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Mechanism of Action
Tolterodine acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors. 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 5-hydroxymethyl tolterodine (5-HMT), the major pharmacologically active metabolite. 5-HMT, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and 5HMT 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.
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 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)
|Drug/Dose||N||QTcF (msec) (manual)||QTcF (msec) (machine)||QTcP (msec) (manual)||QTcP (msec) (machine)|
|Tolterodine 2 mg BID*||48||5.01 (0.28, 9.74)||1.16 (-2.99, 5.30)||4.45 (-0.37, 9.26)||2.00 (-1.81, 5.81)|
|Tolterodine 4 mg BID*||48||11.84 (7.11, 16.58)||5.63 (1.48, 9.77)||10.31 (5.49, 15.12)||8.34 (4.53, 12.15)|
|Moxifloxacin 400 mg QD †||45||19.26‡ (15.49, 23.03)||8.90 (4.77, 13.03)||19.10‡ (15.32, 22.89)||9.29 (5.34, 13.24)|
|*At Tmax of 1 hr; 95% Confidence Interval.
†At Tmax of 2 hr; 90% Confidence Interval.
‡The effect on QT interval with 4 days of moxifloxacin dosing in this QT trial may be greater than typically observed in QT trials of other drugs.
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 post-marketing experience with DETROL or DETROL LA [see WARNINGS AND PRECAUTIONS].
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 5-HMT (“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.
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. 5HMT is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and 5-HMT 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.
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 metabolite, 5-HMT. 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 of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6, the enzyme responsible for the formation of 5-HMT from 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 5-HMT.
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 5-HMT.
A summary of mean (± standard deviation) pharmacokinetic parameters of tolterodine extended release and 5HMT in extensive (EM) and poor (PM) metabolizers is provided in Table 3. 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 3:. Summary of Mean (±SD) Pharmacokinetic
Parameters of Tolterodine Extended Release and its Active Metabolite
(5-Hydroxymethyl Tolterodine) in Healthy Volunteers
|tmax * (h)||Cmax (μg/L)||Cavg (μg/L)||t½ (h)||tmax * (h)||Cmax (μg/L)||Cavg (μg/L)||t½ (h)|
|Single dose 4 mg† EM||4 (2–6)||1.3 (0.8)||0.8 (0.57)||8.4 (3.2)||4 (3–6)||1.6 (0.5)||1.0 (0.32)||8.8 (5.9)|
|Multiple dose 4 mg|
|EM||4 (2–6)||3.4 (4.9)||1.7 (2.8)||6.9 (3.5)||4 (2–6)||2.7 (0.90)||1.4 (0.6)||9.9 (4.0)|
|PM||4 (3–6)||19 (16)||13 (11)||18 (16)||‡||‡||‡||‡|
|Cmax = Maximum serum concentration; tmax = Time of
occurrence of Cmax;
Cavg = Average serum concentration; t1/2 = Terminal elimination half-life.
*Data presented as median (range).
†Parameter dose-normalized from 8 to 4 mg for the single-dose data.
‡ = not applicable.
Potent CYP2D6 inhibitors: 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 5-hydroxymethyl tolterodine (5-HMT, the pharmacologically active metabolite of tolterodine). Fluoxetine thus alters the pharmacokinetics in patients who would otherwise be CYP2D6 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 5-HMT are only 25% higher during the interaction. No dose adjustment is required when tolterodine and fluoxetine are co-administered.
Potent 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 CYP2D6 poor metabolizers. In the presence of ketoconazole, the mean Cmax and AUC of tolterodine increased by 2- and 2.5fold, respectively. Based on these findings, other potent CYP3A4 inhibitors may also lead to increases of tolterodine plasma concentrations.
For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, miconazole, clarithromycin, ritonavir, the recommended dose of DETROL LA is 2 mg daily [see 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/levo-norgestrel 150 μg) as evidenced by the monitoring of ethinyl estradiol and levo-norgestrel 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.
Effect of tolterodine on other drugs metabolized by Cytochrome P450 enzymes: 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-HMT are devoid of any significant inhibitory potential regarding the other isoenzymes.
DETROL LA Capsules 2 mg were evaluated in 29 patients in a Phase 2 dose-effect study. DETROL LA 4 mg was evaluated for the treatment of overactive bladder with symptoms of urge urinary incontinence and frequency in a randomized, placebo-controlled, multicenter, double-blind, Phase 3, 12-week study. A total of 507 patients received DETROL LA 4 mg once daily in the morning and 508 received placebo. The majority of patients were Caucasian (95%) and female (81%), with a mean age of 61 years (range, 20 to 93 years). In the study, 642 patients (42%) were 65 to 93 years of age. The study included patients known to be responsive to tolterodine immediate release and other anticholinergic medications, however, 47% of patients never received prior pharmacotherapy for overactive bladder. At study entry, 97% of patients had at least 5 urge incontinence episodes per week and 91% of patients had 8 or more micturitions per day.
The primary efficacy assessment was change in mean number of incontinence episodes per week at week 12 from baseline. Secondary efficacy measures included change in mean number of micturitions per day and mean volume voided per micturition at week 12 from baseline.
Patients treated with DETROL LA experienced a statistically significant decrease in number of urinary incontinence per week from baseline to last assessment (week 12) compared with placebo as well as a decrease in the average daily urinary frequency and an increase in the average urine volume per void.
Mean change from baseline in weekly incontinence episodes, urinary frequency, and volume voided between placebo and DETROL LA are summarized in Table 4.
Table 4: 95% Confidence Intervals (CI) for the Difference
between DETROL LA (4 mg daily) and Placebo for Mean Change at Week 12 from
|Treatment Difference, vs. Placebo (95% Cl)|
|Number of incontinence episodes/ week|
|Mean Change from Baseline||–11.8 (SD 17.8)||–6.9 (SD 15.4)||(–6.9, –2.8)|
|Number of micturitions/day|
|Mean Change from Baseline||–1.8 (SD 3.4)||–1.2 (SD 2.9)||(–1.0, –0.2)|
|Volume voided per micturition (mL)|
|Mean Change from Baseline||34 (SD 51)||14 (SD 41)||(14, 26)|
|SD = Standard Deviation.
* Intent-to-treat analysis.
† 1 to 2 patients missing in placebo group for each efficacy parameter.
‡ The difference between DETROL LA and placebo was statistically significant.
Last reviewed on RxList: 9/5/2012
This monograph has been modified to include the generic and brand name in many instances.
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