pharmacokinetics, metabolism, and saliva output during transdermal and extended-release oral...

Transdermal and Extended-Release Oral Oxybutynin Mayo Clin Proc, June 2003, Vol 78696

Mayo Clin Proc. 2003;78:696-702 696 © 2003 Mayo Foundation for Medical Education and Research

Original Article

Pharmacokinetics, Metabolism, and Saliva Output During Transdermaland Extended-Release Oral Oxybutynin Administration in Healthy Subjects

RODNEY A. APPELL, MD; M ICHAEL B. CHANCELLOR , MD; R. HOWARD ZOBRIST, PHD; HEATHER THOMAS, PHD;AND STEVEN W. SANDERS, PHARM D

From the Department of Urology, Baylor College of Medicine, Hous-ton, Tex (R.A.A.); Division of Urological Surgery, University of Pitts-burgh School of Medicine, Pittsburgh, Pa (M.B.C.); and WatsonLaboratories, Inc, Salt Lake City, Utah (R.H.Z., H.T., S.W.S.).

Financial support provided by Watson Pharmaceuticals, Inc.

Dr Appell is on the Medical Advisory Board of Ortho-McNeil Pharma-ceutical, Watson Pharmaceuticals, Inc, and Indevus Pharmaceuti-cals, Inc. Dr Chancellor is on the Medical Advisory Board of Ortho-McNeil Pharmaceutical and Watson Pharmaceuticals, Inc.

Address reprint requests and correspondence to Rodney A. Appell,MD, Department of Urology, Baylor College of Medicine, 6560Fannin, Suite 2100, Houston, TX 77030 (e-mail: [email protected]).

• Objective: To compare the pharmacokinetics and ad-verse effect dynamics of 2 modified-release oxybutynintreatments.

• Subjects and Methods: Between October 15 and No-vember 6, 2001, 13 healthy subjects (7 men and 6 women)participated in a randomized, 2-way crossover study oftransdermal (Oxytrol, 3.9 mg/d) and extended-release oral(Ditropan XL, 10 mg) oxybutynin. Multiple blood andsaliva samples were collected. Pharmacokinetic param-eters and total salivary output were assessed. Statisticalanalyses included 95% confidence intervals, paired t test,analysis of variance, and linear regression.

• Results: Steady-state plasma concentrations wereachieved after the first transdermal application and afterthe second extended-release oral dose. Mean ± SD 24-houroxybutynin areas under the concentration-time curvewere comparable during transdermal and oral extended-release treatments, 10.8±2.4 vs 9.2±3.3 ng · h–1 · mL–1,respectively. However, the ratio of area under the curve(N-desethyloxybutynin/oxybutynin) after transdermal ad-

ministration (1.2±0.3) was significantly lower (P<.001)than after extended-release oral administration (4.1±0.9).Mean plasma concentrations were less variable duringtransdermal compared with extended-release oral ad-ministration. Mean ± SD saliva output was greater dur-ing transdermal than extended-release oral treatment(15.7±9.3 vs 12.2±6.8 g, respectively; P=.02). Lower N-desethyloxybutynin during transdermal application wasassociated with greater saliva output (r=–0.59, P=.04). Noclinically important treatment-related adverse effectswere observed.

• Conclusions: Transdermal oxybutynin administra-tion results in greater systemic availability and minimizesmetabolism to N-desethyloxybutynin compared with ex-tended-release oral administration. Lower N-desethyloxy-butynin plasma concentration and greater saliva outputduring transdermal treatment correspond to the reportedlow incidence of dry mouth in patients with overactivebladder.

Mayo Clin Proc. 2003;78:696-702

Oxybutynin is a well-known antimuscarinic agent thathas been prescribed extensively to alleviate urinary

urgency, urinary frequency, and urge urinary inconti-nence associated with detrusor instability.1-5 Transder-mal oxybutynin treatment offers several potential thera-peutic advantages over oral administration. Sustaineddelivery during the dosing period results in more stableplasma concentrations, without the high peak plasmaconcentrations observed after oral administration.6-8 Theextensive presystemic metabolism that occurs after oraladministration does not occur with transdermal delivery;

thus, the formation of the primary active metabolite N-desethyloxybutynin is reduced. This difference between oraland transdermal administration is increased when the activeR-enantiomer of N-desethyloxybutynin is compared be-tween the 2 types of administration.7 Reduced circulatingmetabolite concentrations may attenuate the anticholinergicadverse effects observed with oral dosing, thereby improv-ing tolerability.1-3 Transdermal delivery also requires lessfrequent dosing than oral administration and may improvepatient compliance and convenience.

For editorial comment, see page 681.

The efficacy of transdermal oxybutynin, at a dose of 3.9mg/d, was shown in a controlled multicenter study of 520patients with overactive bladder and incontinence.9 Anti-cholinergic adverse effects were comparable between pla-cebo and active treatments, with dry mouth occurring inless than 10% of the patients. Efficacy of transdermaltreatment vs oral immediate-release oxybutynin was com-parable in a short-term study of previously treated pa-tients with urodynamically confirmed detrusor instability.10

Transdermal treatment led to a lower incidence of anti-cholinergic adverse effects compared with oral treatment

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Mayo Clin Proc, June 2003, Vol 78 Transdermal and Extended-Release Oral Oxybutynin 697

and was associated with a reduction in adverse effectscompared with prestudy oxybutynin treatment.

The current study in healthy subjects compared oxy-butynin pharmacokinetics and metabolism during trans-dermal and extended-release oral dosing and examined therelationship between plasma concentrations and saliva pro-duction, a surrogate marker of dry mouth.

SUBJECTS AND METHODSThe protocol was reviewed and approved by the St CharlesCommunity Institutional Review Board. Written informedconsent was obtained from each subject before participa-tion in any study-related procedures. The study was con-ducted between October 15 and November 6, 2001.

Healthy male and female subjects, 18 years of age orolder, were recruited for the study. Subjects were requiredto have a body mass index of 20 to 30 kg/m2 (weight inkilograms divided by the square of height in meters) andweight between 50 kg and 90 kg. Subjects were excludedon the basis of any preexisting condition or finding on theprestudy examination that would place them at risk duringthe study. Prestudy screening examinations included medi-cal history, physical examination, clinical laboratory tests(complete blood cell count, serum chemistries, urinalysis,and a pregnancy test for the women), and training for salivacollection. Subjects reported to the clinic in St Charles, Mo,for all study procedures and were confined for drug admin-istration and sample collection for 4 days during each studyperiod, during which they followed a standardized mealand activity program.

Treatments were administered according to a random-ized, open-label, 2-way crossover design and includedtransdermal (Oxytrol, 3.9 mg/d, Watson Pharmaceuticals,Inc, Corona, Calif) and extended-release oral (DitropanXL, 10 mg, Ortho-McNeil Pharmaceutical, Raritan, NJ)oxybutynin. Steady-state conditions were achieved by se-quentially applying 2 transdermal systems to the abdomen,the first for 84 hours and the second for 96 hours, andadministering oral doses daily for 6 days.

Venous blood samples (10 mL per sample) were col-lected at baseline (within 30 minutes before application ofthe first transdermal system or administration of the firstoral tablet) and periodically throughout each study period.Sample times were matched according to the time after thesecond transdermal system application and the third oraltablet.

Plasma concentrations of racemic and individual R- andS-enantiomers of oxybutynin and N-desethyloxybutyninwere measured by using a validated high-performance liq-uid chromatography–tandem mass spectrometry method(MDS Pharma Services, Inc, Lincoln, Neb). The methodwas validated for oxybutynin and N-desethyloxybutynin

over a concentration range of 0.05 to 50.0 ng/mL. Bothintraday and interday precision were evaluated at concen-trations of 0.15, 10.0, and 40.0 ng/mL with values of 8.0%or less and 6.6% or less, respectively, for oxybutynin and10.7% or less and 11.3% or less, respectively, for N-desethyloxybutynin. The method for R- and S-enantiomersof oxybutynin was validated over a concentration range of0.05 to 25.0 ng/mL. Interday precision was 12.4% or lessand 13.0% or less for R- and S-enantiomers of oxybutynin,respectively. The validated concentration range for R- andS-enantiomers of N-desethyloxybutynin was 0.25 to 25.0ng/mL. Interday precision was 10.2% or less and 8.6% orless for R- and S-enantiomers of N-desethyloxybutynin,respectively.

Saliva output was assessed every 12 hours after applica-tion of the second transdermal system and after the thirdextended-release oral tablet. At the specified time, eachsubject rinsed his or her mouth with approximately 2 oz oftap water, expectorating the water after rinsing. Ten min-utes later, each subject swallowed any saliva in his or hermouth, and an accurately weighed 1 × 1 in square of par-affin was placed on each subject’s tongue. The subject thenchewed the paraffin for 2 minutes, after which any accumu-lated saliva and the chewed paraffin was expectorated intoa previously weighed clear dry receptacle, and the recep-tacle was reweighed.11

Pharmacokinetic parameters included area under theplasma concentration-time curve and minimum and maxi-mum plasma concentrations. Area under the curve wasexpressed as a mean per 24 hours based on the period from0 to 84 hours for transdermal and from 0 to 96 hours fororal treatment. The fluctuation index was calculated as the(maximum – minimum plasma concentration)/averageplasma concentration. Area under the curve ratios are pre-sented as N-desethyloxybutynin/oxybutynin. Attainmentof steady state was assessed by comparing the troughoxybutynin plasma concentration with use of the paired ttest. Pharmacokinetic parameters were compared by 95%confidence intervals. Metabolism of oxybutynin betweenthe treatments was assessed by comparing the area underthe curve ratios of N-desethyloxybutynin to oxybutyninwith use of an analysis of variance. Saliva weights weresummed for each subject and analyzed by the paired ttest. Linear regression was performed with assessment ofsignificance of the Pearson product moment correlationcoefficient.

RESULTSFifteen subjects were screened and enrolled into the study.Two subjects withdrew because of non–study-relatedevents. The 13 subjects, 7 men and 6 women, who com-pleted the study had a mean ± SD age of 35±12 years, mean



Figure 1. Mean ± SD steady-state oxybutynin and N-desethyloxybutynin plasma concentrations (ng/mL) during transdermal (left) andextended-release oral (right) administration. * = oral tablet administration.

± SD weight of 71±8 kg, and mean ± SD body mass indexof 25±2 kg/m2. Complete pharmacokinetic data and pairedanalyses were available for 12 subjects.

Steady-state conditions were achieved after applicationof the first transdermal system and after administration ofthe second extended-release oral tablet. The mean oxy-butynin plasma concentration obtained 84 hours after ap-plication of the first and second transdermal systems wascomparable (2.3 vs 2.2 ng/mL, respectively, P=.49). Like-wise, similar mean oxybutynin plasma concentrations wereobserved 24 hours after administration of the second andsixth extended-release oral tablets (2.0 vs 1.9 ng/mL, re-spectively, P=.63).

Mean oxybutynin plasma concentrations were generallygreater and less variable after transdermal compared withextended-release oral administration (Figure 1, Table 1).Mean ± SD oxybutynin maximum plasma concentrationvalues were similar between transdermal (4.2±1.0 ng/mL)and extended-release oral (4.0±1.5 ng/mL) administra-tion. Likewise, the 24-hour area under the curve was com-parable for transdermal (10.8±2.4 ng · h–1 · mL–1) vs ex-tended-release oral (9.2±3.3 ng · h–1 · mL–1) administration.Plasma concentrations during transdermal treatment wereless variable than during extended-release oral treatment(fluctuation index, 0.7 vs 1.3; 95% confidence interval,–0.9 to –0.3).

Mean N-desethyloxybutynin plasma concentrationsduring transdermal application paralleled oxybutyninplasma concentrations (Figure 1), with a mean ± SD maxi-mum plasma concentration of 4.9±2.0 ng/mL and 24-hourarea under the curve of 13.4±4.7 ng · h–1 · mL–1, resulting inan N-desethyloxybutynin/oxybutynin area under the curve

ratio of 1.2±0.3. After extended-release oral administra-tion, mean ± SD N-desethyloxybutynin plasma concentra-tions greatly exceeded those of oxybutynin, resulting in anarea under the curve ratio of 4.1±0.9 (extended-release oralN-desethyloxybutynin maximum plasma concentration,15.2±6.7 ng/mL; area under the curve, 38.0±17.8 ng · h–1 ·mL–1). N-desethyloxybutynin plasma concentrations werealso less variable after transdermal application, resulting insubstantially lower fluctuation index values compared withextended-release oral administration (Table 1).

Average plasma concentrations of individual R- and S-enantiomers showed stereoselective metabolism of R-en-antiomers of oxybutynin (Figure 2). During transdermaltreatment, average plasma concentrations were 1.2 and 1.7ng/mL for R- and S-enantiomers of oxybutynin, respec-tively, with little difference between R- and S-enantiomersof N-desethyl-oxybutynin (1.6 and 1.7 ng/mL, respec-tively). In contrast, after extended-release oral treatment,the average plasma concentration for the R-enantiomer ofoxybutynin was 50% lower than that for the S-enantiomerof oxybutynin (0.7 vs 1.4 ng/mL), resulting in an aver-age R-enantiomer of N-desethyloxybutynin plasma con-centration that was 22% greater than the S-enantiomerof N-desethyloxybutynin (5.0 vs 4.1 ng/mL, respectively;Figure 2).

Saliva output was consistently greater during transder-mal vs extended-release oral treatment at each measure-ment time point. Mean ± SD total saliva weight was15.7±9.3 g during transdermal application compared with12.2±6.8 g during extended-release oral tablet administra-tion (P=.02). Overall mean paired difference in total salivaweight between transdermal and extended-release oral

Time (hours after first transdermal application)

0 84 96 108 120 132 144 156 168 1800.0

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treatment was 3.5±4.5 g (range, –0.3 to 14.4 g), with 11 ofthe 12 subjects exhibiting greater saliva weight duringtransdermal treatment.

Individual paired differences in average oxybutyninplasma concentrations showed that transdermal treatmentresulted in greater oxybutynin concentrations in 9 of the 12subjects. For N-desethyloxybutynin, average plasma con-centrations were lower during transdermal treatment in all12 subjects. In general, a greater paired difference in N-desethyloxybutynin plasma concentrations was associatedwith a greater difference in saliva weight, correspondingto greater saliva production and lower N-desethyloxy-butynin plasma concentrations during transdermal treat-ment (Figure 3).

Regression analysis between average N-desethyloxy-butynin plasma concentrations and total saliva showed asignificant correlation (r=–0.59; P=.04). The correlationbetween oxybutynin plasma concentrations and saliva wasnot significant (r=–0.40; P=.18). Comparable results wereobtained for R-enantiomers, with a nonsignificant correla-tion (r=–0.27; P=.39) found between the R-enantiomer ofoxybutynin plasma concentrations and a stronger, althoughnonsignificant, correlation (r=–0.53; P=.07) found be-tween the R-enantiomer of N-desethyloxybutynin plasmaconcentrations and total saliva.

Six subjects (40%) experienced a total of 9 adverseevents, and 9 subjects (60%) experienced no adverseevents. Treatment-related adverse events were limited toone subject who reported nausea (1/15; 7%) during ex-tended-release oral oxybutynin administration. Adhesion

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of the transdermal systems was excellent, with 95% of allevaluations indicating greater than 90% adhesion through-out the application period.

DISCUSSIONTransdermal administration of oxybutynin leads to clini-cally important changes in pharmacokinetics, metabolism,and pharmacodynamic effects of oxybutynin comparedwith extended-release oral treatment. Achieving greateroxybutynin plasma concentrations with a lower daily dosedue to reduced metabolism to N-desethyloxybutynin andsustained delivery over 3 to 4 days may explain the thera-peutic advantages of transdermal administration over oral

Figure 2. Mean ± SD steady-state plasma concentrations (areaunder the curve/84 h) of individual R- and S-enantiomers ofoxybutynin and N-desethyloxybutynin during transdermal andextended-release oral oxybutynin administration.

Table 1. Pharmacokinetic Parameters for Oxybutynin and N-Desethyloxybutynin*

Oxybutynin N-desethyloxybutynin

Extended-release Extended-releaseParameter Transdermal oral P value Transdermal oral P value

Plasma concentration (ng/mL)Maximum 4.2±1.0 4.0±1.5 4.9±2.0 15.2±6.7

(95% CI) (–1.0 to 1.3) .78 (–14.4 to –6.5) <.001Minimum 2.1±0.3 1.3±0.7 2.8±1.1 5.5±4.1

(95% CI) (0.3 to 1.3) .004 (–4.9 to –0.4) .02Area under the curve

(ng · h–1 · mL–1)Total† 259±57 222±75 321±114 911±427

(95% CI) (–25 to 98) .22 (–842 to –344) <.00124-hour 10.8±2.4 9.2±3.3 13.4±4.7 38.0±17.8

(95% CI) (–1.1 to 4.1) .22 (–35.1 to –14.4) <.001Fluctuation index 0.7±0.2 1.3±0.5 0.5±0.1 1.1±0.4

(95% CI) (–0.9 to –0.3) .002 (–0.9 to –0.4) <.001

Transdermal Extended-release oral P value

Area under the curve ratio 1.2±0.3 4.1±0.9(95% CI) (–3.4 to –2.3) <.001

*Values represent mean ± SD unless indicated otherwise. CI = confidence interval.†Represents the period 0 to 84 hours (31/2 days) for transdermal and 0 to 96 hours (4 days) for extended-release oral administration.



–10

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administration that have been observed in clinical trials ofpatients with overactive bladder.9,10 Although saliva pro-duction is a surrogate marker of complaints of dry mouth,the consistently greater saliva production during trans-dermal application is consistent with the low incidenceof dry mouth and other common anticholinergic adverseeffects during transdermal and other delivery modes, suchas direct intravesical instillation,12-15 that do not resultin presystemic gastrointestinal and hepatic oxybutyninmetabolism.

Steady-state conditions, demonstrated by consistenttrough plasma concentrations, are rapidly attained duringoxybutynin treatment. Accounting for the known skin de-pot effect with transdermal oxybutynin that prolongs theapparent half-life to approximately 10 hours, continuousand constant (zero-order) drug administration would leadto steady state in 3.5 days.7,8 Steady state occurs with thesecond daily oral dose of controlled-release oxybutynin,reflecting the 2- to 4-hour half-life after oral dosing.6,16

Although transdermal and extended-release oral deliv-ery resulted in relatively little fluctuation in plasma con-centrations of the parent compound, metabolite concentra-tions varied widely over the dosing interval after extended-release oral administration. This may be due to variablemetabolism during transit of the tablet through the gas-trointestinal tract, with greater metabolism and thereforepeak N-desethyloxybutynin concentrations occurring soonafter administration when the drug passes through the up-per portions of the gastrointestinal tract.16 With transdermal

administration, N-desethyloxybutynin concentrations par-allel those of oxybutynin, with a ratio reflecting systemicdrug clearance.

Zobrist et al7 reported a greater conversion of the R-enantiomer of oxybutynin to the R-enantiomer of N-desethyloxybutynin compared with the S-enantiomer fororal and transdermal oxybutynin. These results were con-firmed in the current study with the greatest effect observedafter extended-release oral treatment, as reported previ-ously for immediate-release oxybutynin. This stereoselec-tive effect contributes to the metabolic differences thatinfluence transdermal and oral pharmacokinetics. The re-duced metabolism of the R-enantiomer of oxybutynin leadsto greater plasma concentrations of the parent compoundduring transdermal administration and thus lower plasmaconcentrations of the R-enantiomer of N-desethyloxy-butynin metabolite. The R-enantiomers of both oxybutyninand N-desethyloxybutynin have antimuscarinic activitybased on comparable in vitro effects on isolated tissues.17,18

Despite these findings, effects in vivo may be different andmay be tissue specific. Modiri et al19 reported greater invivo inhibition of detrusor contractions for oxybutynincompared with N-desethyloxybutynin in rats. In contrast,small but significantly greater binding affinity was re-ported for N-desethyloxybutynin compared with oxy-butynin in human parotid tissue.20 These reports mayexplain the observed in vivo similarities in efficacy anddifferences in dry mouth adverse events reporting duringclinical trials. Additional studies are needed to clarify fur-

Figure 3. Individual paired differences (transdermal minus extended-release oral administration) inmean oxybutynin and N-desethyloxybutynin plasma concentrations and total saliva weight.



ther the potential interplay of multiple receptor subtypes,expression, and binding affinities that will determine tissueresponses to antimuscarinic agents.

Saliva production has been used as a surrogate markerof dry mouth in previous pharmacodynamic studies.21-23

Sathyan et al22 showed that saliva production was de-creased and associated with increased dry mouth severityafter oral immediate-release compared with oral extended-release oxybutynin. Decreased saliva production correlatedwith increasing plasma N-desethyloxybutynin concentra-tions, with no apparent relationship to oxybutynin plasmaconcentrations. Comparable relationships were observed inthe current study, supporting the conclusion that dry mouthoccurring during oxybutynin administration is associatedwith circulating N-desethyloxybutynin. The sum of parentand metabolite plasma concentrations led to a reduction inthe association between concentrations and saliva output(data not shown). Further evidence of the major contribu-tion of N-desethyloxybutynin to the occurrence of drymouth was shown in a metabolic interaction study.23 Thecoadministration of extended-release oral oxybutynin withketoconazole resulted in an approximate 2-fold increase inthe R-enantiomer of oxybutynin area under the curve, witha negligible effect on the R-enantiomer of N-desethyloxy-butynin. No difference in dry mouth severity was observed,suggesting that the R-enantiomer of oxybutynin is mostlikely not responsible for causing dry mouth at the plasmaconcentrations observed. Although a control period with notreatment was not performed in the current study, the ran-domized crossover design was used to avoid sequence oftreatment effects. Average saliva production was consis-tently greater during transdermal oxybutynin administra-tion at all study time points, implying a consistent treat-ment-related effect.

Pharmacodynamic study results also support the find-ings of minimal anticholinergic adverse events during in-travesical oxybutynin administration.12-15 Oxybutyninplasma concentrations achieved with intravesical admin-istration are comparable to those measured during oraltreatment; however, few, if any, anticholinergic adverseeffects are reported. The lower incidence of adverse ef-fects with transdermal treatment compared with oral treat-ment has been attributed to the significantly lower N-desethyloxybutynin concentrations. Presystemic gastro-intestinal and hepatic first-pass metabolism are avoidedwith both transdermal and intravesical administration ofoxybutynin.

CONCLUSIONSThis study confirms the pharmacokinetic, metabolic,and pharmacodynamic differences between extended-release oral and transdermal oxybutynin administration.

A substantially lower fluctuation in oxybutynin and N-desethyloxybutynin plasma concentrations, reduced N-desethyloxybutynin formation, and greater saliva pro-duction during the dosing period are a direct result oftransdermal oxybutynin administration. Transdermal de-livery of oxybutynin appears to be the optimal routeof administration for this safe and effective antimusca-rinic compound. Patients with overactive bladder shouldbenefit from therapeutic use of this novel drug deliverysystem.

This study was conducted at the facilities of Gateway MedicalResearch, Inc, St Charles, Mo, under the direction of Earl J.Wipfler, Jr, MD, principal investigator. Bioanalytical serviceswere provided by MDS Pharma Services Inc, Lincoln, Neb, andSunnyvale, Calif. Clinical laboratory support was provided byQuest Diagnostics, St Louis, Mo.

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