- Email: [email protected]
A comparison of the effects of saliva output of oxybutynin chloride and tolterodine tartrate
CLINICAL THERAPEUTICSVVOL.
23, NO. 5,201
A Comparison of the Effects on Saliva Output of Oxybutynin Chloride and Tolterodine Tartrate Michael B. Chancellor, MD,’ Rodney A. Appell, A4D,2 Gayatn’ Sathyan, PhD,3 and Suneel K. Guptu, PhD3 IDepartment of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 2The Cleveland Clinic, Cleveland, Ohio, and jALZA Corporation, Mountain View, California
ABSTRACT Background:
Oxybutynin
chloride and tolterodine tartrate are anticholinergic agents bladder contractions in urinary incontinence. They act by inhibiting binding of acetylcholine to the muscarinic receptors in the detrusor muscle of the bladder. The same types of muscarinic receptors are found in the salivary glands; thus anticholinergic agents may decrease saliva production and cause dry mouth, a commonly cited reason for discontinuation of therapy. Objective: The primary objective of this study was to compare saliva output, which is an objective measure of dry mouth, in subjects taking immediate- or extended-release oxybutynin, tolterodine, or placebo. Methods: This was a single-site, single-dose, randomized, double-blind, 4-treatment, 4-period crossover study. Subjects were randomly assigned to 1 of 4 treatment sequences that included extended-release oxybutynin 10 mg, tolterodine 2 mg, immediate-release oxybutynin 5 mg, and placebo. Saliva output was measured objectively before dosing with each treatment and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after dosing. Results: Thirty-six healthy adult volunteers (22 women and 14 men) participated in the study. They ranged in age from 19 to 42 years (mean, 27 years). Thirty-one were white, 3 Asian, and 2 black. There were no significant differences in predose saliva output between the 4 study groups. With placebo, saliva output increased throughout the day. Saliva output was maintained at predose levels throughout the day with extended-release oxybutynin. Two hours after dosing with tolterodine and immediate-release oxybutynin, saliva output decreased nearly 0.5 g in specimens collected over 2 minutes. All 3 active treatments were associated with lower saliva output compared with placebo. Extendedrelease oxybutynin and tolterodine were similar with respect to area under the saliva concentration-time curve but were associated with significantly greater saliva output than used to suppress involuntary
Accepted
for publication
February 28, 200
Printed in the USA. Reproduction
0149-2918/011$19.00
1.
in whole or part is not permitted.
753
CLINICAL THERAPEUTICS”
was immediate-release oxybutynin (P < 0.01). There were no serious adverse events @Es) in this study. AEs were similar between treatments, although the incidence of headache was higher in the activetreatment groups than with placebo. Conclusions: Objective assessment of saliva output in healthy adult volunteers indicated that extended-release oxybutynin and tolterodine had less impact on saliva output than did conventional immediaterelease oxybutynin, suggesting that they may yield lower levels of dry mouth. Key words: anticholinergic agents, salivation, oral health, xerostomia. (Clin The,: 2001;23:753-760)
INTRODUCTION Urinary incontinence affects millions of adults over 60 years of age.’ It has been associated with significant reductions in social functioning and, in severe cases, loss of independence.* Oxybutynin chloride, which is available in both immediaterelease* and extended-release? formulations, has a long history of success as a treatment for overactive bladder and urge incontinence.’ Tolterodine tartratei is another agent used to suppress involuntary bladder contractions. Because these agents act by inhibiting binding of acetylcholine to the muscarinic receptors in the detrusor muscle of the bladder, anticholinergic (antimuscarinic) symptoms are the primary adverse events (AEs) associated with both drugs. The same types of muscarinic receptors found in the bladder are also found
*Trademark: tain View, +Trademark: *Trademark: pack, New
754
Ditropan@ (ALZA Corporation, MounCalifornia). Ditropan XL@ (ALZA Corporation). DetroPM (Pharmacia Corporation, PeaJersey).
in the salivary glands, and anticholinergic agents may decrease saliva production and cause dry mouth, a reason commonly cited by patients who discontinue these medications. Anticholinergic agents such as oxybutynin and tolterodine are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrowangle glaucoma. The usual starting dosage of tolterodine is 2 mg twice daily.4 Immediate- and extended-release oxybutynin have been studied at doses ranging from 5 to 30 mg/d, with the majority of patients maintained at doses of 5 to 15 mg/d.5,6 Two trials demonstrated a similar reduction in episodes of urge incontinence with immediate- and extended-release oxybutynin chloride.s,6 In another placebo-controlled study comparing immediate-release oxybutynin and tolterodine,7 the mean number of episodes of incontinence was decreased by 71%, 47%, and 19% in patients taking oxybutynin, tolterodine, and placebo, respectively. Although the reduction in episodes of urge incontinence with oxybutynin was significantly greater than with placebo (P = 0.023), the reduction with tolterodine did not differ significantly from placebo. Oxybutynin’s metabolite is active, and in 1 study,8 saliva output decreased and dry mouth was more severe as metabolite concentrations increased; however, there was no correlation between the concentration of parent drug and saliva output or dry mouth. When ketoconazole was administered with oxybutynin in another study,9 there were significant increases in concentrations and area under the curve (AUC) of oxybutynin but not in metabolite levels, and the severity of dry mouth was similar with and without ketoconazole. Although a slower increase in oxybutynin levels and a
M.B. CHANCELLOR
ET AL.
lower peak concentration may help reduce dry mouth,9 there is evidence suggesting that metabolite levels may have more influence on the severity of dry mouth than does parent drug concentration.8-1 1 Extended-release oxybutynin delivers drug primarily to the colon, potentially minimizing first-pass metabolism by the cytochrome P450 enzyme system in the upper gastrointestinal tract, thus reducing metabolite formation.t” In a safety and efficacy study,5 the incidence of dry mouth was significantly lower with extended-release oxybutynin than with the immediate-release formulation (P = 0.04). Although the overall incidence of dry mouth was not significantly different between immediate- and extendedrelease oxybutynin in a second safety and efficacy study, l2 a significantly lower proportion of patients taking extended-release oxybutynin had moderate to severe dry mouth (P = 0.007) or any dry mouth (P = 0.003). The primary objective of the present study was to compare saliva output-an objective measure of the potential for dry mouth-in subjects taking immediate- or extended-release oxybutynin, tolterodine, or placebo.
SUBJECTS
AND METHODS
Inclusion and Exclusion
Criteria
Subjects were healthy men and women who were within 15% of ideal weight for height and had no clinically relevant abnormalities, as determined by medical history, physical examination, blood chemistry, complete blood count, urinalysis, and electrocardiography. Subjects who had clinically significant medical problems, glaucoma, obstructive uropathy, par-
tial or complete obstruction or narrowing of the gastrointestinal tract, paralytic ileus, intestinal atony, colitis, or myasthenia gravis were excluded, as were male subjects with hemoglobin levels ~13 g/dL and female subjects with hemoglobin levels ~11.5 g/dL. Subjects who were using prescription medications (except for estrogen replacement or birth control) within 14 days before the start of the study, who had known allergies to the study drugs, who had smoked tobacco within the past 3 months, or who drank 22 ounces of alcoholic beverages per day or >40 ounces of caffeine-containing beverages per day were also excluded. The institutional review board of the participating study center approved the study, and each participant provided written informed consent. The study was conducted in accordance with guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practices, and the Declaration of Helsinki.
Study Design This was a single-site, single-dose, randomized, double-blind, 4-treatment, 4period crossover study in healthy adult volunteers. Subjects were randomly assigned to 1 of 4 treatment sequences that included extended-release oxybutynin 10 mg, tolterodine 2 mg, immediate-release oxybutynin 5 mg, and placebo. There was a washout period of 5 to 7 days between treatments.
Study Assessments Saliva output was measured objectively. At each assessment, the subject was asked
755
CLINICALTHERAPEUTKY
to swallow his or her saliva. Then, a 1” x 1” square of Parafilm@’ (American National Can Co, Norwalk, Connecticut) was placed on the subject’s tongue, and the subject was instructed to chew the Parafilm without swallowing saliva for 2 minutes. The subject then spit into a clean, dry, preweighed beaker. The difference between the weight of the saliva-filled beaker (with the chewed Paratilm) and the empty beaker (with dry Paratilm) was the weight of saliva produced. Saliva output was measured before dosing and at 0.5, 1,2,3,4,6,8, 10, and 12 hours after dosing with each treatment. Saliva output was integrated over 12 hours as the AUC of saliva output versus time. The point of minimal saliva production (trough) was estimated for the 12-hour period. Sitting heart rate and blood pressure were measured manually before dosing and 8 and 12 hours after dosing.
Statistical Analysis Saliva output was summarized by treatment and evaluation time point. Saliva output AUC and trough were analyzed using a mixed-effect analysis-of-variance model that included treatment, period, sequence, fixed effects, and subject-within-sequence random effect. The Student-Newman-Keul multiple-comparison test was used to compare treatments. All statistical tests were performed at a significance level of P < 0.05using SAS@’version 6.12 (SAS Institute, Cary, North Carolina). The statistical analysis of data from this study provided >95% power to detect the observed differences in saliva output.
RESULTS Thirty-six healthy adult volunteers (22 women and 14 men) participated in the
756
study. They ranged in age from 19 to 42 years (mean, 27 years). Thirty-one were white, 3 Asian, and 2 black. One subject missed a single assessment for personal reasons; all available data for this subject were included in the analysis. There were no significant differences in predose saliva output between the 4 study groups (Figure). Saliva output increased throughout the day with placebo. With extended-release oxybutynin, saliva output was maintained at the predose level throughout the day. Two hours after dosing with immediate-release oxybutynin and tolterodine, saliva output decreased almost 0.5 g in specimens collected over 2 minutes. The lowest trough value was seen with tolterodine (Table I, Figure). All 3 active medications, however, resulted in significantly lower saliva AUCs compared with placebo (P< 0.01) (Table II). AUCs were not significantly different between extended-release oxybutynin and tolterodine, but these agents resulted in significantly higher saliva production than immediate-release oxybutynin (P< 0.01) (Tables I and II). No serious AEs were observed in this study, and the types and incidences of AEs were similar between treatments (Table III). Headache was the most commonly reported AE, occurring with a similar incidence between active treatments and with a higher incidence between active treatments and placebo.
DISCUSSION Saliva production may be diminished by the use of anticholinergic medications, chronic mouth breathing, radiation therapy, dehydration, autoimmune disease, diabetes mellitus, nephritis, or thyroid dysfunction. l3 Because decreased saliva
M.B. CHANCELLOR
ET AL.
-0. U -A- -x 3.5
Extended-release oxbutynin Tolterodine tartrate Immediate-release oxybutynin Placebo
1
1.50
I 2
I 4
I 6
I 6
I 10
I 12
Time, h Figure.
Comparison of mean saliva output after single doses of extended-release (10 mg) and immediate-release (5 mg) oxybutynin chloride, tolterodine tartrate (2 mg), and placebo (N = 36). Higher values are better and lower values worse.
production is associated with dry mouth,‘4 the measurement of saliva output in pharmacologic studies provides an objective estimate of a drug’s potential to produce clinical symptoms of dry mouth. Minimizing the occurrence and severity of dry mouth is important, because severe dry mouth creates a predisposition to secondary oral mu-
cosal diseasei and may interfere with compliance with prescribed medications.3 In this single-dose, placebo-controlled study, we evaluated the effect on saliva output of 3 active treatments that have demonstrated efficacy in treating the symptoms of overactive bladder.4-7sL6 Single doses were used so that saliva production could be as-
Table I. Mean (SD) values on measures of saliva output, by treatment group (N = 36). Measure AUC, g/h Trough, gl2 min
Extended-Release 30 (15) 1.7 (1.0)
OXY
TOL
Immediate-Release
29 (17) 1.4 (0.9)
27 (15) 1.5 (0.9)
OXY
Placebo 33 (17) 2.0 (1.1)
OXY = oxybutynin; TOL = tolterodine; AUC = area under the curve.
757
CLINICAL THERAPEUTICS”
Table II. Statistical comparisons
Measure AUC, s/h Trough, g/2 min
e Active Treatments Versus Placebo
of measures of saliva output. c ExtendedVersus ImmediateRelease OXY
fl TOL Versus ImmediateRelease OXY
e ExtendedRelease OXY Versus TOL
0.01
0.005
0.80
0.05
0.96
0.06
OXY = oxybutynin; TOL = tolterodine; AUC = area under the curve.
sessed during normal waking hours. Dose selection included the lowest initial doses of the 2 immediate-release products, tolterodine 2 mg and oxybutynin 5 mg. A lo-mg dose of extended-release oxybutynin was chosen for comparison because this formulation is designed to release drug more slowly than the immediate-release formulations. All 3 anticholinergic treatments decreased overall saliva output significantly compared with placebo (Table II). However, saliva output as integrated over the day was not significantly different with extendedrelease oxybutynin and tolterodine, which were developed in part to help minimize anticholinergic side effects. Both agents had less impact on saliva output than did immediate-release oxybutynin, suggesting that extended-release oxybutynin and tolterodine may reduce the incidence and
severity of dry mouth compared with immediate-release oxybutynin. Interestingly, tolterodine produced the sharpest decrease in saliva output compared with predose levels, and the initial observed reductions in saliva output with tolterodine were greater than those with immediateor extended-release oxybutynin. This pharmacokinetic study was conducted in healthy volunteers rather than patients with overactive bladder, and the effects of the active treatments on saliva output may differ in these populations. Nevertheless, obtaining objective measures such as saliva output in a crossover fashion allowed comparison between treatments. Our results clearly demonstrate the propensity of antimuscarinic agents to limit saliva output, even in a healthy population not taking other prescription medications.
Table III. Numbers of patients with adverse events possibly related to treatment.
Adverse Event Headache Nausea Vomiting Dyspepsia Vasodilatation
Extended-Release OXY (n = 36) 6 0 1 0 0
OXY = oxybutynin; TOL = tolterodine.
758
Immediate-Release OXY (n = 35) 6 1 2 1 0
TOL (n = 36)
Placebo (n = 36)
I 0
4 1
1
0
0 0
0 1
M.B. CHANCELLOR
ET AL.
CONCLUSIONS Overactive bladder and urinary incontinence are common problems. Although effective treatments are available, side effects such as dry mouth limit compliance. Minimizing dry mouth is important in preventing secondary oral mucosal diseases and encouraging compliance. Newer formulations for the treatment of overactive bladder have been designed to reduce anticholinergic side effects. Objective evaluation of saliva output in this study indicated that extended-release oxybutynin and tolterodine had less impact on saliva output than did conventional immediaterelease oxybutynin, suggesting that these 2 agents may yield lower levels of dry mouth.
ACKNOWLEDGMENT This study was sponsored by ALZA Corporation, Mountain View, California.
REFERENCES Public Health Service, Agency for Health Care Policy and Research. Clinical Practice Guideline: Urinary Incontinence in Adults. Washington DC: US Dept of Health and Human Services; 1996. Publication 96-0682.
4. Chancellor M, Freedman S, Mitcheson HD, et al. Tolterodine, an effective and well tolerated treatment for urge incontinence and other overactive bladder symptoms. Clin Drug Invest. 2ooO;19:83-91. 5. Anderson RU, Mobley D, Blank B, et al, for the OROS Oxybutynin Study Group. Once-daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. ./ Ural. 1999; 16 1: 18091812. 6. Gleason DM, Susset J, White C, et al, for the Ditropan XL Study Group. Evaluation of a new once-daily formulation of oxybutynin for the treatment of urinary urge incontinence. Urolog_v. 1999;54:420-423. 7. Abrams P, Freeman R, Anderstrom C, Mattiasson A. Tolterodine, a new antimuscarinic agent: As effective but better tolerated than oxybutynin in patients with an overactive bladder. Br .I Ural. 1998; 81:801-810. 8. Sathyan G, Chancellor M, Gupta SK. Effect of OROS controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride. Br .I Clin Pharmacol. In press. 9. Sathyan G, Hu W, Chancellor MB, Gupta SK. Comparison of CYP3A4 inhibitor effects on the stereoselective pharmacokinetics of extended release oxybutynin and conventional oxybutynin. Pharm Sci Echno1 Today. 1999;1:2056. Abstract.
Lenderking WR, Nackley JF, Anderson RB, Testa MA. A review of the quality-oflife aspects of urinary urge incontinence. Pharmacoeconomics. 1996:9:1 l-23.
10. Gupta SK, Sathyan G. Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol. 1999;39:289-296.
Yarker YE, Goa KL, Fitton A. Oxybutynin. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging. 1995;6:243-262.
11. Buyse G, Waldeck K, Verpoorten C, et al. Intravesical oxybutynin for neurogenic bladder dysfunction: Less systemic side effects due to reduced first pass metabolism. J Ural. 1998;160:892-896.
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CLINICAL THERAPEUTICS”
12 Versi E, Appell R, Mobley D, et al, for the Ditropan XL Study Group. Dry mouth with conventional and controlled-release oxybutynin in urinary incontinence. Obstet Gynecol. 2000;95:718-721. 13. Astor FC, Hanft KL, Ciocon JO. Xerostomia: A prevalent condition in the elderly.
community dwelling Project. J Rheumatol.
elderly:
The SEE
1998;25:486-491.
15. Jensen JL, Barkvoll P. Clinical implications of the dry mouth. Oral mucosal diseases. Ann New York Acad Sci. 1998;842: 156-162.
Ear Nose Throat J. 1999;78:476-479.
14. Hochberg MC, Tielsch J, Munoz B, et al. Prevalence of symptoms of dry mouth and their relationship to saliva production in
Address correspondence of Pittsburgh Pittsburgh,
760
School
to: Michael
of Medicine,
PA 15213. E-mail:
16. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: A pooled analysis. Urology. 1997; SO(Suppl 6A):90-96.
B. Chancellor, Kaufman
MD, Urological
Building,
[email protected]
Suite
700,
Surgery, 3471
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Avenue,
23, NO. 5,201
A Comparison of the Effects on Saliva Output of Oxybutynin Chloride and Tolterodine Tartrate Michael B. Chancellor, MD,’ Rodney A. Appell, A4D,2 Gayatn’ Sathyan, PhD,3 and Suneel K. Guptu, PhD3 IDepartment of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 2The Cleveland Clinic, Cleveland, Ohio, and jALZA Corporation, Mountain View, California
ABSTRACT Background:
Oxybutynin
chloride and tolterodine tartrate are anticholinergic agents bladder contractions in urinary incontinence. They act by inhibiting binding of acetylcholine to the muscarinic receptors in the detrusor muscle of the bladder. The same types of muscarinic receptors are found in the salivary glands; thus anticholinergic agents may decrease saliva production and cause dry mouth, a commonly cited reason for discontinuation of therapy. Objective: The primary objective of this study was to compare saliva output, which is an objective measure of dry mouth, in subjects taking immediate- or extended-release oxybutynin, tolterodine, or placebo. Methods: This was a single-site, single-dose, randomized, double-blind, 4-treatment, 4-period crossover study. Subjects were randomly assigned to 1 of 4 treatment sequences that included extended-release oxybutynin 10 mg, tolterodine 2 mg, immediate-release oxybutynin 5 mg, and placebo. Saliva output was measured objectively before dosing with each treatment and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after dosing. Results: Thirty-six healthy adult volunteers (22 women and 14 men) participated in the study. They ranged in age from 19 to 42 years (mean, 27 years). Thirty-one were white, 3 Asian, and 2 black. There were no significant differences in predose saliva output between the 4 study groups. With placebo, saliva output increased throughout the day. Saliva output was maintained at predose levels throughout the day with extended-release oxybutynin. Two hours after dosing with tolterodine and immediate-release oxybutynin, saliva output decreased nearly 0.5 g in specimens collected over 2 minutes. All 3 active treatments were associated with lower saliva output compared with placebo. Extendedrelease oxybutynin and tolterodine were similar with respect to area under the saliva concentration-time curve but were associated with significantly greater saliva output than used to suppress involuntary
Accepted
for publication
February 28, 200
Printed in the USA. Reproduction
0149-2918/011$19.00
1.
in whole or part is not permitted.
753
CLINICAL THERAPEUTICS”
was immediate-release oxybutynin (P < 0.01). There were no serious adverse events @Es) in this study. AEs were similar between treatments, although the incidence of headache was higher in the activetreatment groups than with placebo. Conclusions: Objective assessment of saliva output in healthy adult volunteers indicated that extended-release oxybutynin and tolterodine had less impact on saliva output than did conventional immediaterelease oxybutynin, suggesting that they may yield lower levels of dry mouth. Key words: anticholinergic agents, salivation, oral health, xerostomia. (Clin The,: 2001;23:753-760)
INTRODUCTION Urinary incontinence affects millions of adults over 60 years of age.’ It has been associated with significant reductions in social functioning and, in severe cases, loss of independence.* Oxybutynin chloride, which is available in both immediaterelease* and extended-release? formulations, has a long history of success as a treatment for overactive bladder and urge incontinence.’ Tolterodine tartratei is another agent used to suppress involuntary bladder contractions. Because these agents act by inhibiting binding of acetylcholine to the muscarinic receptors in the detrusor muscle of the bladder, anticholinergic (antimuscarinic) symptoms are the primary adverse events (AEs) associated with both drugs. The same types of muscarinic receptors found in the bladder are also found
*Trademark: tain View, +Trademark: *Trademark: pack, New
754
Ditropan@ (ALZA Corporation, MounCalifornia). Ditropan XL@ (ALZA Corporation). DetroPM (Pharmacia Corporation, PeaJersey).
in the salivary glands, and anticholinergic agents may decrease saliva production and cause dry mouth, a reason commonly cited by patients who discontinue these medications. Anticholinergic agents such as oxybutynin and tolterodine are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrowangle glaucoma. The usual starting dosage of tolterodine is 2 mg twice daily.4 Immediate- and extended-release oxybutynin have been studied at doses ranging from 5 to 30 mg/d, with the majority of patients maintained at doses of 5 to 15 mg/d.5,6 Two trials demonstrated a similar reduction in episodes of urge incontinence with immediate- and extended-release oxybutynin chloride.s,6 In another placebo-controlled study comparing immediate-release oxybutynin and tolterodine,7 the mean number of episodes of incontinence was decreased by 71%, 47%, and 19% in patients taking oxybutynin, tolterodine, and placebo, respectively. Although the reduction in episodes of urge incontinence with oxybutynin was significantly greater than with placebo (P = 0.023), the reduction with tolterodine did not differ significantly from placebo. Oxybutynin’s metabolite is active, and in 1 study,8 saliva output decreased and dry mouth was more severe as metabolite concentrations increased; however, there was no correlation between the concentration of parent drug and saliva output or dry mouth. When ketoconazole was administered with oxybutynin in another study,9 there were significant increases in concentrations and area under the curve (AUC) of oxybutynin but not in metabolite levels, and the severity of dry mouth was similar with and without ketoconazole. Although a slower increase in oxybutynin levels and a
M.B. CHANCELLOR
ET AL.
lower peak concentration may help reduce dry mouth,9 there is evidence suggesting that metabolite levels may have more influence on the severity of dry mouth than does parent drug concentration.8-1 1 Extended-release oxybutynin delivers drug primarily to the colon, potentially minimizing first-pass metabolism by the cytochrome P450 enzyme system in the upper gastrointestinal tract, thus reducing metabolite formation.t” In a safety and efficacy study,5 the incidence of dry mouth was significantly lower with extended-release oxybutynin than with the immediate-release formulation (P = 0.04). Although the overall incidence of dry mouth was not significantly different between immediate- and extendedrelease oxybutynin in a second safety and efficacy study, l2 a significantly lower proportion of patients taking extended-release oxybutynin had moderate to severe dry mouth (P = 0.007) or any dry mouth (P = 0.003). The primary objective of the present study was to compare saliva output-an objective measure of the potential for dry mouth-in subjects taking immediate- or extended-release oxybutynin, tolterodine, or placebo.
SUBJECTS
AND METHODS
Inclusion and Exclusion
Criteria
Subjects were healthy men and women who were within 15% of ideal weight for height and had no clinically relevant abnormalities, as determined by medical history, physical examination, blood chemistry, complete blood count, urinalysis, and electrocardiography. Subjects who had clinically significant medical problems, glaucoma, obstructive uropathy, par-
tial or complete obstruction or narrowing of the gastrointestinal tract, paralytic ileus, intestinal atony, colitis, or myasthenia gravis were excluded, as were male subjects with hemoglobin levels ~13 g/dL and female subjects with hemoglobin levels ~11.5 g/dL. Subjects who were using prescription medications (except for estrogen replacement or birth control) within 14 days before the start of the study, who had known allergies to the study drugs, who had smoked tobacco within the past 3 months, or who drank 22 ounces of alcoholic beverages per day or >40 ounces of caffeine-containing beverages per day were also excluded. The institutional review board of the participating study center approved the study, and each participant provided written informed consent. The study was conducted in accordance with guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practices, and the Declaration of Helsinki.
Study Design This was a single-site, single-dose, randomized, double-blind, 4-treatment, 4period crossover study in healthy adult volunteers. Subjects were randomly assigned to 1 of 4 treatment sequences that included extended-release oxybutynin 10 mg, tolterodine 2 mg, immediate-release oxybutynin 5 mg, and placebo. There was a washout period of 5 to 7 days between treatments.
Study Assessments Saliva output was measured objectively. At each assessment, the subject was asked
755
CLINICALTHERAPEUTKY
to swallow his or her saliva. Then, a 1” x 1” square of Parafilm@’ (American National Can Co, Norwalk, Connecticut) was placed on the subject’s tongue, and the subject was instructed to chew the Parafilm without swallowing saliva for 2 minutes. The subject then spit into a clean, dry, preweighed beaker. The difference between the weight of the saliva-filled beaker (with the chewed Paratilm) and the empty beaker (with dry Paratilm) was the weight of saliva produced. Saliva output was measured before dosing and at 0.5, 1,2,3,4,6,8, 10, and 12 hours after dosing with each treatment. Saliva output was integrated over 12 hours as the AUC of saliva output versus time. The point of minimal saliva production (trough) was estimated for the 12-hour period. Sitting heart rate and blood pressure were measured manually before dosing and 8 and 12 hours after dosing.
Statistical Analysis Saliva output was summarized by treatment and evaluation time point. Saliva output AUC and trough were analyzed using a mixed-effect analysis-of-variance model that included treatment, period, sequence, fixed effects, and subject-within-sequence random effect. The Student-Newman-Keul multiple-comparison test was used to compare treatments. All statistical tests were performed at a significance level of P < 0.05using SAS@’version 6.12 (SAS Institute, Cary, North Carolina). The statistical analysis of data from this study provided >95% power to detect the observed differences in saliva output.
RESULTS Thirty-six healthy adult volunteers (22 women and 14 men) participated in the
756
study. They ranged in age from 19 to 42 years (mean, 27 years). Thirty-one were white, 3 Asian, and 2 black. One subject missed a single assessment for personal reasons; all available data for this subject were included in the analysis. There were no significant differences in predose saliva output between the 4 study groups (Figure). Saliva output increased throughout the day with placebo. With extended-release oxybutynin, saliva output was maintained at the predose level throughout the day. Two hours after dosing with immediate-release oxybutynin and tolterodine, saliva output decreased almost 0.5 g in specimens collected over 2 minutes. The lowest trough value was seen with tolterodine (Table I, Figure). All 3 active medications, however, resulted in significantly lower saliva AUCs compared with placebo (P< 0.01) (Table II). AUCs were not significantly different between extended-release oxybutynin and tolterodine, but these agents resulted in significantly higher saliva production than immediate-release oxybutynin (P< 0.01) (Tables I and II). No serious AEs were observed in this study, and the types and incidences of AEs were similar between treatments (Table III). Headache was the most commonly reported AE, occurring with a similar incidence between active treatments and with a higher incidence between active treatments and placebo.
DISCUSSION Saliva production may be diminished by the use of anticholinergic medications, chronic mouth breathing, radiation therapy, dehydration, autoimmune disease, diabetes mellitus, nephritis, or thyroid dysfunction. l3 Because decreased saliva
M.B. CHANCELLOR
ET AL.
-0. U -A- -x 3.5
Extended-release oxbutynin Tolterodine tartrate Immediate-release oxybutynin Placebo
1
1.50
I 2
I 4
I 6
I 6
I 10
I 12
Time, h Figure.
Comparison of mean saliva output after single doses of extended-release (10 mg) and immediate-release (5 mg) oxybutynin chloride, tolterodine tartrate (2 mg), and placebo (N = 36). Higher values are better and lower values worse.
production is associated with dry mouth,‘4 the measurement of saliva output in pharmacologic studies provides an objective estimate of a drug’s potential to produce clinical symptoms of dry mouth. Minimizing the occurrence and severity of dry mouth is important, because severe dry mouth creates a predisposition to secondary oral mu-
cosal diseasei and may interfere with compliance with prescribed medications.3 In this single-dose, placebo-controlled study, we evaluated the effect on saliva output of 3 active treatments that have demonstrated efficacy in treating the symptoms of overactive bladder.4-7sL6 Single doses were used so that saliva production could be as-
Table I. Mean (SD) values on measures of saliva output, by treatment group (N = 36). Measure AUC, g/h Trough, gl2 min
Extended-Release 30 (15) 1.7 (1.0)
OXY
TOL
Immediate-Release
29 (17) 1.4 (0.9)
27 (15) 1.5 (0.9)
OXY
Placebo 33 (17) 2.0 (1.1)
OXY = oxybutynin; TOL = tolterodine; AUC = area under the curve.
757
CLINICAL THERAPEUTICS”
Table II. Statistical comparisons
Measure AUC, s/h Trough, g/2 min
e Active Treatments Versus Placebo
of measures of saliva output. c ExtendedVersus ImmediateRelease OXY
fl TOL Versus ImmediateRelease OXY
e ExtendedRelease OXY Versus TOL
0.01
0.005
0.80
0.05
0.96
0.06
OXY = oxybutynin; TOL = tolterodine; AUC = area under the curve.
sessed during normal waking hours. Dose selection included the lowest initial doses of the 2 immediate-release products, tolterodine 2 mg and oxybutynin 5 mg. A lo-mg dose of extended-release oxybutynin was chosen for comparison because this formulation is designed to release drug more slowly than the immediate-release formulations. All 3 anticholinergic treatments decreased overall saliva output significantly compared with placebo (Table II). However, saliva output as integrated over the day was not significantly different with extendedrelease oxybutynin and tolterodine, which were developed in part to help minimize anticholinergic side effects. Both agents had less impact on saliva output than did immediate-release oxybutynin, suggesting that extended-release oxybutynin and tolterodine may reduce the incidence and
severity of dry mouth compared with immediate-release oxybutynin. Interestingly, tolterodine produced the sharpest decrease in saliva output compared with predose levels, and the initial observed reductions in saliva output with tolterodine were greater than those with immediateor extended-release oxybutynin. This pharmacokinetic study was conducted in healthy volunteers rather than patients with overactive bladder, and the effects of the active treatments on saliva output may differ in these populations. Nevertheless, obtaining objective measures such as saliva output in a crossover fashion allowed comparison between treatments. Our results clearly demonstrate the propensity of antimuscarinic agents to limit saliva output, even in a healthy population not taking other prescription medications.
Table III. Numbers of patients with adverse events possibly related to treatment.
Adverse Event Headache Nausea Vomiting Dyspepsia Vasodilatation
Extended-Release OXY (n = 36) 6 0 1 0 0
OXY = oxybutynin; TOL = tolterodine.
758
Immediate-Release OXY (n = 35) 6 1 2 1 0
TOL (n = 36)
Placebo (n = 36)
I 0
4 1
1
0
0 0
0 1
M.B. CHANCELLOR
ET AL.
CONCLUSIONS Overactive bladder and urinary incontinence are common problems. Although effective treatments are available, side effects such as dry mouth limit compliance. Minimizing dry mouth is important in preventing secondary oral mucosal diseases and encouraging compliance. Newer formulations for the treatment of overactive bladder have been designed to reduce anticholinergic side effects. Objective evaluation of saliva output in this study indicated that extended-release oxybutynin and tolterodine had less impact on saliva output than did conventional immediaterelease oxybutynin, suggesting that these 2 agents may yield lower levels of dry mouth.
ACKNOWLEDGMENT This study was sponsored by ALZA Corporation, Mountain View, California.
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16. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: A pooled analysis. Urology. 1997; SO(Suppl 6A):90-96.
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