Table 37. Mean Pharmacokinetic Parameters of Tolterodine after Oral Administration (DAY 5)
`
`
`
`1% (h)
`AUC 0-12 h (pg hm
`
`
`
`
`
`Pharmacodynamics
`seemed to
`After 2 mg b.i.d. the average decrease in stimulated salivation was about 50%. Subject
`have a decrease in systolic blood pressure. No other significant disturbances on the effect parameters
`were noticed.
`
`showed
`After 4 mg b.i.d. the average decrease in salivation was slightly more pronounced. Subject
`a transient decrease in systolic and diastolic blood pressure, -32%!-43%. No other significant disturbances
`on the effect parameters were noticed.
`
`showed a
`After 6 mg b.i.d. the average decrease in stimulated salivation was about -80%. Subject
`general increased in heart rate. Some disparate results in diastolic blood pressure were measured.
`in
`subject
`- an increase with 16% followed by a decrease with 25%, while in the other two subjects a
`slight increase was noticed.
`
`Adverse reactions
`
`experienced micturation difficulties starting on day 3
`At 2 mg b.i.d. two subjects out of four
`in addition subject
`reported more frequent
`and in the afternoon of day 2, respectively.
`micturitions on days 2. 3 and 4 and on days 2 and 3, respectively. No other reactions were reported.
`
`this
`At 4 mg b.i.d. three of the four subjects reported problems discharging urine. In subject
`only experienced
`was more or less pronounced at all micturitions from the first day, while subject
`voiding problems twice, and less frequent micturitions during all the 5 days. The duration of inhibited
`bladder function in subject
`was roughly estimated to 4-8 hours after drug administration. Dry
`mouth was experienced by all the four subjects; by
`in most instances together with dry eyes.
`
`At 6 mg b.i.d. all subjects (3 out of 3} reported dry mouth and disturbed micturation. Two subjects
`experienced micturation difficulties during all the 5 days while subject
`reported more frequent
`micturation and difficulties holding the urine but difficulties voiding on only one occasion. Dry mouth
`generally commenced 1 hour after drug administration with an approximate duration of 1-6 hours. Subject
`also exhibited gastrointestinal disturbances
`(abdominal cramps and constipation,
`
`respectively).
`Sponsor's Conclusions:
`1. The three multiple-dose regimens (2, 4 and 6 mg b.i.d. for 5 days) were well tolerated. The clinical '
`chemistry variables were within the normal range as well as the tests on liver enzymes.
`2. The safety measurements on heart rate and blood pressure during the regimens did not reveal
`anything abnormal.
`3. Linear kinetics within the whole dose" range was evident in one subject while proportionaiity up to 4 mg
`b.i.d. was apparent in one additional subject. The remaining two subjects showed almost unchanged AUC
`and Cm with increasing dose.
`4. The stimulated secretion of saliva was significantly inhibited with increasing dose. One subject showed
`an increase in heart rate at the highest dose.
`After 6 mg b.i.d. all subjects reported micturation disturbances and two subjects had effects on the
`gastrointestinal-tract.
`
`aen wner,
`
`3
`
`' arma m— X II
`
`

`
`Reviewers Comments:
`1. The amount of unchanged drug eliminated in the urine was 0.1 — 0.2% of the administered dose.
`
`

`
`Study Number: 92-OATA 001
`
`study Title: Electrophysiological heart effects of repeated iv. Atropine injections. repeated oral dosage of
`tolterodine and placebo to healthy human volunteers in a parallel group design (study 8)
`
`Study Objectives: The study was designed to discover potential electrophysiological heart effects of
`tolterodine at two different doses in healthy human volunteers. A comparison was made to treatment with
`placebo and treatment with atropine.
`
`As a secondary objective a phannacokinetic evaluation of tolterodine was performed.
`
`It was
`Study design: The study was single-blind, placebo controlled and with three parallel arms.
`randomized for 36 subjects. 12 in each of the three groups. The three groups received the following
`sequences of drug:
`
`
`
`EIIEEIEI
`Em
`Ii
`T
`
`
`
`
`
`
`
`
`
`Subjects: The study was designed for 36 healthy volunteers, 12 in each of the three groups. The choice
`of sample size was based on power considerations and on results from previous studies of utilizing
`determination of QTC-prolongation in healthy subjects.
`
`Phenotyping for Cytochrome P-450 2D6 (Debrisoquine) and 2C19 (Mephenytoin) was performed prior to
`the study and the result was used in the inclusionlexclusion process. The procedure was as follows:
`
`After emptying the bladder at bedtime, each subject took one tablet of Mephenytoin (100 mg) and 1/2 a
`tablet Debrisoquine (10 mg) orally. Urine was collected over night and the concentration relation
`(metabolic ratio. MR) between Debrisoquine and 4-OH-Debrisoquine as well as the concentration relation
`between the enantiomers of mephenytoin (enantiomeric ratio, SIR) were determined by
`
`A subject with a metabolic ratio of more than 12.2 for Debrisoquine I 4-OH-Debrisoquine andlor a SIR
`enantiomeric ratio of mephenytoin of approximately 1 were considered as a poor metabolizer.
`The analysis of urine for phenotyping as described (above) was performed at
`0
`
`nd Administration:
`
`Dosage Fonns, Dosagga
`tolterodine table. 2 mg
`Pharmacia AB). Batch no 3022-0—A1
`_
`Placebo (tolterodine) table.
`Pharmacia AB). Batch no DFP 344
`Atropine sulph. inj. sol., 0.5 mglml -.
`Pharrnacia AB), Batch no SG 090A.
`Sodium chloride. sterile solution 9 mgiml.
`Pharrnacia AB), Batch no 3011222.
`Debrisoquine tablet. 20 mg (for phenotyping).
`Batch no 1180.
`Mephenytoin tablet, 100 mg (for phenotyping).
`Batch no 361 F3575.
`
`Saline injections:
`l.v.
`injection of 5 ml saline during 1 minute with a subsequent catheter flush with 5 ml saline. The
`procedure was repeated 5 times with half an hour intervals.
`
`47
`
`aen wner,
`
`:
`
`' arma m— XII
`
`

`
`Atrogine day:
`l.v. injection of 1 ml atropine (0.5 mglml) in 4 ml saline during 1 minute with a subsequent catheter flush
`with 5 ml saline. The procedure was repeated 5 times with half an hour intervals. Five doses of atropine
`were a maximum and it was optional to give fewer injections at the discretion of the investigator.
`
`tolterodine lglacebo day 1- 7:
`
`morning only.
`
`The tablets were intended to be taken in the morning (8 am) and evening (8 pm) and were to be
`swallowed with half a glass of water. The exact time was to be recorded on a special form by the subjects.
`Blood sampling: Blood samples (7 ml) for determination tolterodine in serum was drawn by means of an
`intravenous catheter as follows:
`Day 1: Prior to first dose (baseline) and 0.5, 1, 1.5. 2, 3.5, 5, 7, 9 and 12 hours thereafter.
`Day 4: Prior to morning dose and 1 and 5 hours after morning dose.
`Day 7: Prior to morning dose and 0.5. 1. 1.5, 2. 3.5, 5, 7. 9 and 12 hours thereafter.
`Day 8: 24 hours after last dose
`Day 9: 48 hours after last dose
`
`Analvtical methodology:
`
`RESULTS
`ECG-variables
`Atropine treatment
`During atropinelplacebo treatment there were statistically significant differences between treatments for
`the ECG-.varlables HR, QT, QTc. TDUR and T-wave amplitude (positive defiection, +Tampl in leads I-Ill,
`aVF, V,-V5 and negative deflection, -Tampl in leads aVR and V.) as regards mean changes from baseline.
`I For the other ECG-variables investigated in this study (PDUR, PR. QRS and T-wave amplitude - positive
`and negative — in other leads than those mentioned above) no more than occasional statistically significant
`differences could be shfim. although there were tendencies to a decrease in mean value for several of
`these variables.
`
`4
`
`The differences between placebo and atropine are fully expected. The increase in HR which is a result of
`the parasympathetic inhibition by atropine is logically followed by a shortening of several individual ECG
`parameters. The manual evaluation of T wave morphology in V” after atropine did not reveal any change
`in this parameter.
`/I
`
`Tolterodine treatment
`During tolterodine lplacebo treatment statistically significant differences between treatments as regards
`mean changes from baseline could be seen only on a few isolated occasions in time.
`HR was not influenced by 2 mg dosage level. With 4 mg, however, in less than half of the measurements.
`there was a statistically significant
`increase (range; 7-13 beatsimin,
`i.e. < 20%). These increases
`
`48
`
`a en wner, I
`
`-
`
`arma m ' —
`
`X "
`
`

`
`occurred clustered to the first hours after the morning dose, i.e. around time for Cm, This finding was fully
`expected due to the anticholinergic nature of the drug.
`The manual evaluation of T-wave morphology in lead VH5 did not reveal any change in this parameter after
`administration of tolterodine.
`
`No evidence of any increase in GT or QT: after administration of tolterodine were seen, neither when
`looking at the group mean values nor when looking at the individual extreme values.
`Minimum and maximum group mean values of QT and GT‘ during the atropine day and during tolterodine
`day 1 and 7 are shown in Table 39.
`
`Table 39. Minimum and maximum group mean values and (SD) of QT and QTc during the atropine day
`and during tolterodine day 1 and 7.
`
`mg b.i.d.I
`
`
`Qmup
`b.i.d.
`T iflfij 419 (17) _ /410_(1§l
`
`maximum
`minimum
`
`_Atropine
`tolterodine4
`.i.d._ Placebo
`
`
`
`Day 7
`maximum
`minimum
`,
`
`o
`2nd baseline measurement
`
`
`
`_
`
`_
`
`_
`
`_
`
`
`
`
`
`
`Z b
`
`mg b.i.d.
`
`
`
`group
`
`—
`
`minimum
`
`
`
`
`
`
`
`The normal QT, is often stated to be below 440 ms. Recent literature have however shown that the normal
`variability of QT and GT, is substantially higher than previously anticipated. Normal ranges of QTc of up to
`506 ms and of QT up to 487 have been reported. Furthermore, for individual subjects a high degree of
`daily variability in OTC has been shown.
`
`For comparison, the minimum and maximum extreme values obtained during baseline measurement.
`during day 1 and during day 7. for the different groups in this study are presented in Table 40. individual
`values of a OTC > 440 were frequently seen also in our material.
`
`R
`
`49
`
`aen wner,
`
`:
`
`' arma m— X II
`
`

`
`Table 40. Minimum and maximum extreme values of QT and QT,, during the atropine day and during
`tolterodine day 1 and 7.
`
`Baseline‘ maximum
`minimum
`
`Day?
`
`maximum
`minimum
`
`.
`
`,_
`.
`. 9:;
`
`_
`'_
`
`...
`
`maximum
`
`minimum
`maximum
`
`maximum
`minimum
`
`'* 2nd baseline measurement
`
`Blood pressure
`Atropine treatment
`During atropinelplacebo treatment there were statistically significant differences between treatments for
`diastolic blood pressure but not for systolic blood pressure as regards mean changes from baseline. Here,
`baseline was defined as the mean of the two replicate BP measurements recorded immediately before the
`first- iv. injection. These significant differences were present between 1 hour 15 min (after 3rd dose) and 2
`hours 15 min. (after the 5th close). For diastolic blood pressure there was an estimated average difference
`between atropine treated subjects and placebo treated subjects of about +10% (of baseline). An increase
`in diastolic blood pressure was expected. but its magnitude (6.1 - 8.9 mm Hg as a range) was somewhat
`higher than anticipated.
`
`Tolterodine treatment
`
`During tolterodine/placebo treatment there were no statistically significant differences between treatments;
`neither for diastolic nor for systolic blood pressure as regards mean changes from baseline other than on
`a few isolated occasions in time.
`
`The baseline was defined as the mean of the two replicate measurements recorded immediately before
`the first tablet intakegon day 1 of tolterodinelplacebo treatment.
`
`Serious adverse ever“: No serious adverse events occurred during the trial.
`
`Pharmacokinetics: Mean pharmacokinetic parameters of tolterodine and the 5-Hydroxymetabolite (5~'
`HM) are presented in Table 41. below.
`
`

`
`Table 41. Mean (SD) Pharmacokinetic Parameters of tolterodine and 5-Hydroxymetabolite (n=ll).
`Tolterodine
`
`iuslll
`
`(H9-hill
`
`(hi
`
`tug")
`
`lug-hill
`
`lb)
`
`
`
`
`
`4rng.day1
`
`4.2 (5.2)
`
`2.2(o.9)
`
`4mg, day?
`
`4.6 (6.1)
`
`(15.1)
`
`(14.2)
`
`22.4
`
`(33.3)
`
`(34-1)
`
`2.5(1.2)
`
`
`
`
`12.1(3.3)
`
`3.4 (1.7)
`
`25.o(9.a) 3.3(1.2)
`
`25.5(7.3)
`
`3.2 (0.3)
`
`' The AUC values are presented as AUC: after single—dose administration and AUC0 after multiple dose
`administration.
`
`"' Note that subject no 29 received only atropine and is not included in this table.
`
`No accumulation of tolterodine or its metabolite 5-HM was seen after multiple-dose administration. Cm,
`and AUC increased proportionally with increasing dose,
`suggesting linearity of pharrnacokinetics.
`Tolterodine and 5—HM were present within the same concentration range.
`
`Sponsor's Conclusions:
`
`Intermittent intravenous administration of atropine in doses of 0.5 mg significantly depressed T-
`o
`amplitude and shortened the T—duration, QT and QTc between cumulative doses of 1 - 2.5 mg.
`
`o
`
`Tolterodine, 2 and 4 mg b.i.d. did not prolong QT or QT‘.
`
`Toiterodine, 2 and 4 mg b.i.d. did not influence either T—wave amplitude, T-wave duration or T-wave
`-
`morphology.
`
`Tolterodine, 2 and 4 mg b.i.d. has not created any kind of safety concern: neither regarding
`-
`cardiovascular evaluation, clinical chemistry, l1ematolo95'. urinalysis nor adverse events.
`
`-
`
`No accumulation of tolterodine or its 5-hydroxymetabolite was seen after multiple dose administration.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`51
`
`aen wner,
`
`3
`
`' arma m— X II
`
`3
`
`

`
`Study Number: 93-OATA 004
`
`Study Title: Pharmacological effects are kinetics of tolterodine in poor and extensive metabolizers of
`debrisoquine.
`
`Study Objectives: To investigate the pharmacological effects and kinetics of tolterodine in poor and
`extensive metabolizers of debrisoquine.
`
`Study design: This was an open, oomparative. multiple dose study.
`
`Subjects: 16 healthy male volunteers were enrolled
`
`Phenotyping for Cytochrome P-450 2D6 (Debrisoquine) and 2C19 (Mephenytoin) was performed prior to
`the study and the result was used in the inclusionlexclusion process. The procedure was as follows:
`
`After emptying the bladder at bedtime, each subject took one tablet of Mephenytoin (100 mg) and H2 a
`tablet Debrisoquine (10 mg) orally. Urine was collected over night and the concentration relation
`(metabolic ratio, MR) between Debrisoquine and 4-OH-Debrisoquine as well as the concentration relation
`between the enantiomers of mephenytoin (enantiomenc ratio, SIR) were determined by
`
`A subject with a metabolic ratio of more than 12.2 for Debrisoquine I 4—OH-Debrisoquine and/or a SIR
`enantiomeric ratio of mephenytoin of approximately 1 were considered as a poor metabolizer.
`The analysis of urine for phenotyping as described (above) was performed at
`
`Test Product: Tolterodine, 2 mg tablets, batch No. 3022-O—A—1.
`
`Treatment Duration: 4 mg b.i.d. for 8 days.
`
`Results:
`
`The pharmacokinetic parameters of tolterodine from
`Table 42.
`
`Cmax (pg/l)
`
`Cl (llh)
`
`38:15
`
`I
`Sponsors Conclusio
`
`Tolterodine L-tartrx-4 mg b.i.d. and 1.8 mg infusion has not created any kind of safety concern;
`-
`neither regarding cardiovascular evaluation. clinical chemistry. hematology, urinalysis, nor adverse events.
`-
`Tolterodine is highly and selectively metabolized by CYP2D6 to DD01.
`
`It seems that the higher tolterodine concentrations in the poor metabolizers compensate for the
`-
`absence of the active metabolite DD01 in these subjects.
`
`

`
`Study Number: CTN 93-OATA-007
`
`Study Title: Tolerability and pharrnacokinetic effects of tolterodine L-tartrate in elderly. A randomized
`double—blind study in healthy volunteers.
`'
`
`Objectives: To investigate safety and tolerability of tolterodine in elderly with special reference to
`cardiovascular effects. To investigate the pharmacokinetics after single- (1, 2 and 4 mg) and multiple-dose
`(2 mg b.i.d.) administration.
`
`Study Design: Randomised double-blind parallel group design (4 groups).
`
`Subjects : 8 male and 18 female healthy elderly volunteers (age 64-80 years) were enrolled in the study.
`Two (2) subjects,
`(poor metabolizers) were treated separately and received the doses
`unblinded.
`
`Test product: Tolterodine L-tartrate tablets, 1 mg (Pharmacia AB). Batch No: B039303
`Composition
`
`
`
`-—.a
`
`
`in redientr —
`A?__<i____ctIve
`“Q ——
`Cnfiuimamefi
`laMe_t&0fimub
`
`
`
`
`
`mg
`mg
`mg
`mg
`mg
`mg
`mg
`mg
`mg
`mg
`— mum mg
`
`
`
`
`
`
`Reference product: Placebo (Pharmacia AB). Batch No: B019303
`Composition
`
`
`
`
`
`
`
`
`
`Duration of treatment: 1, 2. and 4 mg single-dose administration and 2 mg b.i.d. for 5 days.
`Blood and Urine Samfing:
`Single dose administration: Venous blood samples were drawn before administration of study drugland at
`15, 30, 45 minutes and at 1, 1.5,'2, 4, 6, 8, 10. 12, 24 and 25 hours after drug administration.
`
`Multiple close administration: Venous blood samples were drawn immediately before administration on
`day 4, before administration of study drug on clay 5 and at the following times after administration on day
`5: 15, 30, 45 minutes, 1, 1.5, 2,4,6, 8,_,1U, 12,24 and 25 hours.
`
`Urine: A urine sample was collected immediately before dosing on day one (single dose part). Urine was
`collected quantitatively in the intervals 0-12 and 12-24 hours during single dosing and on day five during
`multiple dosing. Each urine sample was carefully shaken and a 10 ml aliquot was prepared. The samples
`were frozen and stored at -20 “C until analyzed for unchanged drug and DD 01.
`
`aen wner,
`
`=
`
`' arma m— XII
`
`-53
`
`1
`
`

`
`Analytical Methodology:
`
`Serum protein binding:
`The degree of in vivo binding to serum proteins was estimated for tolterodine and DD 01. The free
`concentration (Cu) and total serum concentration (Cs) were measured in the 1 hour serum sample after
`the last dose (day five, multiple dose session). Free fraction (fu) was to be estimated from the ratio of Cu
`to Cs. Free concentration, Cu, in serum was to be measured by means of equilibrium dialysis.
`
`RESULTS
`
`Safety: No treatment related effects on clinical laboratory safety variables were seen comparing screening
`to post-study assessment. No clinically significant findings were seen considering changes in QTc. or in
`the other measured ECG parameters .
`
`Pharmacokinetics: A summary of the pharmacokinetic parameters is presented below.
`
`Table 43. Mean (SD) Pharmacokinetic Parameters of Tolterodine and DD 01 after multiple dose (5 days)
`administration of 2 mg b.i.d. tolterodine L-tartrate
`
`
`
`
`
`t1/2 (h)
`AUCO-t (pghll)
`CLO (llh)
`fe (% of dose)
` -Eliflfij
`
`
`
`
`
`Table 44. Mean (SD) Pharmacokinetic Parameters of Tolterodine and DD 01 after single oral
`administration of tolterodine L-tartrate.
`
`
`i
`
`- Dose
`tmax
`Cmax
`Cav
`t1,r2
`AUC
`CLO
`tmax Cmax
`Cav
`t1 )2
`AUC
`0-!
`(mg)
`(hi
`lust!)
`(ugh)
`(h)
`(m1)
`(h)
`(iJ9(|)
`(1191!)
`(11)
`0-t
`lughfll
`(iJ9hIi)
`
`
`3.9
`0.47
`1.1
`0.53
`372
`2.4
`0.22
`0.79
`0.33
`1
`2.5
`5.7
`(1.1)
`(0.15)
`(0.39)
`(0.14)
`(235)
`(1.2)
`(0.13)
`(0.45)
`(0.20)
`(n=6)
`(1.5)
`(2.0)
`2.9
`0.92
`2.5
`0.83
`353
`1.9
`0.35
`1.5
`0.72
`2
`4.4
`11
`(0.2)
`(0.31)
`(0.73)
`(0.33)
`(151)
`(0.55)
`(0.12)
`(0.55)
`(0.20)
`(n=5)
`(1.4)
`(3.7)
`3.5
`2.1
`5.0
`0.71
`399
`2.3
`1.2
`3.3
`0.53
`4
`14
`25
`
`
`(0.72)
`(1.0)
`(2.1)
`(0.19)
`(330)
`(0.43)
`(1.0)
`(3.2)
`(0.14)
`(n=s)
`(12)
`(12)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Poor metaboiizers
`
`The poor metabolizers showed no detectable concentrations of DD 01. The half-life of tolterodine was 3-4
`times longer than in Extensive metabolizers, Table 45.
`5%
`Table 45. Pharmacokinetic parameters of tolterodine in Poor Metabolizers (P-450 2D6).
`fe (% of_
`Subject
`Dose
`tmax
`Cmax
`Cavg
`t1)r2
`AUC‘
`Clo (Uh)
`dose)
`No.
`(019)
`(h)
`(1491!)
`(H91!)
`(11)
`(u9h(|)
`-a-—m.=——:1
`
`
`
`
`
`
`
`ijfmIII - ji
`
`
`
`
`
`
`
`steady-state maximum
`proportionality. The
`suggests dose
`pharmacokinetics
`single-dose
`The
`concentrations of tolterodine and DD 01 were 1.6 and 2.7 pgll, respectively and the respective, ha|f—Iives
`were 2.8 and 3.6 hours. No accumulation of tolterodine or DD 01 was seen after b.i.d. multiple dose
`administration with the exception of the poor metabolizer. This subject had a two-fold accumulation, which
`is in accordance with the longer half-life (16 hours).
`
`aen wner,
`
`=
`
`' arma m— x II
`
`I
`
`

`
`Steady-state serum concentration-time profiles of tolterodine and DD 01 after multiple doses of tolterodine
`(2 mg b.i.d.) are depicted in Figures 6 and 7.
`
`Figure 6. Serum Concentration versus Time Profile of Tolterodine
`
`(pgfll
`Serumconcentration
`
`Figure 7. Serum Concentration versus Time Profile of DD01.
`
`Time (h)
`
`6
`‘Fume (I1)
`
`B
`
`10
`
`I2
`
`M
`
`5-
`
`4-
`
`3-
`
`2-
`
`1-
`
`O—
`002
`
`4
`
`»‘=':‘
`U1
`3C
`.9
`E
`EG)UC
`3
`
`Ea0
`
`U’)
`
`3?:
`Sponsor's Conclusions:
`-
`From the present study with eldeny subjects it can be concluded that tolterodine 1, 2 and 4 mg given.
`as single doses and 2 mg b.i.d did not create any kind of safety concerns; neither
`regarding
`cardiovascular effects (ECG. heart rate and blood pressure). clinical chemistry. hematology, urinalysis nor
`adverse events.
`a
`
`o
`
`The sing|e—dose pharmacokinetics suggests dose proportionality with respect to Cmax and AUC.
`
`No accumulation of tolterodine or DD 01 was seen after multiple dose with exception for the poor
`-
`metabolizer_ This subject had a two-fold accumulation, which is in accordance with the longer half-life in
`this subject.
`
`aen wner,
`
`3
`
`' arma m— X II
`
`

`
`o Cavg , Cmax and AUC of tolterodine and DD 01 increased proportionally with increasing dose and
`time. There were no consistent dose-dependent changes in half-life of tolterodine or DD 01 or orai
`clearance of tolterodine.
`
`The serum concentration levels of DD 01 was about the same or a little higher than those of
`-
`toiterodine. No accumulation of either tolterodine or DD 01 was seen after multiple-dose administration.
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`APPEARS THIS WAY
`ON ORIGINAL
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`aen wner, =' arma m— XII
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`I -
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`

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`study Number: CTN: 94-OATA-013
`
`Study Title: Safety and tolerability of tolterodine after multiple-dose administration to elderly subjects: A
`randomized, double-blind, placebo-controlled study
`
`Objectives: The primary objective was to assess the safety and tolerability of multiple doses of tolterodine
`in elderly subjects at least 70 years of age. A secondary objective was to determine the serum
`concentrations of both tolterodine and DD 01. and a final objective was to assess the feasibility of
`administration of micturation charts in this age group.
`
`Study Design: This was a multi-center.
`controlled study.
`
`randomized. double-blind. parallel,
`
`three groups, placebo
`
`Subjects: Thirty three elderly subjects 70 years of age or older; at least 50% >75 years were enrolled in
`the study. The subjects were randomized, 7 to the placebo and 26 to the active treatment (14 - 1 mg and
`12 - 2 mg) groups. Four subjects (12%) were phenotype for CYP2D6 as poor metabolizers according to
`the dextro-methorphan assay.
`'
`
`Test product: Tolterodine L—tartrate tablets (0.5 and 1- mg) batch No. BB121027 and B039303.
`respectively
`
`Duration 8. Dosage: The subjects received either placebo, or tolterodine 1 or 2 mg b.i.d. for 28
`consecutive days.
`
`Assay Methodology:
`
`Blood Sampling: Venous blood samples (5 mL Vacutainer® tube, no additives) for assessment of serum
`drug I metabolite levels were collected pre- and post-morning dose at 0, 0.5. 1. 2, 4, 6 and 8 hr on Days 1
`and 28. On Day 7, bur blood samples were obtained at 0, 0.5. 1 and 2 hours post-morning dose.
`Results
`k
`Kinetics aftera Single Dose (Day 1)
`Absorption of tolterodine was rapid with the T"... attained following both doses between 0.5 to 2 hours."
`For the 1 and the 2 mg doses respectively, the single dose estimates (mean 1- SD) of tolterodine were:
`Cm, 2.8 (12.8) and 2.8 (12.1) ngfmL, AUCCL, 7.09 (14.75) and 8.76 (26.09) ng.hrlmL, the terminal half-life
`(t,,,,2t,) 2.06 (20.68) and 2.16 ($0.44) hr..-Body weight normalized estimates of CL, were 2.18 (11.43) and
`3.02 (::1.64) Llhrlkg, and for Va}, were 6.2 (14.30) and 9.0 (24.7) Ukg following the 1 and 2 mg doses,
`respectively.
`
`_
`
`Except for Cmy, no statistically significant differences between the 1 and 2 mg doses were seen in the
`dose-normalized tolterodine estimates: AUC°_, (p = 0.218), CLO (p = 0.660) or Va (p = 0.761) following
`single doses. Both Tm, and t,,2,i.z were independent of the dose.
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`aen wner,
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`3
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`' arma m— X II
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`'
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`

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`For DD 01, the estimates of T,,,_,, and C,,.,,, (mean 1 SD) were 0.9 (10.4), 0.8 (10.3) hr and 2.0 (11.4) and
`3.5 (11.6) ngImL following the 1 and 2 mg tolterodine doses, respectively. The AUC¢, (mean 1 SD) for
`those respective doses were 10.7 (17.41) and 16 (18.05) ng.hrImL. Ten-ninal t,,,,A., for DD 01 was about
`3.57 (11.41) and 2.89 (10.37) hr following the 1 and 2 mg tolterodine doses, respectively. Except for
`t,,2,Jt,, no statistically significant differences between the 1 and 2 mg single doses were seen in the dose-
`normalized DD 01 parameters C,,,,,, (p = 0.155) or AUC.,,, (p = 0.094). Overall, the DD 01 elimination
`profile was similar to tolterodine.
`
`ng/mL and was attained in -1 hr.
`In poor metabolizers (n = 4), tolterodine C,,,,,, ranged from
`Consistent with the magnitude of the dextromethorphan phenotype estimate, the corresponding AUCM
`ranged from
`ng.hrIml_ and the CL,, from
`Lrhrlkg. Although the kinetic parameters
`obtained from PMs were not compared statistically to those obtained from EMS,
`it
`is apparent that
`relatively higher values of C,,,,,,, AUCM and t,,2,Jt, for tolterodine were observed.
`
`Kinetics after Repeat Dosing (Day 23): Steady-Stare
`Given the short half-life of tolterodine, its steady state was easily achieved by Day 28. The steady-state
`estimates (mean 1 SD) of C,,,,,,, were 2.4 (11.6) and 4.1 (13.8) ngImL, and were attained within 1 hr (Tm)
`post-1 and 2 mg doses (b.i.d regimen), respectively. For these two doses. the estimates of AUG“, were
`8.59 (1 4.87) and 13.5 (19.38) ng.hrImL. The t,Q,JL, was about 2 hr for both dose ievels, hence
`independent of dose. Weight normalized oral clearance (CL,,) at steady-state was 1.94 (11.69) and 2.61
`(12.42) Llhrlkg, while estimates of V,,,?t, were 5.69 (15.41) and 7.5 (15.9) L/kg following twice daily
`regimen of 1 and 2 mg doses, respectively, for 28 days.
`
`No statistically significant differences were apparent between the 1 and 2 mg dose levels in the dose-
`normalized estimates for tolterodine C,,,,,,, (p = 0.647), AUCo_,, (p = 0.909), CLO (p = 0.298) or V, (p =
`0.796). T,,,,,, (p = 0.867) and t,,,,;\, (p = 0.713) were unaltered. Lack of dose effect on kinetic parameters
`suggested dose-independent kinetics for the two dose levels.
`
`At steady state, the peak metabolite concentrations following both doses were similar to the C,,,,,,, of the
`parent drug. The estimates (mean 1 SD) of C,,,,,,, were 2.5 (11.5) and 3.9 (12.2) ngImL. which were
`attained at about 1 hr (T,,,,,,,) following the 1 and 2 mg tolterodine doses, respectively. The corresponding
`estimates of AUCM, were 10.60 (1 4.74) and 18.30 (19.07) ng.hrImL, and the t.,,,7l., were 3.74 (10.77) and
`3.67 (11.20) hr, respectively.
`
`No statistically significant differences between the 1 and 2 mg doses were seen in the dose-norrnalized
`kinetic estimate for DD 01 C,,,,,, (p = 0.389) and AUC.,_, (p = 0.902). No dose related changes were
`apparent in Tm, (p = 0.91) or t,,,,2t, (p = 0.187) on Day 28. Metabolite kinetics at steady-state supported
`the assessment based on the parent drug of a lack of dose effect on kinetics.
`I
`
`nglmL, attained in -1 hr.
`tolterodine C,,,,,, ranged from
`, (n = 3),
`In the poor metaboliz '
`itude of the dextromethorphan phenotype estimate, the corresponding AUCo_,;,_
`Consistent with the m
`(area over a dosing interval) ranged from
`ng.hrImL and the CL, from
`L/hrlkg. Due
`to bioanalytical limitations, tolterodine kinetics could not be estimated for one PM (#102).
`
`Single versus Multiple Dose Pharmacokinetics
`Multiple oral dosing (steady—state) with 1 mg resulted in no significant changes (signed rank test) in
`tolterodine T,,,_.,,, (p = 0.25), C,,,,,,, (p = 0.867), AUCNZ (p = 0.432), t,,,,A,, (p = 0.695), CL,, (p = 0.509) or V, (p
`= 0.769) compared to the estimates following the first dose on Day 1. Similarly, no significant changes in
`pharmacokinetic parameters, attesting to a lack of accumulation, could be detected following the 2 mg
`twice daily regimen compared with the first dose kinetics. The steady-statelsingle dose ratios (R;
`accumulation factor) for C,,,,,, and AUC, estimating drug accumulation, were 1.05 and 1.25. respectively,
`following the 1 mg dose, while for the 2 mg dose these were 1.45 and 1.46.
`Although an increase of
`46% in the mean C,,,,,,, for tolterodine was observed when Day 28 data for the 2 mg are compared to the
`
`

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`this change was not statistically
`single dose; given the variability in EMS (due to phenotype status).
`different (p = 0.211). The power was < 94% based on C,,,,,,, estimate. Obviously. two subjects
`with relatively high Cm, could account for increase in the mean Cm, (see 95% Cl). However, the
`steady-state (Day 28) mean AUCM for tolterodine following the 2 mg dose was significantly (p = 0.027)
`higher compared to the AUCM estimate following the first dose (Day 1).
`
`No significant changes were apparent in DD 01 kinetics following 1 and 2 mg doses of tolterodine that
`suggested drug accumulation.
`interestingly, the DD 01 t,,,,7l., estimate increased significantly (p = 0.019)
`at steady—state (Day 28) following the 2 mg dose.
`
`The ratio estimates for DD 01 C,,,,,, and AUC were 1.27, 1.15 (1 mg) and 1.12, 1.16 (2 mg), respectively,
`and did not suggest any accumulation. Overall, both the parent drug and the metabolite data failed to
`exhibit and support accumulation following 1 or 2 mg tolterodine b.i.d. regimen.
`
`Dose-proportionality Assessment
`The following analysis was perfomred in order to provide indications regarding dose proportionality or
`deviations from that and may serve as supportive data to a formal dose proportionality study. Figure 3
`shows AUC vs. tolterodine close regression (forced through zero) plots. Although limited in nature to
`address the dose—proportionality, these data are suggestive of proportionality based on single doses (r7 =
`0.183, slope = 4.95 [95% CI: 3.31-6.59]) and linear kinetics based on steady-state (r2 = 0.198, slope =
`7.10 (95% CI: 4.92-9.28]). The low coefficients of determination are reflective of the intersubject variability
`inherent in the magnitude of the extensive metabolizer phenotype. Given the degrees of freedom, the
`correlation coefficients for both regressions are statistically significant. The overlap (estimation error) in
`the slope estimates for the single and multiple dosing states appears to be related to this variation.
`
`Sponsor’s Conclusions:
`o
`Relative to the placebo. both 1 and 2 mg tolterodine doses administered on a b.i.d. regimen for 28
`days were well tolerated in elderly subjects (age; 270 years).
`
`-
`
`-
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`Tolterodine and DD 01 kinetics in this cohort appear to be similar to those previously reported.
`
`Tolterodine kinetics following the 2 mg b.i.d. regimen suggested minor accumulation.
`
`There were no clinically significant findings with respect to safety variables,
`c
`pressure, heart rate, clinical chemistry or hematology.
`
`including ECG, blood
`
`APBEARS rrris wnv
`‘ON ORIGINAL
`
`59
`
`aen wner,
`
`=
`
`' arma m— X II
`
`A
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`r
`
`

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`Study Number: 95-OATA-D22
`
`Title of the study The influence of food on the bioavailability of tolterodine. An open, single close cross
`over study in healthy volunteers.
`
`Objective: To study the influence of food on the bioavailability of tolterodine after a single dose
`administration of 2 mg.
`
`Study Design: Open, single-dose. cross-over
`
`Subjects: Twenty-four healthy females and males.
`
`Study product: Tolterodine L-tartrate tablet, 2 mg Batch No. A 049404.
`
`Statistical methods: Descriptive statistics. including means and standard deviations were calculated for
`the pharmacokinetic parameters. AUC-, and C,,._, were evaluated with analysis of variance (ANOVA) and
`90% confidence interval
`
`Results
`
`Table 47. Pharmacokinetic parameters (mean 1 SD; median with range for t,,,,,) for tolterodine and DD 01
`after oral administration of tolterodine with and without food.
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`mj
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`jj
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`Table 48. AUC, and Cm, ratios, i.e. relative bioavailability (geometric mean with 90 % CI) for tolterodine
`and DD 01. Treatment with food compared to fasting.
`AUC, ratio
`1.53 (1_35- 1.72)
`W 1.09 ;1.o4— 1.15)
`
`
`
`
`
`
`1.49 (1.30-1.71)
`0.96 (o.a7- 1.06)
`
`e
`Sponsor's Conclusiorh:
`-
`Bioequivaience could not be concluded for tolterodine when given with and without food. A 53%
`increase in serum levels (AUC,) was seen when the drug was given with food.
`However, more "
`importantly, bioequivalence was shown for the active metabolite DD 01 with respect to both AUC, and
`CW, when treatment with food was compared to fasting administration.
`
`- Approximately 75 % of the systemically available tolterodine is metabolized to DD 01 by CYP2D6 in
`extensive metabolizers. This implies’that other routes of elimination have a minor contribution to the
`systemic clearance. In the pre