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`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1007 - Page 1
`
`

`
`288
`
`Brynne, Stahl, Hall4n et al.
`
`patients with bladder overactivity [Yarker et al. 1995]. The
`utility of this agent is restricted by a high incidence of
`adverse effects, such as dryness of the mouth [Cardozo et
`al. 19871.
`No currently available therapeutic agent has a selec-
`tive action on the muscarinic receptors of the bladder. A
`drug with a high antimuscarinic potency and a more blad-
`der-selective action is therefore desired. Preclinical data
`have shown that tolterodine ((R)-N,N-diisopropyl-3-(2-
`hydroxy-5-methylphenyl)-3-phenylpropanamine) exerts a
`high antimuscarinic potency in guinea pig and human
`detrusor muscle [Naerger et al. 7995, Nilvebrant et al'
`19941.It has also been shown that tolterodine displays a
`favorable tissue selectivity for the urinary bladder over
`salivary glands in the anesthetized cat [Gillberg et al.
`19941.
`Preliminary studies in healthy volunteers suggest that
`tolterodine bxerts a marked inhibitory effect on micturition
`fStahl et al. 1995]. The objective ofthe present study was
`to determine the pharmacokinetics, pharmacodynamics,
`and safety of tolterodine following single oral and intrave-
`nous (i.v.) doses in healthy volunteers. A secondary aim
`was to identify major urinary metabolites of tolterodine
`following oral administration and to quantify urinaryfecal
`excretion (mass balance).
`
`Subjects, material and methods
`
`Study drugs
`Tolterodine is a weak base (pKa 9.9) with an oc-
`tanol/phosphate buffer partition coefficient (log D) at room
`temperature of 1.8 at pH 7.3 (data on file lPharmacia &
`Upjohn ABI). For the purposes of this study, tolterodine
`(as the tarlrate salt) was prepared as water solutions (150
`ml) for use in dose escalation studies while a solution of
`1laC)-tolterodine (labelled in the u-posirion, 957o radio-
`chemical purity), together with unlabelled tolterodine, was
`prepared for determination of mass balance. Oral solutions
`of tolterodine were prepared by the Pharmacy, Lund Uni-
`versity Hospital, Sweden, while i.v. solutions of
`tolterodine were prepared by Pharmacia and Upjohn AB,
`Stockholm, Sweden.
`
`Subjects
`
`A total of 23 male Caucasian volunteers were in-
`cluded in the 3 parts ofthe study (oral dose escalation, i.v.
`administration, and mass balance determination). All vol-
`unteers were judged to be healthy by clinical examination,
`electrocardiography, and evaluation of laboratory parame-
`ters prior to study enrolment. Seventeen volunteers partici-
`pated in the oral dose escalation studies. Their mean (+
`standard deviation, SD) demographic characteristics were:
`age 28 + 7 years, body weight 77 ! 10 kg, and height 1.8 I
`
`I 0.04 m. Eight of these subjects subsequently received
`tolterodine i.v., while 6 additional volunteers received
`(14C)-tolterodine orally for determination of mass balance.
`The mean (t SD) demographic characteristics of these 6
`volunteers were: age 45 + 6 years, body weight 15 X 4kg,
`and height 1.80 I 0.06 m. Each participant provided in-
`formed written consent and the study protocol was ap-
`proved by the Ethics Committee of the University of Lund,
`Sweden.
`
`Study design
`
`The subjects fasted ovemight (from l0 p.m.) before
`drug administration and they abstained from food until a
`standardized lunch was given (4 h after drug administra-
`tion). No other drugs were allowed for 2 weeks prior to and
`48 h after each administration. In addition, smoking and
`the consumption of alcohol and caffeine-containing bever-
`ages were restricted prior to and for 48 h after drug intake.
`In the dose escalation part of the study, tolterodine
`was given as a single oral dose of 0.2,0.4,0.8, 1.6, 3.2,6.4,
`or 12.8 mg. Two subjects per dose were included in the
`lower dose interval (0.2 - 1.6 mg), while 8 subjects re-
`ceived 3.2, 6.4 and 12.8 mg, respectively. Blood samples
`( l0 ml) were drawn into Vacutainer tubes without additives
`prior to and at 0.33, 0.66, 1, 2, 3, 4, 6, 8, and 24 h after drug
`administration. After coagulation at room temperature for
`approximately 0.5 - I h the blood samples were centrifuged
`(1,000 g for 10 min). Serum was immediately separated,
`fuozen, and stored at -20o C pending analysis. Urine was
`collected quantitatively O - 24 h and 24 - 48 h after
`tolterodine dosage. Heart rate and blood pressure (supine)
`were simultaneously recorded by an automatic, noninva-
`sive, digital blood pressure meter (UA-751 , A and D Com-
`pany Ltd, Japan). Nearpoint of vision was determined
`using a RAF nearpoint rule (Clement Clarke Ltd., UK).
`Stimulated salivation was measured with a slightly modi-
`fied method used by Dollery et al. fl9761. The subjects
`chewed I tablet of paraffin (Orion Diagnostica, Espoo,
`Finland) altemately on the left and right side of the mouth
`for 5 min. All saliva was carefully collected in a plastic cup
`and weighed in order to calculate salivation flow (g/5 min).
`Measurement of heart rate, blood pressure, nearpoint of
`vision and stimulated salivation were performed prior to
`and at 0.25, 0.15, 1.25, 1.15,2.25,2.15,3.25,3.75, 4.15,
`5.25, 5.7 5, 6.25, 6 ;7 5, 1 .25, and 7 ;7 5 h after the administra-
`tion oftolterodine.
`Eight ofthe 17 subjects included in the dose escalation
`also received tolterodine i.v. Two subjects received a 5-min
`infusion of tolterodine 0.64 mg while all 8 subjects re-
`ceived an i.v. infusion of tolterodine 1.28 mg over 10 min.
`Blood samples (10 ml) were drawn prior to and immedi-
`ately after the infusion, and at 0.33, 0.66, 1, 2,3, 4,6,8,
`and 24 h after completion of the infusion. Quantitative
`collection of urine and measurement of heart rate, blood
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1007 - Page 2
`
`

`
`Qd puo xd aulporalloJ
`
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`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1007 - Page 3
`
`

`
`290
`
`Brynne, Stahl, Hall4n et al,
`
`TableI pertinentkineticestimatesobtainedaftersimultaneousfitoforaldata(3.2,6.4,arfi12.8mg)andinfusiondata(1.28mg)afteradministration
`of tolterodine to healthy volunteers.
`
`Parameter
`
`C*u* (pgA)
`t *(h)
`F (Vo)
`Vss G/kg)
`cL (l/h&e)
`MRr (h)
`trpp G)
`cLlF (l/h/kg)c
`
`Mean
`
`6.2u
`0.gu
`43
`1.4
`0.36
`4.1
`3.2
`1.6d
`
`3.2ms.h=4)
`Range
`
`CY (Va)
`
`54ms(n=3)
`Range
`
`cv (sa)
`
`Mean
`
`12.8 ms (n = 5)
`Range
`
`cv (qo)
`
`<0.7 - 13
`0.7 - 1.0
`23 -74
`0.9 - 1.6
`0.24-0.46
`2.9 - 6.7
`2.4 - 52
`0.38 - 3.1
`
`74
`t9
`51
`25
`2l
`44
`41
`63
`
`g.6b
`
`0.9b
`34
`1.4
`0.37
`4.2
`J.J
`2.4b
`
`2.5 - l7
`0.7 - 1.5
`23-48
`1.1 - 1.6
`0.23 - 0.47
`2.8 -7.0
`2.3 -5.3
`0.56 - 5.4
`
`63
`33
`38
`l8
`34
`57
`51
`83
`
`25b
`1.1b
`33
`1.3
`0.43
`3.0
`2.4
`l.7b
`
`56
`53
`55
`13
`
`6.8 - 54
`o.3 -2.0
`10-60
`1.1 - 1.4
`0.32 - 0.52 18
`2.7 - 4
`2.t - 2.9
`\ 0.71 - 4.8
`
`9.3
`13
`76
`
`a=basedonTsubjects,b=basedon8subjects,'=estimatedbynoncompartmentalanalysis,d=basedon6subjects,C.u*=peakserumconcentration'
`tmu = time to Cmu, F = bioavailability, Vs5 = volume of distribution at steady-state, CL = systemic semm clearance, MRT
`mean residence time,
`trpp = elimination half-life, cLA = oral clearance, cv = coefficient of variation
`
`1
`
`Fig. I Serum concentration time
`profiles of tolterodine after 6.4 mg
`oral (panel A) and 1.28 mg intrave-
`nous (panel B) single-dose admini-
`stration of tolterodine to 8 healthy
`volunteers.
`
`6b
`_10
`.E
`
`Eeoocoorl
`
`?oo
`
`bc
`
`.9
`
`10
`
`EcogboE
`
`Poo
`
`1
`
`were estimated according to standard equations [Gibaldi
`and Perrier 19821.
`Radioactivity in urine and feces was deterrnined quan-
`titatively and described as a function of time.
`
`Results
`
`AII subiects complied with the study protocol and
`completed the trial. Since only 2 subjects per dose level
`were included for the lower oral doses of 0.2 - 1.6 mg this
`presentation will emphasize the pharmacokinetics and
`pharmacodynamics after tolterodine doses of 3.2,6.4' and
`12.8 mg (8 volunteers per group).
`
`Pharmacokinetics
`
`Pharmacokinetic parameters from the noncompart-
`mental analysis and the simultaneous fit to oral and i.v. data
`are presented in Table 1 and serum concentration time
`
`profiles after 6.4 mg oral and 1.28 mg i.v. administration
`in Figure 1. Tolterodine was rapidly absorbed at all dose
`levels, time to peak serum levels (tmax) following oral
`administration was 0.8 - 1.1 h. A proportional increase in
`mean peak serum concentration (Cma*) (6.2 - 25 Fg/l) was
`observed at doses of 3.2 - 12.8 mg. CLiF showed high
`interindividual variability (range 0.38 - 5.4 Uh/r;g without
`any obvious dose relationship. Mean 1172 was constant (2.5
`- 3.0 h) with increasing dose. After a mean thg of 0.3 t 0.3
`h, tolterodine was absorbed withal'/;aof 0.4 + 0.3 h. The
`initial distribution phase was rapid (1.1tz11 < 0.33 h).
`Bioavailability exhibited high variability between indi-
`viduals, ranging from 10 to 74%o,while V55 and CL ranged
`from 0.9 to l.6lkg and from 0.23 to 052lhkg, respec-
`tively. On the basis of these results, MRT and elimination
`half-life (trlzp) were estimated to be 3 - 7 h and 2 - 3 h,
`respectively. Renal excretion of unchanged tolterodine was
`< l7o duringthe first 48 h and was independent of dose and
`route of administration. Similarresults were obtained when
`urine samples were incubated with B-glucuronidase prior
`to analysis.
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1007 - Page 4
`
`

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`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1007 - Page 5
`
`

`
`II
`
`TI
`
`Brynne, Stahl, Hall4n et al.
`
`Flg. 3 Mean (t SEM) heart rate
`(panel A), nearpoint of vision (panel
`B) and stimulated salivation (panel
`C) time profiles after single oral
`doses of tolterodine 3.2 mg (trian-
`gles),6.4 mg (squares) and 12.8 mg
`(circles) in healthy volunteers (8
`subjects in each dose group).
`
`292
`
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`complete inhibition of stimulated salivation was achieved.
`No clinically significant changes in either systolic or dia-
`stolic blood pressure were seen in any subject.
`
`C o nc e ntr ation-r e sp ons e r e lations hip
`
`The heart rate and salivation responses paralleled the
`tolterodine serum concentration time curves, peak re-
`sponses were observed around tmax &Ild declined with the
`elimination of tolterodine. There was a slight delay be-
`tween serum concentrations and heart rate response, but no
`apparent hysteresis for the effect on stimulated salivation.
`In Figure 4 the relationship between effects on heart rate
`and stimulated salivation versus serum concentrations of
`
`tolterodine has therefore been illustrated by a logJinear
`regression line (slope 2.5 (based on salivation data)). The
`Figure illustrates the lack of selectivity between the 2
`measured effects. However, a considerable difference in
`the maximal degree of the responses was seen. Maximal
`changes in heart rate and stimulated salivation observed
`after 12.8 mg were about+30Vo md-90Vo, respectively, of
`the pre-dose value. Figure 5 shows the salivary response
`versus serum concentrations after oral and i.v. administra-
`tion of tolterodine. Although comparable serum tolterodine
`concentrations were achieved after oral and i.v. administra-
`tion, only small decreases in stimulated salivation were
`observed after i.v. infusion compared with the oral route.
`Figures 4 and5 are based on observation up to 4 hours after
`dose.
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1007 - Page 6
`
`

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`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1007 - Page 7
`
`

`
`294
`
`Brynne, Stahl, Hall4n et al.
`
`estimated bioavailability (10 - 707o) cleatly suggested
`variable first-pass elimination, which may reflect differ-
`ences between subjects with respect to metabolic capacity.
`The systemic clearance of subject 1 6 (0.23 lkkg was thus
`notably lower than the overall average, and h2p of
`tolterodine in this subject was considerably longer (5'3 h).
`This dissimilarity was probably due to differences in he-
`patic metabolic capacity. Recently, Stahl et al. [1995]
`reported a subject with atr2gof 15 h following a single 6.4
`mg oral dose of tolterodine. The metabolic phenotype of
`this subject was subsequently characterized, using
`mephenytoin and debrisoquine - two probe drugs that are
`well established for determination of the polymorphically
`distributed cytochromes P450 2Cl9 and P450 2D6
`(CYP2CI9 and CYP2D6) [Bertilsson 1995]. The subject
`was classified as an extensive metabolizer of mephenytoin
`and a poor metabolizer of debrisoquine, which indicates
`that CYP2D6 may be involved in the metabolic clearance
`of tolterodine.
`Since it is difficult to obtain consecutive response
`measurements on the bladder over time, we assessed
`known antimuscarinic effects - such as increases in heart
`rate and nearpoint of vision and decrease in stimulated
`salivation - in order to characterize the pharmacological
`effects of tolterodine. While the absence of a placebo group
`in this study limited the interpretation of the effects of
`tolterodine, overall trends could be observed. At a dose of
`12.8 mg the maximum increase in heart rate was 20
`beats/min and an almost total inhibition of stimulated
`salivation occurred. Both responses were superimposable
`and suggest that the concentrations of tolterodine at an
`approximate half maximal response, on heart rate and
`salivation, were about 6 - 8 pg/I. The differences in mag-
`nitude might indicate that muscarinic M: receptors in
`glands are more sensitive to blockade than Mz receptors in
`the heart. However, there was an overlap between the
`serum concentrations where the respective responses oc-
`curred, which is in agreement with preclinical findings that
`did not demonstrate selectivity for a single muscarinic
`receptor subtype [Nilvebrant et al. 19961.
`Data from a urodynamic study in healthy volunteers
`by Stahl et al. [1995] showed that a single 6.4 mg oral dose
`of tolterodine exerts a powedul inhibitory effect on mic-
`turition, both subjectively and objectively. The reported
`rapid onset of an effect on the bladder is in agreement with
`the pharmacokinetic data in this study. Stahl and colleagues
`concluded that a dose of 6.4 mg would be too high for use
`in a future patient population. No effect on accommodation
`for nearvision was found at the dose used by Stahl et al.,
`while at a dose of 3.2 mg no apparent effect on hearl rute
`and only a slight inhibition of stimulated salivation was
`found. In contrast to the salivary response, the effect of
`tolterodine on urodynamic parameters did not change
`markedly between 1 and 5 h after drug administration
`lStahl et al. 1995]. The cause of the relatively longer
`duration of the bladder response is at present unclear.
`
`However, data from preclinical studies in the anesthetized
`cat have shown a more shallow dose-response relationship
`for effect on the bladder compared with effect on salivation
`[Gillberg et al. 1994]. If there is a similar dose-response
`relationship in man this might be associated with the sub-
`jective reports of persistent micturition difficulties for up
`to 16 h after drug administration in this study.
`There was a large discrepancy between the observed
`effect and tolterodine serum concentrations after oral and
`i.v. administration. This was evident for decreased saliva-
`tion as well as increased heart rate. This suggested a major
`contribution from an active metabolite(s) besides the phar-
`macological activity of tolterodine. Since the salivation
`response profile closely followed the tolterodine serum
`concentration time curve it seems likel! that the pharma-
`cokinetics of the active metabolite(s) is formation rate-lim-
`ited. The effect on salivation might have a pharmacody-
`namic ICso value at metabolite concentrations correspond-
`ing to 6 - 8 pgA ofparent tolterodine after oral dosage (but
`not after i.v. administration).
`The incidence of adverse effects was less frequent at
`lower doses and typical antimuscarinic adverse effects
`were clearly dose-related up to 12.8 mg. In view of the
`adverse events profile, clinical laboratory and vital signs
`data, tolterodine was judged to be well tolerated at all dose
`levels up to 12.8 mg.
`
`Acknowledgements
`
`We thank Dr. Karl-Erik Andersson and Dr. Bengt Sparf for their
`valuable contributions to the development of these initial human phatma-
`cological studies. We are grateful to R.N. Gertrud Lundquistforher skilful
`assistance.
`
`REFERENCES
`
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`muscles and penile erectile tissues. Pharmacol Rev 45: 253-308
`B ertil ss on Z 1995 GeographicaVinterracial differences in polymorphic
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`(CYP) 2D6 and2Cl9. Clin Pharmacokinet29: 192-209
`B laiv as J G, Labib KB, M ic halik J, Zay e d AAH 7980 Cystometric re sponse
`to prophanteline in detrusor hyperreflexia: therapeutic implications.
`I Urol 124: 259-262
`Cardozo LD, Cooper D, Versi E 1981 Oxybutynin chloride in the man-
`agement of idiopathic detrusor instability. N