CLINICAL PHARMACOLOGY
Tolterodine is a competitive muscarinic receptor
antagonist. Both urinary bladder contraction and salivation
are mediated via cholinergic muscarinic receptors. In the
anesthetized cat, tolterodine shows a selectivity for the
urinary bladder over salivary glands; however, the clinical
relevance of this finding has not been established.
After oral administration, tolterodine is metabolized in
the liver, resulting in the formation of the 5-hydroxymethyl
derivative, a major pharmacologically active metabolite.
The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic
activity similar to that of tolterodine, contributes significantly
to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl
metabolite exhibit a high specificity for muscarinic receptors,
since both show negligible activity or affinity for other
neurotransmitter receptors and other potential cellular
targets, such as calcium channels.
Tolterodine has a pronounced effect on bladder function
in healthy volunteers. The main effects following a 6.4-mg
single dose of tolterodine were an increase in residual
urine, reflecting an incomplete emptying of the bladder,
and a decrease in detrusor pressure. These findings are
consistent with a potent antimuscarinic action on the lower
urinary tract.
Pharmacokinetics
Absorption: In a study
of 14C-tolterodine in healthy volunteers who received a
5-mg oral dose, at least 77% of the radiolabeled dose was
absorbed. Tolterodine is rapidly absorbed, and maximum serum
concentrations (Cmax) typically occur within 1 to 2 hours
after dose administration. The pharmacokinetics of tolterodine,
based on Cmax and area under the concentration-time curve
AUC determinations, are dose-proportional over the range
of 1 to 4 mg.
Effect of Food: Food intake increases
the bioavailability of tolterodine (average increase 53%)
and does not affect the levels of the 5-hydroxymethyl metabolite
in extensive metabolizers. This change is not expected to
be a safety concern and adjustment of dose is not needed.
Distribution: Tolterodine is highly
bound to plasma proteins, primarily a-acid glycoprotein.
Unbound concentrations of tolterodine average 3.7% + 0.13%
is over the concentration range achieved in clinical studies.
The 5-hydroxymethyl metabolite is not extensively protein
bound, with unbound fraction concentrations averaging 36%
+ 4.0%. The blood to serum ratio of tolterodine and the
5-hydroxymethyl metabolite averages 0.6 and 0.8, respectively,
indicating that these compounds do not distribute extensively
into erythrocytes. The volume of distribution of tolterodine
following administration of a 1.28-mg intravenous dose is
113 + 26.7 L.
Metabolism: Tolterodine is extensively
metabolized by the liver following oral dosing. The primary
metabolic route involves the oxidation of the 5-methyl group
and is mediated by the cytochrome P450 2D6 and leads to
the formation of a pharmacologically active 5-hydroxymethyl
metabolite. Further metabolism leads to formation of the
5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites,
which account for 51% + 14% and 29% + 6.3% of the metabolites
recovered in the urine, respectively.
Variability in Metabolism: A subset
(about 7%) of the population is devoid of cytochrome P450
266, the enzyme responsible for the formation of the 5-hydroxymethyl
metabolite of tolterodine. The identified pathway of metabolism
for these individuals, referred to as “poor metabolizers”,
is dealkylation via cytochrome P450 3A4 to N-dealkylated
tolterodine. The remainder of the population is referred
to as “extensive metabolizers”. Pharmacokinetic
studies revealed that tolterodine is metabolized at a slower
rate in p.o. metabolizers than in extensive metabolizers:
This results in significantly higher serum concentrations
of tolterodine and in negligible concentrations of the 5-hydroxvmethyl
metabolite. Because of differences in the protein-binding
characteristics of tolterodine and the 5-hydroxymethyl metabolite,
the sum of unbound serum concentrations of tolterodine and
the 5-hydroxymethyl metabolite is similar in extensive and
p.o. metabolizers at steady state. Since tolterodine and
the 5-hydroxymethyl metabolite have similar antimuscarinic
effects, the net activity of DETROL Tablets is expected
to be similar in extensive and p.o. metabolizers.
Excretion: Following administration
of a 5-mg oral dose of 14C-tolterodine to healthy volunteers,
77% of radioactivity was recovered in urine and 17% was
recovered in feces. Less than 1% (<2.5% in poor metabolizers)
of the dose was recovered as intact tolterodine, and 5%
to 14% (<1% in p.o. metabolizers) was recovered as the
active 5-hydroxymethyl metabolite. Most of the radioactivity
was recovered within the first 24 hours, which is consistent
with the apparent half-life of tolterodine: 1.9 to 3.7 hours
in pharmacokinetic studies.
A summary of mean (+ standard deviation) pharmacokinetic
parameters of tolterodine and the 5-hydroxymethyl metabolite
in extensive (EM) and poor (PM) metabolizers is provided
in the following table. These data were obtained following
single-and multiple-doses of tolterodine 4 mg administered
twice daily to 16 healthy male subjects (8 EM, 8 PM).
| |
Tolterodine
|
5- Hydroxymethyl Metabolite
|
| Phenotype
(CYP2D6)
|
t max
(h)
|
Cmax*
(ug/ L)
|
C avg
(ug/ L)
|
t 1/ 2
(h)
|
CL/ F
(L/ h)
|
t max
(h)
|
Cmax.
(ug/ L)
|
C avg
(ug/ L)
|
t1/ 2
(h)
|
|
Single- dose |
|
EM
PM
|
1.6+ 1.5
1.4+ 0.5
|
1.6+ 1.2
10+ 4.9
|
0.50+0.35
8.3+ 4.3
|
2.0+ 0.7
6.5+ 1.6
|
534+ 697
17+ 7.3
|
1.8t+1.4
|
1.8+ 0.7
|
0.62+ 0.26
|
3.1+ 0.7
|
|
Multiple- dose |
|
EM
PM
|
1.2+ 0.5
1.9+ 1.0
|
2.6+ 2.8
19+ 7.5
|
0.58+0.54
12+ 5.1
|
2.2+ 0.4
9. 6+ 1.5
|
415+ 377
11+ 4.2
|
1.2+ 0.5
|
2.4+ 1.3
|
0.92+ 0.46
|
2.9+ 0.4
|
* Parameter was dose-normalized from 4 mg to 2 mg
C max= Maximum plasma concentration; tmax = Time of occurrence
of Cmax
C avg = Average plasma concentration; t 1/2 = Terminal elimination
half-life; CL/F = Apparent oral clearance
t = not applicable
Pharmacokinetics In Special Populations
Age: In Phase 1, multiple-dose
studies in which tolterodine 2 mg was administered twice
daily, serum concentrations of tolterodine and of the 5-hydroxymethyl
metabolite were similar in healthy elderly volunteers (aged
64 through 80 years) and healthy young volunteers aged less
than 40 years). In another Phase 1 study, elderly volunteers
(aged 71 through 81 years) were given tolterodine 1 or 2
mg twice daily. Mean serum concentrations of tolterodine
and the 5-hydroxymethyl metabolite in these elderly volunteers
were approximately 20% and 50% higher, respectively, than
reported in young healthy volunteers. However, no overall
differences were observed in safety between older and younger
patients in Phase 3, 12-week, controlled clinical studies;
therefore, no dosage adjustment is recommended (see PRECAUTIONS,
Geriatric Use).
Pediatric: The pharmacokinetics
of tolterodine have not been established in pediatric patients.
Gender: The pharmacokinetics of
tolterodine and the 5-hydroxymethyl metabolite are not influenced
by gender. Mean Cmax, of tolterodine (1 6 ug/L in males
versus 2.2 ug/L in females) and the active 5-hydroxymethyl
metabolite (2.2 ug/L in males versus 2.5 ug/L in females)
are similar in males and females who were administered tolterodine
2 mg. Mean AUC values of tolterodine (6.7 ug/L in males
versus 7.8 ug/L in females) and the 5-hydroxymethyl metabolite
(10 ug/L in males versus 11 ug/L in females) are also similar.
The elimination half-life of tolterodine for both males
and females is 2.4 hours, and the half-life of the 5-hydroxymethyl
metabolite is 3.0 hours in females and 3.3 hours in males.
Race: Pharmacokinetic differences
due to race have not been established.
Renal Insufficiency: The pharmacokinetics
of tolterodine in patients with renal insufficiency have
not been evaluated. The renal excretion of tolterodine and
the 5-hydroxymethyl metabolite are negligible, and a decrease
in total body clearance is not expected in patients with
renal insufficiency. However, patients with renal impairment
should be treated with caution.
Hepatic Insufficiency: Liver impairment
can significantly alter the disposition of tolterodine.
In a study conducted in cirrhotic patients, the elimination
half-life of tolterodine was longer in cirrhotic patients
(mean, 8.7 hours) than in healthy, young and elderly volunteers
(mean, 2 to 4 hours). The clearance of orally administered
tolterodine was substantially lower in cirrhotic patients
(1.1 + 1.7 L/h/kg) than in the healthy volunteers (5.7 +
3.8 L/h/kg). Patients with significantly reduced hepatic
function should not receive doses of DETROL greater than
1 mg twice daily (see PRECAUTIONS, General).
Drug-Drug Interactions
Fluoxetine: Fluoxetine
is a selective serotonin reuptake inhibitor and a potent
inhibitor of cytochrome P450 2D6 activity. In a study to
assess the effect of fluoxetine on the pharmacokinetics
of tolterodine and its metabolites, it was observed that
fluoxetine significantly inhibited the metabolism of tolterodine
in extensive metabolizers, resulting in a 4.8-fold increase
in tolterodine A.C. There was a 52% decrease in Cmax and
a 20% decrease in AUC of the S-hydroxymethyl metabolite.
Fluoxetine thus alters the pharmacokinetics in patients
who would otherwise be extensive metabolizers of tolterodine
to resemble the pharmacokinetic profile in poor metabolizers.
The sums of unbound serum concentrations of tolterodine
and the 5-hydroxymethyl metabolite are only 25% higher during
the interaction. No dose adjustment is required when DETROL
and fluoxetine are coadministered.
Other Drugs Metabolized by Cytochrome P450 2D6: Tolterodine
is not expected to influence the pharmacokinetics of drugs
that are metabolized by cytochrome P450 2D6, such as flecainide,
vinblastine, carbamazepine, and tricyclic antidepressants;
however, the potential effect of tolterodine on the pharmacokinetics
of these drugs has not been formally evaluated.
Warfarin: In healthy volunteers,
coadministration of tolterodine 2 mg twice daily for 7 days
and a single 25-mg dose of warfarin on day 4 had no effect
on prothrombin time, Factor VII suppression, or on the pharmacokinetics
of warfarin.
Oral Contraceptives: Tolterodine
2 mg twice daily had no effect on the pharmacokinetics of
an oral contraceptive ethinyl estradiol 30 ug/levonorgestrel
150 ug as evidenced by the monitoring of ethinyl estradiol
and levonorgestrel over a 2-month cycle in healthy female
volunteers.
Diuretics: Coadministration of
tolterodine up to 4 mg twice daily for up to 12 weeks with
diuretic agents, such as indapamide, hydrochlorothiazide,
triamterene, bendroflumethiazide, chlorothiazide, methylchlorothiazide,
or furosemide, did not cause any adverse electrocardiographic
(ECG effects).
CLINICAL STUDIES
DETROL Tablets were evaluated for the treatment
of patients with an overactive bladder with symptoms of
urinary frequency, urgency, or urge incontinence in three
placebo-controlled, 12-week studies. A total of 339 patients
received DETROL 2 mg twice daily and 177 patients received
placebo. The majority of patients were Caucasian (95%) and
female (75%), with a mean age of 60 years (range, 19 to
91 years). At study entry, nearly all patients perceived
they had urgency (98%) and most patients had increased frequency
of micturitions (89%) and urge incontinence (83%). These
characteristics were well balanced across treatment groups
for the three studies.
The efficacy endpoints included the change from baseline
for:
- number of micturitions per 24 hours (averaged over 7 days)
- number of incontinence episodes per 24 hours (averaged
over 7 days)
- volume of urine voided per micturition (averaged over
2 days).
Efficacy results for the three placebo-controlled, 12-week
studies are presented in the following figures:
95% Confidence Intervals for the Difference
between DETROL (2 mg body and Placebo for the median Change
at Week 12 from Baseline
|
Number of Micturitions
Per 24 Hours
|
| |
DETROL
|
Placebo
|
| Study
008 |
|
|
118
|
56
|
|
|
10.5
|
10.6
|
|
|
-2.2 (3.8)
|
-1.1 (3.6)
|
| Study
009 |
|
|
128
|
64
|
|
|
10.4
|
10.4
|
|
|
-2.2 (2.1)
|
-1.2 (2.3)
|
| Study
010 |
|
|
108
|
56
|
|
|
11.0
|
10.9
|
|
|
-1.6 (2.3)
|
-1.1 (2.8)
|
|
Number of Incontinence Episodes Per 24 Hours
|
| |
DETROL
|
Placebo
|
| Study
008 |
|
|
93
|
40
|
|
|
2.4
|
2.5
|
|
|
-1.2 (3.2)
|
-0.8 (1.5 )
|
| Study
009 |
|
|
116
|
55
|
|
|
2.5
|
3.2
|
|
|
-1.4 (2.5)
|
-1.1 (2.5)
|
| Study
010 |
|
|
90
|
50
|
|
|
2.7
|
2.2
|
|
|
-1.5 (2.4)
|
-0.9 (2.1)
|
|
Volume voided per
Micturition (mL)
|
| |
DETROL
|
Placebo
|
| Study
008 |
| |
118
|
56
|
| |
156
|
155
|
| |
34 (54)
|
5 (421)
|
| Study
009 |
| |
128
|
64
|
| |
149
|
157
|
| |
34 (50)
|
8 (47)
|
| Study
010 |
|
|
108
|
56
|
|
|
148
|
164
|
|
|
27 (45)
|
10 (52)
|
The difference between DETROL and placebo was statistically
significant.
|
|
