Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder
contraction and salivation are mediated via cholinergic muscarinic receptors.
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. Effects on urodynamic parameters
before and 1 and 5 hours after a single 6.4-mg dose of tolterodine immediate release
were determined in healthy volunteers. The main effects of tolterodine at 1 and
5 hours were an increase in residual urine, reflecting an incomplete emptying of
the bladder, and a decrease in detrusor pressure. These findings are consistent
with an antimuscarinic action on the lower urinary tract.
Pharmacokinetics
Absorption: In a study with 14C-tolterodine
solution in healthy volunteers who received a 5-mg oral dose, at least 77% of the
radiolabeled dose was absorbed. Cmax and area under the
concentration-time curve (AUC) determined after dosage of tolterodine immediate
release are dose-proportional over the range of 1 to 4 mg. Based on the sum of unbound
serum concentrations of tolterodine and the 5-hydroxymethyl metabolite ("active
moiety"), the AUC of tolterodine extended release 4 mg daily is equivalent to tolterodine
immediate release 4 mg (2 mg bid). Cmax and Cmin
levels of tolterodine extended release are about 75% and 150% of tolterodine immediate
release, respectively. Maximum serum concentrations of tolterodine extended release
are observed 2 to 6 hours after dose administration.
Effect of Food: There is no effect of food on the pharmacokinetics
of tolterodine extended release.
Distribution: Tolterodine is highly bound to plasma proteins, primarily
α1-acid glycoprotein. Unbound concentrations of tolterodine
average 3.7% ± 0.13% 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 (CYP2D6) 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 Caucasian population
is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl
metabolite of tolterodine. The identified pathway of metabolism for these individuals
("poor metabolizers") is dealkylation via cytochrome P450 3A4 (CYP3A4) 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 poor metabolizers than in extensive metabolizers; this results in significantly
higher serum concentrations of tolterodine and in negligible concentrations of the
5-hydroxymethyl metabolite.
Excretion: Following administration of a 5-mg oral dose of
14C-tolterodine solution to healthy volunteers, 77% of radioactivity
was recovered in urine and 17% was recovered in feces in 7 days. Less than 1% (<
2.5% in poor metabolizers) of the dose was recovered as intact tolterodine, and
5% to 14% (<1% in poor metabolizers) was recovered as the active 5-hydroxymethyl
metabolite.
A summary of mean (± standard deviation) pharmacokinetic parameters of tolterodine
extended release and the 5-hydroxymethyl metabolite in extensive (EM) and poor (PM)
metabolizers is provided in Table 1. These data were obtained following single and
multiple doses of tolterodine extended release administered daily to 17 healthy
male volunteers (13 EM, 4 PM).
Table 1. Summary of Mean (±SD) Pharmacokinetic Parameters of Tolterodine Extended
Release and its Active Metabolite (5-hydroxymethyl metabolite) in Healthy Volunteers
Pharmacokinetics in Special Populations
Age: In Phase 1, multiple-dose studies in which tolterodine immediate
release 4 mg (2 mg bid) was administered, 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 immediate release 2 or 4 mg (1 or 2 mg bid). 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 on tolterodine in the Phase 3, 12-week, controlled clinical studies; therefore,
no tolterodine dosage adjustment for elderly patients is recommended (see PRECAUTIONS,
Geriatric Use).
Pediatric: Efficacy in the pediatric population has not been demonstrated.
The pharmacokinetics of tolterodine extended release capsules have been evaluated
in pediatric patients ranging in age from 11–15 years. The dose-plasma concentration
relationship was linear over the range of doses assessed. Parent/metabolite ratios
differed according to CYP2D6 metabolizer status: EMs had low serum concentrations
of tolterodine and high concentrations of the active 5- hydroxymethyl metabolite,
while PMs had high concentrations of tolterodine and negligible active metabolite
concentrations.
Gender: The pharmacokinetics of tolterodine immediate release and
the 5-hydroxymethyl metabolite are not influenced by gender. Mean Cmax
of tolterodine immediate release (1.6 µg/L in males versus 2.2 µg/L in females)
and the active 5-hydroxymethyl metabolite (2.2 µg/L in males versus 2.5 µg/L in
females) are similar in males and females who were administered tolterodine immediate
release 2 mg. Mean AUC values of tolterodine (6.7 µg•h/L in males versus 7.8 µg•h/L
in females) and the 5-hydroxymethyl metabolite (10 µg•h/L in males versus 11 µg•h/L
in females) are also similar. The elimination half-life of tolterodine immediate
release 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: Renal impairment can significantly alter the
disposition of tolterodine immediate release and its metabolites. In a study conducted
in patients with creatinine clearance between 10 and 30 mL/min, tolterodine immediate
release and the 5-hydroxymethyl metabolite levels were approximately 2–3 fold higher
in patients with renal impairment than in healthy volunteers. Exposure levels of
other metabolites of tolterodine (e.g., tolterodine acid, N-dealkylated tolterodine
acid, N-dealkylated tolterodine and N-dealkylated hydroxy tolterodine)
were significantly higher (10-30 fold) in renally impaired patients as compared
to the healthy volunteers. The recommended dose for patients with significantly
reduced renal function is tolterodine 2 mg daily (see PRECAUTIONS, General and DOSAGE
AND ADMINISTRATION).
Hepatic Insufficiency: Liver impairment can significantly alter the
disposition of tolterodine immediate release. In a study of tolterodine immediate
release conducted in cirrhotic patients, the elimination half-life of tolterodine
immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy,
young, and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered
tolterodine immediate release was substantially lower in cirrhotic patients (1.0
± 1.7 L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended
dose for patients with significantly reduced hepatic function is tolterodine 2 mg
daily (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions
Fluoxetine: Fluoxetine is a selective serotonin reuptake inhibitor
and a potent inhibitor of CYP2D6 activity. In a study to assess the effect of fluoxetine
on the pharmacokinetics of tolterodine immediate release and its metabolites, it
was observed that fluoxetine significantly inhibited the metabolism of tolterodine
immediate release in extensive metabolizers, resulting in a 4.8-fold increase in
tolterodine AUC. There was a 52% decrease in Cmax and
a 20% decrease in AUC of the 5-hydroxymethyl metabolite. Fluoxetine thus alters
the pharmacokinetics in patients who would otherwise be extensive metabolizers of
tolterodine immediate release to resemble the pharmacokinetic profile in poor metabolizers.
The sums of unbound serum concentrations of tolterodine immediate release and the
5-hydroxymethyl metabolite are only 25% higher during the interaction. No dose adjustment
is required when tolterodine and fluoxetine are coadministered.
Other Drugs Metabolized by Cytochrome P450 Isoenzymes: Tolterodine
immediate release does not cause clinically significant interactions with other
drugs metabolized by the major drug metabolizing CYP enzymes. In vivo drug-interaction
data show that tolterodine immediate release does not result in clinically relevant
inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on
the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole. In vitro
data show that tolterodine immediate release is a competitive inhibitor of CYP2D6
at high concentrations (Ki 1.05 µM), while tolterodine immediate release as well
as the 5-hydroxymethyl metabolite are devoid of any significant inhibitory potential
regarding the other isoenzymes.
CYP3A4 Inhibitors: The effect of a 200-mg daily dose of ketoconazole
on the pharmacokinetics of tolterodine immediate release was studied in 8 healthy
volunteers, all of whom were poor metabolizers (see Pharmacokinetics, Variability
in Metabolism for discussion of poor metabolizers). In the presence of ketoconazole,
the mean Cmax and AUC of tolterodine increased by 2 and
2.5 fold, respectively. Based on these findings, other potent CYP3A4 inhibitors
such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics
(eg, erythromycin, clarithromycin) or cyclosporine or vinblastine may also lead
to increases of tolterodine plasma concentrations (see PRECAUTIONS and DOSAGE
AND ADMINISTRATION).
Warfarin: In healthy volunteers, coadministration of tolterodine immediate
release 4 mg (2 mg bid) for 7 days and a single dose of warfarin 25 mg on day 4
had no effect on prothrombin time, Factor VII suppression, or on the pharmacokinetics
of warfarin.
Oral Contraceptives: Tolterodine immediate release 4 mg (2 mg bid)
had no effect on the pharmacokinetics of an oral contraceptive (ethinyl estradiol
30 µg/levonorgestrel 150 µg) as evidenced by the monitoring of ethinyl estradiol
and levonorgestrel over a 2-month period in healthy female volunteers.
Diuretics: Coadministration of tolterodine immediate release up to
8 mg (4 mg bid) 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.
Cardiac Electrophysiology
The effect of 2 mg BID and 4 mg BID of Detrol immediate release (tolterodine IR)
tablets on the QT interval was evaluated in a 4-way crossover, double-blind, placebo-
and active-controlled (moxifloxacin 400 mg QD) study in healthy male (N=25) and
female (N=23) volunteers aged 18–55 years. Study subjects [approximately equal representation
of CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs)] completed sequential
4-day periods of dosing with moxifloxacin 400 mg QD, tolterodine 2 mg BID, tolterodine
4 mg BID, and placebo. The 4 mg BID dose of tolterodine IR (two times the highest
recommended dose) was chosen because this dose results in tolterodine exposure similar
to that observed upon coadministration of tolterodine 2 mg BID with potent CYP3A4
inhibitors in patients who are CYP2D6 poor metabolizers (see PRECAUTIONS, Drug-Drug
Interactions). QT interval was measured over a 12-hour period following
dosing, including the time of peak plasma concentration (Tmax)
of tolterodine and at steady state (Day 4 of dosing).
Table 2 summarizes the mean change from baseline to steady state in corrected QT
interval (QTc) relative to placebo at the time of peak tolterodine (1 hour) and
moxifloxacin (2 hour) concentrations. Both Fridericia’s (QTcF) and a population-specific
(QTcP) method were used to correct QT interval for heart rate. No single QT correction
method is known to be more valid than others. QT interval was measured manually
and by machine, and data from both are presented. The mean increase of heart rate
associated with a 4 mg/day dose of tolterodine in this study was 2.0 beats/minute
and 6.3 beats/minute with 8 mg/day tolterodine. The change in heart rate with moxifloxacin
was 0.5 beats/minute.
Table 2: Mean (CI) change in QTc from baseline to steady state (Day 4 of dosing)
at Tmax (relative to placebo)
The reason for the difference between machine and manual read of QT interval is
unclear.
The QT effect of tolterodine immediate release tablets appeared greater for 8 mg/day
(two times the therapeutic dose) compared to 4 mg/day. The effect of tolterodine
8 mg/day was not as large as that observed after four days of therapeutic dosing
with the active control moxifloxacin. However, the confidence intervals overlapped.
Tolterodine's effect on QT interval was found to correlate with plasma concentration
of tolterodine. There appeared to be a greater QTc interval increase in CYP2D6 poor
metabolizers than in CYP2D6 extensive metabolizers after tolterodine treatment in
this study.
This study was not designed to make direct statistical comparisons between drugs
or dose levels. There has been no association of Torsade de Pointes in the international
postmarketing experience with Detrol or Detrol LA. (See PRECAUTIONS, Patients with
Congenital or Acquired QT Prolongation).