine is well
`tolerated and it exerts a marked effect on bladder function in healthy volunteers.
`Phase II data indicate that tolterodine is an efficacious and safe treatment for
`patients with idiopathic detrusor instability or detrusor hyperreflexia. An optimal
`efficacy/side-effect profile is obtained with tolterodine, at a dosage of 1 or 2 mg
`twice daily, which seems to have less propensity to cause dry mouth than the
`currently available antimuscarinic drugs.
`
`Key Word!-: urinary bladder, incontinence, dry mouth, in vivo, human
`
`Urinary incontinence is reported by 5-10% of the adult population and the prevalence, particularly
`of urge incontinence, increases with age (1). The symptoms of an unstable bladder comprise urge
`incontinence, urgency and frequency. Unstable bladder is presumably caused by uncontrolled
`detrusor contractions during the filling phase. It is generally agreed that contractions of the human
`bladder are mediated mainly by cholinergic muscarinic receptors (2). The bladders of various
`species, including humans, contain a mixed popUlation of muscarinic Mzll112 and M/m3 receptors
`(3). The M2/1112 receptors predominate, but it is generally believed that the contractile response is
`mediated only by the M/m3 receptors (3). The pharmacological treatment of unstable bladder has
`for many years been based on muscarinic receptor antagonists (2) and oxybutynin is currently the
`drug of choice. The effectiveness of oxybutynin has been documented in several controlled
`clinical studies, but its usefulness is limited by classical antimuscarinic side-effects, which often
`leads to discontinuation of treatment (4). Dry mouth, for example, is experienced by at least 50%
`of patients treated with oxybutynin (4).
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2004 - 0001
`
`

`
`1130
`
`Tolterodine and Bladder Selectivity
`
`Vol. 60, Nos. 13/14, 1997
`
`Tolterodine (PNU-200583, (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropan(cid:173)
`amine) is a new muscarinic receptor antagonist under clinical development for the treatment of
`unstable bladder. In this paper, the antimuscarinic in vitro and in vivo profiles oftolterodine and a
`major active metabolite (the 5-hydroxymethyl derivative, PNU-200577, Labcode DD 01) are
`reviewed in comparison to those of oxybutynin and some other selective muscarinic receptor
`antagonists. Clinical data on tolterodine from phase I studies in healthy volunteers and from phase
`II studies in patients with detrusor hyperreflexia and idiopathic detrusor instability are also
`presented.
`
`Preclinical pharmacology
`
`Tolterodine is a potent and competitive inhibitor of carbachol-induced contractions of isolated
`urinary bladder preparations from guinea pig (KB 3.0 nM) (5) and humans (K8 4.0 nM) (6) and it
`binds with high affinity to muscarinic receptors in the bladder (Table I) and other tissues (5).
`Tolterodine does not exhibit any selectivity with respect to the human muscarinic receptors,
`expressed in Chinese hamster ovary (CHO) cells. The Ki values determined at mt-m5 receptors
`are (nM): 3.0, 3.8, 3.4, 5.0 and 3.4, respectively (7) (c.f. Table I). The in vitro profile of the 5-
`hydroxymethyl metabolite oftolterodine (PNU-200577), is similar to that oftolterodine (8).
`
`Although M/m2 receptors predominate in the urinary bladder of various species, bladder
`contraction is considered to be mediated by the minor population of M)rru receptors (3). This
`hypothesis is supported by functional in vitro data determined in the guinea pig urinary bladder
`(KB, Table I) (7) for the selective reference compounds darifenacin (M3 selective) (9), UH-AH 37
`(low affinity for M2/m2) (10) and AQ-RA 741 (M/m2 selective) (11). On the other hand, the data
`on oxybutynin do not fit into this scheme. Oxybutynin shows a distinct selectivity profile with
`respect to the human mt-m5 receceptors expressed in CHO-cells, with the highest affinity at m3
`receptors (Ki 0.67 nM) > m4, mt (Ki 2.0 and 2.4 nM) ~ m2 (Ki 6.7 nM) ~ m5 (Ki 11 nM) (7),
`but the KB-value derived from studies on bladder contraction (4.4 nM) obviously correlates with
`binding data at rn2, rather than at m3 receptors (Table I).
`
`Functional (KB) and Binding (Ki) Data in Guinea Pig Tissues and CHO-Cells
`
`Table I
`
`Drug
`
`KB (nM)
`
`Urinary
`Bladder
`
`Ki (nM)
`
`Urinary
`Bladder
`
`Parotid
`Gland
`
`Tolterodine
`PNU-200577
`Oxybutynin
`
`Atropine
`Darifenacin
`UH-AH 37
`AQ-RA 741
`
`3.0
`0.84
`4.4
`
`0.70
`0.87
`5.2
`140
`
`2.7
`2.9
`4.0
`
`1.6
`78
`82
`12
`
`4.8
`5.2
`0.62
`
`0.85
`1.7
`26
`170
`
`Data from refs. 5, 7- 8.
`
`m2
`
`3.8
`2.0
`6.7
`
`2.9
`56
`49
`4.4
`
`m3
`
`3.4
`2.5
`0.67
`
`1.0
`1.2
`7.2
`55
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2004 - 0002
`
`

`
`Vol. 60, Nos. 13/14, 1997
`
`Tolterodine and Bladder Selectivity
`
`1131
`
`Tolterodine and PNU-200577 have about 8 times lower affinity than oxybutynin in the parotid
`gland (M3) and 4-5 times lower affinity at m3 receptors in CHO-cells (Table I) but they are not
`less potent than oxybutynin in inhibiting carbachol-induced contractions of the guinea pig bladder
`(5) (Table I). PNU-200577 is in fact 5 times more potent than oxybutynin in this respect. This
`cannot be explained by additional action(s) at other cellular targets, since both tolterodine and
`PNU-200577 show a very high degree of specificity for muscarinic receptors (5, 8 and
`Nilvebrant, unpublished data). Morover, both tolterodine and oxybutynin effectively inhibit
`electrically induced contractions of human detrusor strips, with IC50 values (tolterodine: 2.5 nM,
`oxybutynin: 3.2 nM) that are similar to the KB- and Ki- values determined in guinea pig bladder
`(12). The lack of correlation between functional data on bladder contraction and binding affinity
`at M/m3 receptors is not unique for oxybutynin. A similar profile has been found for
`dicyclomine: the KB value determined for dicyclomine in guinea pig bladder is 24 nM,
`(Nilvebrant, unpublished data), while the Ki -values determined in heart (M 2) and parotid gland
`(M3) are 24 nM and 2.8 nM, respectively (13). Whether these data indicate that not only M/m3
`receptors are involved in bladder contraction (14, 15) or that MJ receptors may be heterogeneous
`(16), remains to be clarified.
`
`Table II
`
`Selectivity Profiles In Vivo and in In Vitro Binding Studies
`
`Anaesthetised cat ID 50 nmol/kg
`
`Affinity ratios in vitro
`
`Drug
`
`Bladder
`Contraction
`
`Salivation Selectivity
`
`Guinea pig Tissues
`Bladder/Parotid gland
`
`CHOcells
`m2/m3
`
`Tolterodine
`101
`15
`PNU-200577
`Oxybutynin 200
`
`Atropine
`Darifenacin
`UH-AH 37
`AQ-RA 741
`
`18
`119
`311
`1060
`
`257
`40
`104
`
`21
`99
`120
`1536
`
`Bladder
`Bladder
`Salivary gland
`
`Non-selective
`Salivary gland
`Salivary gland
`Bladder
`
`0.6
`0.6
`6.5
`
`1.9
`46
`3.2
`0.07
`
`1.1
`0.8
`10
`
`2.9
`47
`6.8
`0.08
`
`Data from refs. (5, 7, 8, 17). Bladder contraction in vivo was induced by acetylcholine
`(i. a.) and salivation was induced by electrical stimulation of the chorda-lingual nerve.
`Antagonists were administered by intravenous infusion. Affinity ratios were calculated
`from the Ki-values displayed in Table I.
`
`The most interesting feature of tolterodine and PNU-200577 is that they are significantly more
`potent in inhibiting urinary bladder contractions than salivation in the anaesthetised cat (17, 8)
`(Table II). This favourable selectivity profile can obviously not be attributed to selectivity for a
`single muscarinic receptor subtype. However, the reference compounds which in binding studies
`show a selectivity for parotid gland over bladder and for m3 over m2 receptors in CHO-cells,
`oxybutynin, darifenacin and UH-AH 37, are more effective in inhibiting salivation than bladder
`contraction in vivo (Table II). Thus, a selectivity for M/m3 over M/m2 receptors is not necessary
`for an effective inhibition of bladder contraction in vivo, but may result in a more pronounced
`effect on salivation (Fig. 1).
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2004 - 0003
`
`

`
`1132
`
`Tolterodine and Bladder Selectivity
`
`Vol. 60, Nos. 13/14, 1997
`
`Bladder Contraction
`
`Salivation
`
`100
`
`75
`
`50
`
`25
`
`o
`
`c
`a
`P
`:9
`~
`c
`;f!.
`
`100
`
`75
`
`50
`
`25
`
`0
`
`c
`a
`P
`:0 :c
`E
`;f!.
`
`J.
`
`.25 L-~~~"--~~~""-~
`100
`1000
`10
`(Drug) nmol/kg
`
`·25
`10
`
`100
`
`1000
`
`(Drug) nmol/kg
`
`Fig. I
`Effects on urinary bladder contraction and salivation in the anaesthetised cat The rank
`order of potency for tolterodine (f::.), oxybutynin (.) and darifenacin (e) is different
`with respect to these two responses. Plots constructed from data in (7).
`
`The mechanism behind the bladder selectivity demonstrated for tolterodine and PNU-200577 in
`vivo is not known. Based on the combined in vitro and in vivo data, it may be speculated either
`that the M/m3 receptors in glands are more sensitive than those in the bladder, or that the M3
`receptors are heterogeneous (15). On the other hand, the Mjm2 selective antagonist AQ-RA 741
`exhibits a bladder selectivity which, although less pronounced, is similar to that demonstrated for
`tolterodine and PNU-200577 (7). This may suggest that Ml/rn2 receptors are involved in bladder
`contraction (c.f. 14-16) and that blockade of M/rn2 receptors in the bladder contributes to the
`favourable selectivity profiles of tolterodine and PNU-200577. However, muscarinic receptors
`involved in transmitter release are present on both adrenergic and cholinergic nerves in the
`detrusor of different species (2). A mixed prejunctional popUlation of inhibitory Ml and
`facilitating M I receptors has been demonstrated on postganglionic cholinergic nerves in the
`detrusor (18). The regulation of bladder function is complex and the relative functional
`importance of the different muscarinic receptors in vivo remains to be clarified. Nevertheless, the
`bladder selectivity demonstrated for tolterodine and PNU-200577 in the preciininical
`pharmacological in vivo studies seems to occur also in humans, as indicated by the data from the
`clinical phase I and II studies presented below.
`
`Clinical pharmacokinetics/pharmacology
`
`Tolterodine is rapidly absorbed and an approximate dose-proportional increase in peak serum
`levels is observed after about I h (19). Basic pharmacokinetic parameters are: half-life 2-3 h,
`systemic clearance about 30 llh and volume of distribution about 110 1. The major metabolic
`pathway of tolterodine involves hydroxylation of the 5-methyl group, mediated by cytochrome
`P450 2D6, resulting in the 5-hydroxymethyl derivative PNU-200577 (19-21), which is
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2004 - 0004
`
`

`
`Vol. 60, Nos. 13/14, 1997
`
`Tolterodine and Bladder Selectivity
`
`1133
`
`pharmacologically active (8). Similar mean peak serum concentrations (Cmax) oftolterodine and
`PNU-200577 are found in most human subjects (20). The 5-hydroxymethyl metabolite is further
`metabolised to the corresponding carboxylic acid. The other primary metabolic pathway, which is
`of minor quantitative importance, involves N-dealkylation oftolterodine (21). Excretion of the 5-
`carboxylic acid and the N-dealkylated 5-carboxylic acid metabolites accounts for about 80% of
`the dose excreted in urine. The excretion of intact tolterodine is low «1%) (19).
`
`In the first clinical phase I study, tolterodine was given as single oral doses (0.2-12.8 mg) to
`healthy volunteeers (19). After 12.8 mg, heart rate was increased by 35% after 1 h and salivary
`secretion (induced by chewing of paraffin wax) was decreased. Long-lasting (until the next day)
`and marked effects on bladder function, such as micturition difficulties, were reported by the
`healthy volunteers (22). Effects on the bladder were noticed also when dry mouth was no longer
`reported. This was the first indication that the selectivity for bladder over salivary glands is
`present also in humans. In a later study (23), in which effects on bladder function were measured
`by cystometry, it was confirmed that tolterodine exerts a significant inhibitory effect on bladder
`function after a single oral dose of 6.4 mg. Stimulated salivary secretion was also inhibited, but
`only around Cmax, while the effects on the bladder were more persistent. Thus, significant effects
`on cystometric variables were registered 5 h after dose and one subject experienced micturition
`difficulties up to 10 h after dose. No significant effects on blood pressure or heart rate were
`found. However, a considerable volume of residual urine was observed (23).
`
`One subject was found to have significantly higher serum levels of tolterodine than the other
`volunteers, without showing divergent urodynamic effects. It was speculated that this subject was
`a poor metaboliser of tolterodine (23). Later, in the clinical phase II studies, the majority of
`patients in the four dose groups (0.5, 1,2 and 4 mg) were found to have median peak serum
`concentrations oftolterodine of 0.4, 0.7,1.5 and 3.8 ~g/l, respectively, and concentrations of the
`5-hydroxymethyl metabolite PNU-200577 in the same range (20). However, a small proportion
`of the patients showed a pharmacokinetic profile in accordance with poor metabolisers, having
`about ten times higher tolterodine concentrations but no measurable concentrations of the 5-
`hydroxymethyl metabolite. The unbound fraction of the metabolite in human serum is, however,
`lO-fold higher than for tolterodine (3.7%) (Pahlman and Gozzi, manuscript in preparation) and,
`together with the data on the antimuscarinic potency in vitro (8), this indicates that the 5-
`hydroxymethyl metabolite (PNU-200577) accounts for the major part of the pharmacological
`effect oftolterodine in extensive metabolisers. In Caucasians, it can be expected that about 7% of
`the population are poor metabolisers.
`
`The conclusion from the early clinical phase I studies was that tolterodine shows a good
`tolerability over a wide dose-range. There was, however, an increase in urinary residual volumes
`after a dose of 6.4 mg and, therefore, 4 mg was selected as the highest dose for the clinical phase
`II studies. Despite the relatively short half-lives of tolterodine and PNU-200577, a twice daily
`dosage regimen was chosen because of the long-lasting effects on bladder function.
`
`Clinical phase II studies
`
`The safety, tolerability and efficacy of tolterodine have been evaluated in four randomised,
`double-blind, placebo controlled, parallel group, dose-ranging, multi-centre phase II studies.
`Patients with idiopathic detrusor instability (24) were recruited to two of these studies, while the
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2004 - 0005
`
`

`
`1134
`
`Tolterodine and Bladder Selectivity
`
`Vol. 60, Nos. 13/14, 1997
`
`other two studies comprised patients with detrusor hyperreflexia (25-26). Data from the entire
`phase II programme, encompassing 319 patients (203 women and 116 men, mean age 51 years,
`range: 17-76), have been pooled for analysis of safety and efficacy (20). A frequency of at least 8
`micturitions per 24 h, or at least one incontinence episode per 24 h, or both, was required for
`inclusion. A two-week wash-out period, during which any antimuscarinic treatment was
`prohibited, preceded randomisation. The treatment period was 14 days. Patients were randomised
`to one of four dosages oftolterodine tartrate: 0.5 mg bd (n=70), I mg bd (n=62), 2 mg bd (n=65),
`4 mg bd (n=58), or placebo (n=64). The criteria for a per protocol evaluation of efficacy was
`fulfilled by 262 of the 319 randomised patients.
`
`Effects on the bladder were objectively measured by cystometry. Significant dose-effect
`relationships were found for the volume at first contraction, the maximum cystometric capacity
`and residual volume (Fig 2) (20). The volumes at first sensation, normal desire to void, and strong
`desire to void also increased significantly in a dose-dependent manner.
`
`125
`
`100
`
`75
`
`50
`
`25
`
`E
`OJ
`.£
`W
`'"
`ro
`.0
`E
`0
`.....
`L..
`OJ
`01
`c
`ro
`~
`U
`
`0
`
`0.5
`
`2
`Tolterodine (mg, bid)
`Fig. 2
`Effect oftolterodine on cystometric variables measured in clinical phase II studies in
`patients with idiopathic detrusor instability or detrusor hyperreflexia: volume at first
`contraction (.), maximum cystometric capacity ( ... ) and residual volume (.), after
`two weeks of treatment.
`
`Urinary symptoms, recorded in micturition charts, showed a dose-dependent improvement in
`frequency of micturition, average volume voided and number of incontinence episodes (20, 24-
`26). In the groups treated with tolterodine 2 or 4 mg bd, the frequency of micturition decreased by
`about 15% and the average volume voided increased by 24% (20). The number of incontinence
`episodes decreased by 38% (2 mg bd) and 46% (4 mg bd). Many of the patients with detrusor
`hyperreflexia were on clean intermittent self-catherisation (25-26) and their habits cannot be
`expected to change during the rather short treatment period of two weeks. The effects on
`micturition chart variables may therefore be underestimated in the pooled material. Thus, in one
`of the studies on patients with detrusor instability (24), incontinence episodes decreased by 60 -
`65% and the frequency of micturition by 21-27%.
`
`There were no safety concerns with respect to blood pressure, clinical chemistry or haematology
`variables (20, 24-26). A minor, dose-dependent, increase in heart rate was noted (average 6 beats/
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2004 - 0006
`
`

`
`Vol. 60, Nos. 13/14, 1997
`
`Tolterodine and Bladder Selectivity
`
`1135
`
`min at tolterodine 4 mg bd) but there were no clinically significant changes in QT interval, QTc
`or other ECG variables (20). Dose-reduction was allowed during the first week of treatment, but
`this possibility was only used by nine patients. Five of these were in the 4 mg bd group (Table
`III). The number of withdrawals was lower for tolterodine than for placebo. Eighteen of the
`patients treated with tolterodine (n = 255) were tentatively classified as poor metabolisers. The
`tolerability and efficacy profile in these patients did not differ from that in the other patients.
`
`Table III
`
`Withdrawals and Dose-reductions
`
`Treatment Dose (mg bd) Patients (n)
`
`Dose-reductions (n) Withdrawals (n)
`
`0
`0.5
`
`2
`4
`
`Placebo
`Tolterodine
`Tolterodine
`Tolterodine
`Tolterodine
`
`Total
`
`64
`70
`62
`65
`58
`
`319
`
`0
`1
`3
`0
`5
`
`9
`
`5
`2
`2
`2
`3
`
`14
`
`Tolterodine was well tolerated and the adverse events reported were mainly of an antimuscarinic
`nature. Dry mouth was reported by 13% (8/64) of the patients in the placebo group. In the
`tolterodine groups, dry mouth was reported by 7% (5/70) of the patients on 0.5 mg, 13% (8/62)
`on 1 mg, 26% (17/65) on 2 mg and by 36% (21/58) of the patients on 4 mg (20). The dry mouth
`was considered mild to moderate and the incidence seems to compare favourably with reported
`data on oxybutynin (4). However, five cases of urinary retention occured, four in the 4 mg bd
`group and one in the 2 mg bd group. Together with the marked increase in residual volumes
`observed in the 4 mg bd group, this indicates that a dosage of 4 mg bd is too high and, thus, that
`the optimal efficacy/side-effect ratio is achieved with tolterodine in dosages of 1 or 2 mg bd (20,
`24-26). These doses were therefore selected for the phase III clinical programme.
`
`Conclusions
`
`Tolterodine is a potent muscarinic receptor antagonist which exhibits a favourable selectivity for
`the urinary bladder over salivary glands in vivo, in the anaesthetised cat. A major, active
`metabolite, the 5-hydroxymethyl derivative oftolterodine (PNU-200577), has a similar profile.
`The bladder selectivity oftolterodine and PNU-200577 in vivo cannot be attributed to muscarinic
`receptor subtype selectivity. However, data from clinical phase I and II studies indicate that a
`favourable selectivity profile is also obtained in humans. Tolterodine is well tolerated and it
`exerts marked inhibitory effects on bladder function while the propensity to cause dry mouth
`seems to be less pronounced. Phase II data on tolterodine in patients with idiopathic detrusor
`instability or detrusor hyperreflexia indicate that an optimal efficacy/side-effect ratio is achieved
`with tolterodine in dosages of 1 or 2 mg bd.
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2004 - 0007
`
`

`
`1136
`
`Tolterodine and Bladder Selectivity
`
`Vol. 60, Nos. 13/14, 1997
`
`UH-AH 37 and AQ-RA 741 were kindly supplied by Dr. H.N. Doods, Dr. Karl Thomae GmbH
`
`Acknowledegment
`
`References
`
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`Patent Owner, UCB Pharma GmbH – Exhibit 2004 - 0008