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The effect of tolterodine on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive containing ethinyl estradiol and levonorgestrel
CLINICAL THERAPEUTICS®/VOL. 23, NO. 11, 2001
The Effect of Tolterodine on the Pharmacokinetics and Pharmacodynamics of a Combination Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel Birgitta Olsson, MSc, 1 and Britt-Marie Landgren, MD, PhD z 1Experimental Medicine, Biovitrum AB, Stockholm,* and 2Department of Obstetrics and Gynecology, Huddinge Hospital, Huddinge, Sweden
ABSTRACT
Background: Tolterodine is an antimuscarinic agent for the treatment of overactive bladder, a chronic condition that is particularly common in women. Given the prevalence pattern of overactive bladder and the widespread use of oral contraception, circumstances are likely to arise in which physicians may wish to prescribe tolterodine for patients already taking oral contraceptives. Based on a search of MEDLINE from 1990 to 2001, there have been no studies of whether concomitant use of these agents entails a risk of drug-drug interaction or conception. Objective: This study investigated the effects of tolterodine on the pharmacokinetics and pharmacodynamics of a low-dose combination oral contraceptive (ethinyl estradiol 30 txg/levonorgestrel 150 ixg). Methods: This was an open-label, randomized, 2-period crossover study in healthy women. Oral contraception was given for 21 days either alone or in combination with oral tolterodine 2 mg BID (on days 1-14) over two 28-day contraceptive cycles. Pharmacokinetic assessments were performed on day 14 based on plasma levels of ethinyl estradiol and levonorgestrel up to 24 hours after dosing and serum tolterodine levels at 1 to 3 hours after dosing. The potential for pharmacodynamic interaction was assessed in terms of the risk of failure of suppression of ovulation based on serum levels of estradiol and progesterone measured throughout each cycle. Results: Twenty-four healthy women (age, 23-41 years [mean, 30 years]; height, 155-178 cm [mean, 167 cm]; body weight, 51-75 kg [mean, 64 kg]) participated in the *At the time of the author's original involvement in the study, she was an employee of Pharmacia AB, Uppsala, Sweden. Accepted for publication September 10, 2001. Printed in the USA. Reproduction in whole or part is not
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permitted.
0149-2918/01/519.00
B. OLSSON AND B.-M. LANDGREN
study. There was no evidence of a pharmacokinetic interaction between tolterodine and the steroid hormones in the oral contraceptive used, nor did the oral contraceptive show any relevant pharmacokinetic interaction with tolterodine. Serum levels of estradiol and progesterone indicated suppression of ovulation in both treatment periods. Conclusion: In this selected population, coadministration of tolterodine did not affect the contraceptive efficacy of a low-dose combination oral contraceptive containing ethinyl estradiol and levonorgestrel. Key words: drug-drug interactions, ethinyl estradiol, levonorgestrel, oral contraception, ovarian activity, tolterodine. (Clin Ther. 2001;23:1876-1888) INTRODUCTION Numerous drugs are reported to interact both pharmacokinetically and pharmacodynamically with oral contraceptive steroids. 1 Although the exact prevalence of such interactions is not known, the widespread use of oral contraceptives means that there is a potential for drug-drug interactions to affect a large number of women. Tolterodine is an antimuscarinic agent for the treatment of overactive bladder, a chronic condition that is particularly common in women. 2 Pharmacokinetic studies have shown that tolterodine undergoes extensive first-pass metabolism, and 2 major metabolic pathways have been identified: oxidation and N-dealkylation. These 2 pathways are respectively mediated by the cytochrome P450 (CYP) 2D6 and 3A isozymes. 3,4 The 5-hydroxymethyl metabolite (5-HM), produced by the CYP2D6 pathway, has a similar pharmacologic pro-
file to tolterodine.5 However, a small percentage of the population lacks the CYP2D6 enzyme 6 and cannot form 5-HM. These individuals, known as poor metabolizers, have relatively high serum concentrations of tolterodine and metabolize the drug via CYP3A4-mediated N-dealkylation. 7 Both the estrogen and progestin components of combination oral contraceptives are also metabolized by this pathway. 8 Thus, there is a potential for drug-drug interaction during coadministration of tolterodine and combination oral contraceptives, although a MEDLINE search of the medical literature from 1990 to 2001 suggests that this potential has not been investigated. The primary objective of the present study, therefore, was to investigate the effect of tolterodine on the pharmacokinetic characteristics of ethinyl estradiol and levonorgestrel in a low-dose combination oral contraceptive. Secondary objectives were to assess the risk of failure of suppression of ovulation during tolterodine therapy (through determination of serum levels of endogenous estradiol and progesterone throughout the contraceptive cycle) and to assess the pharmacokinetics of tolterodine and 5-HM when tolterodine and the oral contraceptive were administered concomitantly. SUBJECTS AND METHODS
Eh'gibility Criteria To be eligible for participation, women had to be in good health (based on medical history, physical examination, and routine laboratory tests) and of normal body weight for height (_+10%). They were required to have been taking the study oral contraceptive (a typical combination con1877
CLINICAL THERAPEUTICS*
taining ethinyl estradiol 30 ixg and levonorgestrel 150 Ixg*) for at least 3 months before study entry; those taking other combinations of ethinyl estradiol and levonorgestrel could be included after switching to the study contraceptive for 2 months. No subject could have any contraindications to use of this oral contraceptive. Before beginning the study, each participant underwent phenotyping to determine her ability to metabolize debrisoquin (ie, CYP2D6 activity). 9 Subjects with metabolic ratios >12.6 were classified as poor metabolizers.
phenytoin, primidone, rifampin, broadspectrum antibiotics, antidiabetic drugs). Use of such agents constituted grounds for withdrawal from the study, although other drugs necessary for the participant's welfare were allowed at the discretion of the investigator. Written informed consent was obtained from all participants before entry. The study was performed in accordance with the most recent revisions to the Declaration of Helsinki and with approval from the local ethics committee (Karolinska Hospital, Stockholm, Sweden) and the Swedish Medical Products Agency.
Study Design and Procedures This was an open-label, randomized, 2-period crossover study. Participants were randomized to treatment with the study oral contraceptive either alone or in combination with tolterodine 2 mg BID over two 28-day contraceptive cycles, with treatment commencing on day 1 of the first contraceptive cycle after randomization. Subjects crossed over to the other treatment for the following contraceptive cycle. Contraceptive tablets were taken orally at 8 AM from days 1 through 21 of both 28-day cycles, and tolterodine 2 mg (as L-tartrate salt) was taken orally at 8 AM and 8 PM on days 1 through 14 of 1 cycle only, according to the randomization sequence. Compliance was monitored by tablet counts and diaries in which subjects noted the exact time of drug administration. Intake of alcoholic beverages was not permitted from day 1 through 14 of each cycle, nor was concomitant treatment with drugs known to interact with oral contraceptives (eg, barbiturates, carbamazepine, *Trademark: Neovletta® (Schering AG, Berlin, Germany). 1878
Blood and Urine Sampling Venous blood samples for the determination of plasma ethinyl estradiol and levonorgestrel concentrations were obtained on day 14 of cycles 1 and 2 immediately before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after administration of the combination oral contraceptive. All blood samples (7 mL) were collected via venous catheter into heparinized collection tubes. Plasma was subsequently separated by centrifugation and stored frozen at -20°C until analysis. Additional blood samples (7 mL, collected by venous catheter into evacuated collection tubes without additives) were taken for the determination of serum tolterodine and 5-HM concentrations at 1, 2, and 3 hours after administration of tolterodine on day 14 of the treatment cycle that included oral contraception plus tolterodine treatment. Samples were allowed to coagulate for 45 minutes to 1 hour, after which serum was separated by centrifugation. Serum samples were frozen and stored at -20°C until analysis. To assess the risk of failure of suppression of ovulation, levels of endogenous
B. OLSSON AND B.-M. LANDGREN
estradiol and progesterone were determined from serum samples collected on days 1, 3, 8, 12, 13, 14, 15, 16, 18, and 21 of each treatment cycle. Venous blood samples (5 mL) were collected into evacuated collection tubes without additives. Samples were allowed to coagulate for 45 minutes to 1 hour, after which serum was separated by centrifugation. Serum samples were frozen and stored at -20°C until analysis. Pharmacokinetic Assessments For the determination of subjects' CYP2D6 phenotype, urinary concentrations of debrisoquin and 4-hydroxydebrisoquin were determined by gas chromatography with flame-ionization and nitrogen-selective detection, as described by Lennard et al. l° The interassay accuracy of this method was 103% to 115% and 90% to 101% for debrisoquin and 4-hydroxydebrisoquin, respectively, whereas precision (expressed as a coefficient of variation) was better than 12% and 5%, respectively. After liquid/liquid extraction, plasma concentrations of ethinyl estradiol and levonorgestrel were determined by gas chromatography-mass spectrometry using negative- and positive-ion chemical ionization, respectively (AAI Deutschland GmbH & Co KG, Neu-Ulm, Germany). The range of the calibration curve was set at 10 to 1000 pg/mL and 0.25 to 20 ng/mL for ethinyl estradiol and levonorgestrel, respectively. With this method, the interassay accuracy for both analytes was from 95% to 101% over their concentration ranges, and precision was better than 10%. Serum concentrations of tolterodine and 5-HM were determined by gas chromatography-mass spectrometry.ll Interassay accuracy with this method was
98% to 102% and 98% to 105% for tolterodine and 5-HM, respectively, whereas precision was better than 9% and 8%, respectively. Pharmacokinetic calculations based on the plasma concentration-time profiles of ethinyl estradiol and levonorgestrel were performed by noncompartmental analysis using WinNonlin (Pharsight Corporation, Mountain View, California). Area under the plasma concentration-time curve for one 24-hour dose interval (AUC,) was calculated by the linear trapezoidal method. If drug concentrations in samples taken toward the end of the dosing interval fell below the limit of quantification (LOQ), the residual area up to 24 hours after dosing was calculated by extrapolation from a preceding quantifiable data point. The terminal elimination rate constant (Xz) and the predicted concentration of the sampiing point from which the extrapolation was performed were used for this calculation. Maximum (Cmax) and minimum (Cmin) observed plasma drug concentrations and time to Cmax (Tmax) were also calculated. If plasma concentrations were below the LOQ toward the end of the dose interval, Cmi n was estimated by extrapolation using Xz and preceding data points. Relative bioavailability (Frel) with respect to AUC~, Cmax, and Cmin was determined using the tolterodine-free treatment period as a reference point.
Classification of Ovarian Function The assessment of ovarian function during treatment with and without tolterodine was based on endogenous estradiol and progesterone profiles throughout the 21-day contraceptive cycle, as described by Landgren and Diczfalusy. 12 Using this method, ovarian function was classified 1879
CLINICAL THERAPEUTICS®
according to the extent of observed follicular and luteal activity: A-type cycle = no follicular or luteal activity (ie, complete suppression of ovarian function); B-type cycle = follicular but no luteal activity; C-type cycle = inadequate (but not absent) luteal activity; and D-type cycle = normal ovulatory function, with serum progesterone levels >16 nmol/L (5 ng/mL) for a minimum of 5 days. Serum levels of endogenous estradiol and progesterone were measured using a commercially available chemiluminescent technique (Immulite ®, Diagnostic Products Corporation, Los Angeles, California). Representative values of assay performance were as follows: estradiol, interassay accuracy of 94% to 112%, precision better than 16%; progesterone, interassay accuracy of 91% to 117%, precision better than 16%. Estradiol levels below 184 pmol/L (50 pg/mL) throughout the contraceptive cycle were assumed to reflect complete suppression of ovarian activity, whereas progesterone levels below 9.5 nmol/L (3 ng/mL) were indicative of lack of ovulation.
Safety Assessments The tolerability profile and laboratory safety of tolterodine have been extensively documented in numerous clinical studies. 13 Nevertheless, blood and urine samples were obtained for routine laboratory analysis (clinical chemistry, hematology, urinalysis) at baseline, on day 14 of each treatment period, and at the end of the study and analyzed for clinically relevant trends by the study investigator. Similarly, tolerability was assessed in terms of adverse events (including spontaneous reports and investigator observations), the onset and intensity of which were re1880
corded as part of the investigator's determination of possible causality.
Statistical Analysis To determine the number of subjects necessary to achieve sufficient statistical power, intraindividual coefficients of variation of 19% and 13% were assumed for the AUC of ethinyl estradiol and levonorgestrel, respectively. On this basis it was calculated that a minimum of 18 evaluable subjects would be required to show pharmacokinetic equivalence (multiplicative model) of ethinyl estradiol and levonorgestrel in the presence and absence of tolterodine at a power of 80% (ct = 5%). 14 An analysis of variance model was used for statistical analysis of the logtransformed AUC, Cmax, and Cmin data. The covariates were treatment sequence, subject (nested within sequence), period, and treatment. Geometric means of the ratios of pharmacokinetic parameters in the presence and absence of tolterodine, along with the respective 90% CIs, were calculated. Equivalence was assumed if the CI was completely contained within the predetermined equivalence interval (AUC, 80%-125%; Cmax and Cmin,70%-143%). 14'15 All other pharmacokinetic parameters, including those for tolterodine and 5-HM, were analyzed descriptively. Also analyzed descriptively was the classification of ovarian function in the presence and absence of tolterodine. RESULTS Twenty-four women who were users of oral contraceptives participated in the study. Their baseline demographic characteristics were as follows: age, 23 to 41 years (mean, 30 years); height, 155 to 178
B. OLSSON AND B.-M. LANDGREN
cm (mean, 167 cm); and body weight, 51 to 75 kg (mean, 64 kg). Three participants (12.5%) were poor metabolizers of debrisoquin, and 7 (29.2%) were tobacco users. With the exception of 1 participant who withdrew consent shortly after study commencement, all subjects completed the study and were included in the analyses of endogenous hormone, tolterodine, 5-HM, and safety data. Of these, 22 participants were included in the pharmacokinetic analysis of oral contraceptive hormones (1 subject was excluded, as no blood samples were taken on day 14 of the second treatment cycle). Compliance diaries and returned tablet counts indicated good compliance, with no missed doses. However, 2 participants did not take their medication until 11 AM on day 13 of the tolterodine treatment period; this 3-hour delay may have caused overestimation of the AUCr for ethinyl estradiol and levonorgestrel on day 14. On the basis of plasma concentrations at the time of administration and 24 hours thereafter, it was calculated that this overestimation might have been on the order of 3% to 13% in these subjects.
Pharmacokinetics of Ethinyl Estradiol and Levonorgestrel In evaluable subjects (n = 22), mean plasma concentration-time profiles for ethinyl estradiol and levonorgestrel were essentially superimposable in the presence and absence of tolterodine (Figure 1). Mean pharmacokinetic parameters of ethinyl estradiol and levonorgestrel during the 2 treatment periods are summarized in Table I, and values for Fre I with respect to AUC+, Cmax, and Cmin are shown in Table II. Overall, all 90% CIs were within the limits for equivalence.
Further analyses were completed for the 3 individuals who were poor metabolizers of debrisoquin. In these subjects, mean pharmacokinetic parameters of ethinyl estradiol and levonorgestrel in the presence and absence of tolterodine were comparable to those observed in extensive metabolizers (data not shown). Individual plasma concentrationtime profiles for ethinyl estradiol and levonorgestrel in poor metabolizers, which demonstrated no effect of concomitant treatment with tolterodine, are shown in Figure 2.
Maintenance of Suppression of Ovulation Mean serum levels of endogenous estradiol and progesterone for all participants in both cycles are shown in Figure 3. Although there was considerable interindividual variation in the serum profiles of these hormones, there was no discernible effect of tolterodine on the suppression of ovarian function by combination oral contraception. Thus, given that serum progesterone levels did not exceed 9.5 nmol/L (3 ng/mL) in any participant during either cycle, ovulation was suppressed in all subjects both in the presence and absence of tolterodine. This was confirmed by the Landgren and Diczfalusy classification of ovarian function, 12 which showed that the cycle type in each subject was the same in the presence or absence of tolterodine (ie, 15 subjects were type A, 7 type B, 1 type C).
Serum Levels of Tolterodine and 5-HM Serum concentrations of tolterodine at 1 to 3 hours after dosing in both poor and extensive metabolizers of debrisoquin 1881
CLINICAL THERAPEUTICS ®
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Figure 1. Mean plasma concentration-time profiles on day 14 for (A) ethinyl estradiol and (B) levonorgestrel in 22 healthy women receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 txg/levonorgestrel 150 txg) without and with tolterodine (2 mg BID on days 1-14). 1882
B. OLSSON AND B.-M. LANDGREN
Table I. Pharmacokinetic parameters* for ethinyl estradiol and levonorgestrel on day 14 in 22 healthy women receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 ~g/levonorgestrel 150 Ixg) without and with tolterodine (2 mg BID on days 1-14). Without Tolterodine
With Tolterodine
Ethinyl estradiol AUCz, pg-h/mL Cmax, pg/mL Cmin, pg/mL Tmax, h t
864 (284) 99.7 (29.0) 14.0 (8.2) 1.0 (0.5-3)
808 (270) 90.0 (29.2) 13.8 (6.6) 1.5 (1-12)
Levonorgestrel AUCx, ng.h/mL Cmax, ng/mL Cmin, ng/mL Tmax, h*
79.4 (30.5) 6.77 (2.09) 2.02 (0.84) 1.0 (1-24)
70.4 5.80 1.79 1.5
(20.3) (1.25) (0.57) (1-12)
AUC~ = area under the plasma concentration-time curve for 1 dose interval; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; Tm~x = time to Cma~. *Unless otherwise stated, values are expressed as mean (SD). tValues are expressed as median (range).
Table II. Relative bioavailability* (F~l) o f ethinyl estradiol and levonorgestrel on day 14 in 22 healthy women receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 t~g/levonorgestrel 150 Ixg) without and with tolterodine (2 mg BID on days 1 -14). Fr~l, % (90% CI) AUCx
Cmax
Cmin
Ethinyl estradiol
93.5 (85.4-102.3)
90.1 (82.5-98.4)
104.9 (79.6--138.2)
Levonorgestrel
90.3 (84.6-96.4)
86.9 (80.7-93.6)
90.5 (84.7-96.6)
AUCx = area under the plasma concentration-time curve for 1 dose interval; Cr,~x= maximum plasma concentration; Cmi"= minimum plasma concentration. *Values are expressed as geometric mean (90% CI) comparing pharmacokinetic parameters during coadministration of tolterodine and the oral contraceptive with those during administration of the oral contraceptive alone.
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CLINICAL THERAPEUTICS® Subject 5 -"" ._1
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Figure 2. Individual plasma concentration-time profiles on day 14 for ethinyl estradiol and levonorgestrel in 3 poor metabolizers of debrisoquin receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 Ixg/levonorgestrel 150 ixg) without and with tolterodine (2 mg BID on days 1-14). In subject 7, plasma concentrations of ethinyl estradiol at 24 h after dosing (without tolterodine) were below the limit of quantification (<10 pg/mL). 1884
B. OLSSON AND B.-M. LANDGREN
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Figure 3. Mean serum levels of endogenous (A) estradiol and (B) progesterone throughout the 21-day contraceptive cycle in 23 healthy women receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 ixg/levonorgestrel 150 Ixg) without and with tolterodine (2 mg BID on days 1-14).
were consistent with the results of previous studies. 3,16 Thus, at 1 hour after dosing, median serum tolterodine concentrations were -10-fold higher in poor metabolizers than in extensive metabolizers of debrisoquin (18.7 and 1.8 ng/mL, re-
spectively). As expected, 5-HM was undetectable in the serum of poor metabolizers. Median serum concentrations of 5-HM in extensive metabolizers were 2.2, 2.2, and 1.75 ng/mL at 1, 2, and 3 hours after dosing, respectively. 1885
CLINICAL THERAPEUTICS ®
Safety A total of 18 participants reported >1 adverse event during the study. Overall, the adverse-events profile was consistent with previous clinical experience with tolterodine at the therapeutically relevant dosage of 2 mg BID. 13,16 Thus, the most common adverse event overall during the tolterodine treatment phase was mild to moderate dry mouth (9 subjects), judged by the investigator to be probably related to treatment in each instance. No serious adverse events were reported, and there were no clinically relevant changes in the results of routine laboratory tests during the study. DISCUSSION Given the prevalence pattern of overactive bladder 2 and the widespread use of oral contraception, circumstances are likely to arise in which physicians may wish to prescribe tolterodine for patients already taking oral contraceptives. For this reason, it is important to determine whether women may receive concomitant treatment with the 2 types of agents without risking drug-drug interactions or possible conception. The present study was therefore performed to investigate the influence of tolterodine on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive containing ethinyl estradiol and levonorgestrel. Overall, our findings demonstrate no clinically significant interaction between tolterodine given at the clinically relevant dosage of 2 mg BID and a typical combination oral contraceptive. Plasma concentrations of ethinyl estradiol and levonorgestrel were similar both in the presence and absence of tolterodine, and were corn1886
parable to those observed in a previous study. ~7The absence of a pharmacokinetic interaction was confirmed by FreI values for the pharmacokinetic parameters of ethinyl estradiol and levonorgestrel, which indicated equivalence for both steroid hormones throughout the 2 treatment periods. These findings are in accordance with those of an earlier probe-drug study, 18 in which tolterodine had no effect on CYP3A4-mediated metabolism. It is therefore reasonable to assume that interactions between tolterodine and the estrogen and progestin components of other oral contraceptive formulations are unlikely to occur. In addition to performing pharmacokinetic assessments of ethinyl estradiol and levonorgestrel in the present study, we measured levels of endogenous hormones as an index of contraceptive efficacy. Overall, no differences in ovarian function were apparent between the 2 treatment periods, with follicular activity being completely suppressed in the majority of subjects in each cycle. Although some follicular activity was seen, similar observations have been reported in women using low-dose combination oral contraceptives, w,2° Furthermore, no change in ovarian function type, as described using the method of Landgren and Diczfalusy, 12 was observed for any subject in the presence or absence of tolterodine. Thus, contraceptive efficacy is not likely to be impaired during coadministration of tolterodine and combination oral contraceptives. It is well established that CYP2D6 is the major metabolic pathway for tolterodine. 3'4 Since this isozyme is polymorphically distributed, 6 subjects can be clearly identified as poor or extensive metabolizers of the drug. However, this difference
B. OLSSON AND B.-M. LANDGREN
is of minor importance to the antimuscarinic effect) In the present study, 3 subjects were deficient in CYP2D6. Serum concentrations of tolterodine in these individuals, along with concentrations of tolterodine and 5-HM in extensive metabolizers, were in accordance with previously published pharmacokinetic data on tolterodine. 3 Such findings indicate that coadministration of tolterodine with combination oral contraceptives does not affect the metabolic disposition of tolterodine. This is an important finding for poor metabolizers of tolterodine, in whom the CYP3A4-catalyzed N-dealkylation pathway is the major route of metabolism. 3'7 A more significant finding, however, is that a poor-metabolizer phenotype does not appear to predispose an individual to a significant drug-drug interaction between tolterodine and combination oral contraceptives. Theoretically, these individuals would be expected to be at greatest risk for interaction, as the steroid components of combination oral contraceptives are also metabolized by CYP3A4. 8 However, plasma concentrations of ethinyl estradiol and levonorgestrel in poor metabolizers were similar both in the presence and absence of tolterodine, which is consistent with there being no apparent interaction in these individuals. There was also no evidence to suggest that concomitant treatment with tolterodine compromised contraceptive efficacy in poor metabolizers. CONCLUSIONS This study found no evidence of clinically relevant pharmacokinetic or pharmacodynamic interactions between tolterodine and a representative combination oral con-
traceptive containing ethinyl estradiol and levonorgestrel in a selected population of healthy volunteers. Neither did the oral contraceptive show any relevant pharmacokinetic interaction with tolterodine. Coadministration of tolterodine at therapeutically relevant dosages is therefore unlikely to affect the contraceptive efficacy of combination oral contraceptives. ACKNOWLEDGMENTS This study was supported by Pharmacia Corporation, Peapack, New Jersey. The authors wish to thank Helena Engfeldt-Jansson (midwife), Margaretha Strtm (midwife), Eva Rosendahl (assistant nurse), and Mia Karlsson (laboratory assistant) for their technical assistance and Lena Palm& and Johan Szamosi for their useful comments during the writing of this manuscript. REFERENCES 1. Shenfield GM. Oral contraceptives: Are drug interactions of clinical significance? Drug Saf 1993;9:21-37. 2. Versi E, for the Study Group. Screening initiative confirms widespread prevalence of overactive bladder in American adults. lnt Urogynecol J Pelvic Floor Dysfunct. 2001;12:S13. Abstract. 3. Brynne N, Daltn P, AlvAn G, et al. Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of tolterodine. Clin Pharmacol Ther. 1998; 63:529-539. 4. Postlind H, Danielson /~, Lindgren A, Andersson SHG. Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab Dispos. 1998;26:289-293. 1887
CLINICAL THERAPEUTICS ~'~
5. Nilvebrant L, Gillberg PG, Sparf B. Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol. 1997;81: 169-172. 6. Alvfin G, Bechtel P, Iselius L, GundertRemy U, Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol. 1990;39:533-537. 7. Brynne N, Forslund C, Hallrn B, et al. Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity. Br J Clin Pharmacol. 1999;48:564-572. 8. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet. 1996;31:198-214. 9. Evans DA, Mahgoub A, Sloan TP, et al. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. JMed Genet. 1980;17:102-105. 10. Lennard MS, Silas JH, Smith AJ, Tucker GT. Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flameionization and nitrogen-selective detection. J Chromatogr 1977;133:161-166. 11. Palmrr L, Andersson L, Andersson T, Stenberg U. Determination of tolterodine and the 5-hydroxymethyl metabolite in plasma, serum and urine using gas chromatography-mass spectrometry. J Pharm Biomed Anal. 1997;16:155-165. 12. Landgren B-M, Diczfalusy E. Hormonal effects of the 300 txg norethisterone (NET) minipill. I. Daily steroid levels in 43 subjects during a pretreatment cycle and during the second month of NET administration. Contraception. 1980;2l:87-113.
13. Clemett D, Jarvis B. Tolterodine: A review of its use in the treatment of overactive bladder. Drugs Aging. 2001 ; 18:277-304. 14. Guidance for Industry: In Vivo Drug Metabolism~Drug Interaction Studies-Study Design, Data Analysis, and Recommendations for Dosing and Labeling. Rockville, Md: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; November 1999. 15. Note for Guidance on the Investigation of Drug Interactions. London: Committee for Proprietary Medicinal Products; December 1997 (CPMP/EWP/560/95), 16. Larsson G, Hallrn B, Nilvebrant L. Tolterodine in the treatment of overactive bladder: Analysis of the pooled phase II efficacy and safety data. Urology. 1999;53: 990-998. 17. Kuhnz W, al-Yacoub G, Fuhrmeister A. Pharmacokinetics of levonorgestrel in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation. Contraception. 1992;46:455--469. 18. Brynne N, Brttiger Y, Hall~n B, Bertilsson L. Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole. Br J Clin Pharmacol. 1999;47:145-150. 19. Wang E, Shi S, Cekan SZ, et al, Hormonal consequences of "~missing the pill." Contraception. 1982;26:545-566. 20. Landgren B-M, Diczfalusy E. Hormonal consequences of missing the pill during the first two days of three consecutive artificial cycles. Contraception. 1984;29:437-446.
Address correspondence to: Birgitta Olsson, MSc, Experimental Medicine, Biovitrum AB, SE-112 76 Stockholm, Sweden. E-mail: [email protected]
1888
The Effect of Tolterodine on the Pharmacokinetics and Pharmacodynamics of a Combination Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel Birgitta Olsson, MSc, 1 and Britt-Marie Landgren, MD, PhD z 1Experimental Medicine, Biovitrum AB, Stockholm,* and 2Department of Obstetrics and Gynecology, Huddinge Hospital, Huddinge, Sweden
ABSTRACT
Background: Tolterodine is an antimuscarinic agent for the treatment of overactive bladder, a chronic condition that is particularly common in women. Given the prevalence pattern of overactive bladder and the widespread use of oral contraception, circumstances are likely to arise in which physicians may wish to prescribe tolterodine for patients already taking oral contraceptives. Based on a search of MEDLINE from 1990 to 2001, there have been no studies of whether concomitant use of these agents entails a risk of drug-drug interaction or conception. Objective: This study investigated the effects of tolterodine on the pharmacokinetics and pharmacodynamics of a low-dose combination oral contraceptive (ethinyl estradiol 30 txg/levonorgestrel 150 ixg). Methods: This was an open-label, randomized, 2-period crossover study in healthy women. Oral contraception was given for 21 days either alone or in combination with oral tolterodine 2 mg BID (on days 1-14) over two 28-day contraceptive cycles. Pharmacokinetic assessments were performed on day 14 based on plasma levels of ethinyl estradiol and levonorgestrel up to 24 hours after dosing and serum tolterodine levels at 1 to 3 hours after dosing. The potential for pharmacodynamic interaction was assessed in terms of the risk of failure of suppression of ovulation based on serum levels of estradiol and progesterone measured throughout each cycle. Results: Twenty-four healthy women (age, 23-41 years [mean, 30 years]; height, 155-178 cm [mean, 167 cm]; body weight, 51-75 kg [mean, 64 kg]) participated in the *At the time of the author's original involvement in the study, she was an employee of Pharmacia AB, Uppsala, Sweden. Accepted for publication September 10, 2001. Printed in the USA. Reproduction in whole or part is not
1876
permitted.
0149-2918/01/519.00
B. OLSSON AND B.-M. LANDGREN
study. There was no evidence of a pharmacokinetic interaction between tolterodine and the steroid hormones in the oral contraceptive used, nor did the oral contraceptive show any relevant pharmacokinetic interaction with tolterodine. Serum levels of estradiol and progesterone indicated suppression of ovulation in both treatment periods. Conclusion: In this selected population, coadministration of tolterodine did not affect the contraceptive efficacy of a low-dose combination oral contraceptive containing ethinyl estradiol and levonorgestrel. Key words: drug-drug interactions, ethinyl estradiol, levonorgestrel, oral contraception, ovarian activity, tolterodine. (Clin Ther. 2001;23:1876-1888) INTRODUCTION Numerous drugs are reported to interact both pharmacokinetically and pharmacodynamically with oral contraceptive steroids. 1 Although the exact prevalence of such interactions is not known, the widespread use of oral contraceptives means that there is a potential for drug-drug interactions to affect a large number of women. Tolterodine is an antimuscarinic agent for the treatment of overactive bladder, a chronic condition that is particularly common in women. 2 Pharmacokinetic studies have shown that tolterodine undergoes extensive first-pass metabolism, and 2 major metabolic pathways have been identified: oxidation and N-dealkylation. These 2 pathways are respectively mediated by the cytochrome P450 (CYP) 2D6 and 3A isozymes. 3,4 The 5-hydroxymethyl metabolite (5-HM), produced by the CYP2D6 pathway, has a similar pharmacologic pro-
file to tolterodine.5 However, a small percentage of the population lacks the CYP2D6 enzyme 6 and cannot form 5-HM. These individuals, known as poor metabolizers, have relatively high serum concentrations of tolterodine and metabolize the drug via CYP3A4-mediated N-dealkylation. 7 Both the estrogen and progestin components of combination oral contraceptives are also metabolized by this pathway. 8 Thus, there is a potential for drug-drug interaction during coadministration of tolterodine and combination oral contraceptives, although a MEDLINE search of the medical literature from 1990 to 2001 suggests that this potential has not been investigated. The primary objective of the present study, therefore, was to investigate the effect of tolterodine on the pharmacokinetic characteristics of ethinyl estradiol and levonorgestrel in a low-dose combination oral contraceptive. Secondary objectives were to assess the risk of failure of suppression of ovulation during tolterodine therapy (through determination of serum levels of endogenous estradiol and progesterone throughout the contraceptive cycle) and to assess the pharmacokinetics of tolterodine and 5-HM when tolterodine and the oral contraceptive were administered concomitantly. SUBJECTS AND METHODS
Eh'gibility Criteria To be eligible for participation, women had to be in good health (based on medical history, physical examination, and routine laboratory tests) and of normal body weight for height (_+10%). They were required to have been taking the study oral contraceptive (a typical combination con1877
CLINICAL THERAPEUTICS*
taining ethinyl estradiol 30 ixg and levonorgestrel 150 Ixg*) for at least 3 months before study entry; those taking other combinations of ethinyl estradiol and levonorgestrel could be included after switching to the study contraceptive for 2 months. No subject could have any contraindications to use of this oral contraceptive. Before beginning the study, each participant underwent phenotyping to determine her ability to metabolize debrisoquin (ie, CYP2D6 activity). 9 Subjects with metabolic ratios >12.6 were classified as poor metabolizers.
phenytoin, primidone, rifampin, broadspectrum antibiotics, antidiabetic drugs). Use of such agents constituted grounds for withdrawal from the study, although other drugs necessary for the participant's welfare were allowed at the discretion of the investigator. Written informed consent was obtained from all participants before entry. The study was performed in accordance with the most recent revisions to the Declaration of Helsinki and with approval from the local ethics committee (Karolinska Hospital, Stockholm, Sweden) and the Swedish Medical Products Agency.
Study Design and Procedures This was an open-label, randomized, 2-period crossover study. Participants were randomized to treatment with the study oral contraceptive either alone or in combination with tolterodine 2 mg BID over two 28-day contraceptive cycles, with treatment commencing on day 1 of the first contraceptive cycle after randomization. Subjects crossed over to the other treatment for the following contraceptive cycle. Contraceptive tablets were taken orally at 8 AM from days 1 through 21 of both 28-day cycles, and tolterodine 2 mg (as L-tartrate salt) was taken orally at 8 AM and 8 PM on days 1 through 14 of 1 cycle only, according to the randomization sequence. Compliance was monitored by tablet counts and diaries in which subjects noted the exact time of drug administration. Intake of alcoholic beverages was not permitted from day 1 through 14 of each cycle, nor was concomitant treatment with drugs known to interact with oral contraceptives (eg, barbiturates, carbamazepine, *Trademark: Neovletta® (Schering AG, Berlin, Germany). 1878
Blood and Urine Sampling Venous blood samples for the determination of plasma ethinyl estradiol and levonorgestrel concentrations were obtained on day 14 of cycles 1 and 2 immediately before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after administration of the combination oral contraceptive. All blood samples (7 mL) were collected via venous catheter into heparinized collection tubes. Plasma was subsequently separated by centrifugation and stored frozen at -20°C until analysis. Additional blood samples (7 mL, collected by venous catheter into evacuated collection tubes without additives) were taken for the determination of serum tolterodine and 5-HM concentrations at 1, 2, and 3 hours after administration of tolterodine on day 14 of the treatment cycle that included oral contraception plus tolterodine treatment. Samples were allowed to coagulate for 45 minutes to 1 hour, after which serum was separated by centrifugation. Serum samples were frozen and stored at -20°C until analysis. To assess the risk of failure of suppression of ovulation, levels of endogenous
B. OLSSON AND B.-M. LANDGREN
estradiol and progesterone were determined from serum samples collected on days 1, 3, 8, 12, 13, 14, 15, 16, 18, and 21 of each treatment cycle. Venous blood samples (5 mL) were collected into evacuated collection tubes without additives. Samples were allowed to coagulate for 45 minutes to 1 hour, after which serum was separated by centrifugation. Serum samples were frozen and stored at -20°C until analysis. Pharmacokinetic Assessments For the determination of subjects' CYP2D6 phenotype, urinary concentrations of debrisoquin and 4-hydroxydebrisoquin were determined by gas chromatography with flame-ionization and nitrogen-selective detection, as described by Lennard et al. l° The interassay accuracy of this method was 103% to 115% and 90% to 101% for debrisoquin and 4-hydroxydebrisoquin, respectively, whereas precision (expressed as a coefficient of variation) was better than 12% and 5%, respectively. After liquid/liquid extraction, plasma concentrations of ethinyl estradiol and levonorgestrel were determined by gas chromatography-mass spectrometry using negative- and positive-ion chemical ionization, respectively (AAI Deutschland GmbH & Co KG, Neu-Ulm, Germany). The range of the calibration curve was set at 10 to 1000 pg/mL and 0.25 to 20 ng/mL for ethinyl estradiol and levonorgestrel, respectively. With this method, the interassay accuracy for both analytes was from 95% to 101% over their concentration ranges, and precision was better than 10%. Serum concentrations of tolterodine and 5-HM were determined by gas chromatography-mass spectrometry.ll Interassay accuracy with this method was
98% to 102% and 98% to 105% for tolterodine and 5-HM, respectively, whereas precision was better than 9% and 8%, respectively. Pharmacokinetic calculations based on the plasma concentration-time profiles of ethinyl estradiol and levonorgestrel were performed by noncompartmental analysis using WinNonlin (Pharsight Corporation, Mountain View, California). Area under the plasma concentration-time curve for one 24-hour dose interval (AUC,) was calculated by the linear trapezoidal method. If drug concentrations in samples taken toward the end of the dosing interval fell below the limit of quantification (LOQ), the residual area up to 24 hours after dosing was calculated by extrapolation from a preceding quantifiable data point. The terminal elimination rate constant (Xz) and the predicted concentration of the sampiing point from which the extrapolation was performed were used for this calculation. Maximum (Cmax) and minimum (Cmin) observed plasma drug concentrations and time to Cmax (Tmax) were also calculated. If plasma concentrations were below the LOQ toward the end of the dose interval, Cmi n was estimated by extrapolation using Xz and preceding data points. Relative bioavailability (Frel) with respect to AUC~, Cmax, and Cmin was determined using the tolterodine-free treatment period as a reference point.
Classification of Ovarian Function The assessment of ovarian function during treatment with and without tolterodine was based on endogenous estradiol and progesterone profiles throughout the 21-day contraceptive cycle, as described by Landgren and Diczfalusy. 12 Using this method, ovarian function was classified 1879
CLINICAL THERAPEUTICS®
according to the extent of observed follicular and luteal activity: A-type cycle = no follicular or luteal activity (ie, complete suppression of ovarian function); B-type cycle = follicular but no luteal activity; C-type cycle = inadequate (but not absent) luteal activity; and D-type cycle = normal ovulatory function, with serum progesterone levels >16 nmol/L (5 ng/mL) for a minimum of 5 days. Serum levels of endogenous estradiol and progesterone were measured using a commercially available chemiluminescent technique (Immulite ®, Diagnostic Products Corporation, Los Angeles, California). Representative values of assay performance were as follows: estradiol, interassay accuracy of 94% to 112%, precision better than 16%; progesterone, interassay accuracy of 91% to 117%, precision better than 16%. Estradiol levels below 184 pmol/L (50 pg/mL) throughout the contraceptive cycle were assumed to reflect complete suppression of ovarian activity, whereas progesterone levels below 9.5 nmol/L (3 ng/mL) were indicative of lack of ovulation.
Safety Assessments The tolerability profile and laboratory safety of tolterodine have been extensively documented in numerous clinical studies. 13 Nevertheless, blood and urine samples were obtained for routine laboratory analysis (clinical chemistry, hematology, urinalysis) at baseline, on day 14 of each treatment period, and at the end of the study and analyzed for clinically relevant trends by the study investigator. Similarly, tolerability was assessed in terms of adverse events (including spontaneous reports and investigator observations), the onset and intensity of which were re1880
corded as part of the investigator's determination of possible causality.
Statistical Analysis To determine the number of subjects necessary to achieve sufficient statistical power, intraindividual coefficients of variation of 19% and 13% were assumed for the AUC of ethinyl estradiol and levonorgestrel, respectively. On this basis it was calculated that a minimum of 18 evaluable subjects would be required to show pharmacokinetic equivalence (multiplicative model) of ethinyl estradiol and levonorgestrel in the presence and absence of tolterodine at a power of 80% (ct = 5%). 14 An analysis of variance model was used for statistical analysis of the logtransformed AUC, Cmax, and Cmin data. The covariates were treatment sequence, subject (nested within sequence), period, and treatment. Geometric means of the ratios of pharmacokinetic parameters in the presence and absence of tolterodine, along with the respective 90% CIs, were calculated. Equivalence was assumed if the CI was completely contained within the predetermined equivalence interval (AUC, 80%-125%; Cmax and Cmin,70%-143%). 14'15 All other pharmacokinetic parameters, including those for tolterodine and 5-HM, were analyzed descriptively. Also analyzed descriptively was the classification of ovarian function in the presence and absence of tolterodine. RESULTS Twenty-four women who were users of oral contraceptives participated in the study. Their baseline demographic characteristics were as follows: age, 23 to 41 years (mean, 30 years); height, 155 to 178
B. OLSSON AND B.-M. LANDGREN
cm (mean, 167 cm); and body weight, 51 to 75 kg (mean, 64 kg). Three participants (12.5%) were poor metabolizers of debrisoquin, and 7 (29.2%) were tobacco users. With the exception of 1 participant who withdrew consent shortly after study commencement, all subjects completed the study and were included in the analyses of endogenous hormone, tolterodine, 5-HM, and safety data. Of these, 22 participants were included in the pharmacokinetic analysis of oral contraceptive hormones (1 subject was excluded, as no blood samples were taken on day 14 of the second treatment cycle). Compliance diaries and returned tablet counts indicated good compliance, with no missed doses. However, 2 participants did not take their medication until 11 AM on day 13 of the tolterodine treatment period; this 3-hour delay may have caused overestimation of the AUCr for ethinyl estradiol and levonorgestrel on day 14. On the basis of plasma concentrations at the time of administration and 24 hours thereafter, it was calculated that this overestimation might have been on the order of 3% to 13% in these subjects.
Pharmacokinetics of Ethinyl Estradiol and Levonorgestrel In evaluable subjects (n = 22), mean plasma concentration-time profiles for ethinyl estradiol and levonorgestrel were essentially superimposable in the presence and absence of tolterodine (Figure 1). Mean pharmacokinetic parameters of ethinyl estradiol and levonorgestrel during the 2 treatment periods are summarized in Table I, and values for Fre I with respect to AUC+, Cmax, and Cmin are shown in Table II. Overall, all 90% CIs were within the limits for equivalence.
Further analyses were completed for the 3 individuals who were poor metabolizers of debrisoquin. In these subjects, mean pharmacokinetic parameters of ethinyl estradiol and levonorgestrel in the presence and absence of tolterodine were comparable to those observed in extensive metabolizers (data not shown). Individual plasma concentrationtime profiles for ethinyl estradiol and levonorgestrel in poor metabolizers, which demonstrated no effect of concomitant treatment with tolterodine, are shown in Figure 2.
Maintenance of Suppression of Ovulation Mean serum levels of endogenous estradiol and progesterone for all participants in both cycles are shown in Figure 3. Although there was considerable interindividual variation in the serum profiles of these hormones, there was no discernible effect of tolterodine on the suppression of ovarian function by combination oral contraception. Thus, given that serum progesterone levels did not exceed 9.5 nmol/L (3 ng/mL) in any participant during either cycle, ovulation was suppressed in all subjects both in the presence and absence of tolterodine. This was confirmed by the Landgren and Diczfalusy classification of ovarian function, 12 which showed that the cycle type in each subject was the same in the presence or absence of tolterodine (ie, 15 subjects were type A, 7 type B, 1 type C).
Serum Levels of Tolterodine and 5-HM Serum concentrations of tolterodine at 1 to 3 hours after dosing in both poor and extensive metabolizers of debrisoquin 1881
CLINICAL THERAPEUTICS ®
A -i-
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Figure 1. Mean plasma concentration-time profiles on day 14 for (A) ethinyl estradiol and (B) levonorgestrel in 22 healthy women receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 txg/levonorgestrel 150 txg) without and with tolterodine (2 mg BID on days 1-14). 1882
B. OLSSON AND B.-M. LANDGREN
Table I. Pharmacokinetic parameters* for ethinyl estradiol and levonorgestrel on day 14 in 22 healthy women receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 ~g/levonorgestrel 150 Ixg) without and with tolterodine (2 mg BID on days 1-14). Without Tolterodine
With Tolterodine
Ethinyl estradiol AUCz, pg-h/mL Cmax, pg/mL Cmin, pg/mL Tmax, h t
864 (284) 99.7 (29.0) 14.0 (8.2) 1.0 (0.5-3)
808 (270) 90.0 (29.2) 13.8 (6.6) 1.5 (1-12)
Levonorgestrel AUCx, ng.h/mL Cmax, ng/mL Cmin, ng/mL Tmax, h*
79.4 (30.5) 6.77 (2.09) 2.02 (0.84) 1.0 (1-24)
70.4 5.80 1.79 1.5
(20.3) (1.25) (0.57) (1-12)
AUC~ = area under the plasma concentration-time curve for 1 dose interval; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; Tm~x = time to Cma~. *Unless otherwise stated, values are expressed as mean (SD). tValues are expressed as median (range).
Table II. Relative bioavailability* (F~l) o f ethinyl estradiol and levonorgestrel on day 14 in 22 healthy women receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 t~g/levonorgestrel 150 Ixg) without and with tolterodine (2 mg BID on days 1 -14). Fr~l, % (90% CI) AUCx
Cmax
Cmin
Ethinyl estradiol
93.5 (85.4-102.3)
90.1 (82.5-98.4)
104.9 (79.6--138.2)
Levonorgestrel
90.3 (84.6-96.4)
86.9 (80.7-93.6)
90.5 (84.7-96.6)
AUCx = area under the plasma concentration-time curve for 1 dose interval; Cr,~x= maximum plasma concentration; Cmi"= minimum plasma concentration. *Values are expressed as geometric mean (90% CI) comparing pharmacokinetic parameters during coadministration of tolterodine and the oral contraceptive with those during administration of the oral contraceptive alone.
1883
CLINICAL THERAPEUTICS® Subject 5 -"" ._1
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Figure 2. Individual plasma concentration-time profiles on day 14 for ethinyl estradiol and levonorgestrel in 3 poor metabolizers of debrisoquin receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 Ixg/levonorgestrel 150 ixg) without and with tolterodine (2 mg BID on days 1-14). In subject 7, plasma concentrations of ethinyl estradiol at 24 h after dosing (without tolterodine) were below the limit of quantification (<10 pg/mL). 1884
B. OLSSON AND B.-M. LANDGREN
A
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Figure 3. Mean serum levels of endogenous (A) estradiol and (B) progesterone throughout the 21-day contraceptive cycle in 23 healthy women receiving a low-dose combination oral contraceptive (ethinyl estradiol 30 ixg/levonorgestrel 150 Ixg) without and with tolterodine (2 mg BID on days 1-14).
were consistent with the results of previous studies. 3,16 Thus, at 1 hour after dosing, median serum tolterodine concentrations were -10-fold higher in poor metabolizers than in extensive metabolizers of debrisoquin (18.7 and 1.8 ng/mL, re-
spectively). As expected, 5-HM was undetectable in the serum of poor metabolizers. Median serum concentrations of 5-HM in extensive metabolizers were 2.2, 2.2, and 1.75 ng/mL at 1, 2, and 3 hours after dosing, respectively. 1885
CLINICAL THERAPEUTICS ®
Safety A total of 18 participants reported >1 adverse event during the study. Overall, the adverse-events profile was consistent with previous clinical experience with tolterodine at the therapeutically relevant dosage of 2 mg BID. 13,16 Thus, the most common adverse event overall during the tolterodine treatment phase was mild to moderate dry mouth (9 subjects), judged by the investigator to be probably related to treatment in each instance. No serious adverse events were reported, and there were no clinically relevant changes in the results of routine laboratory tests during the study. DISCUSSION Given the prevalence pattern of overactive bladder 2 and the widespread use of oral contraception, circumstances are likely to arise in which physicians may wish to prescribe tolterodine for patients already taking oral contraceptives. For this reason, it is important to determine whether women may receive concomitant treatment with the 2 types of agents without risking drug-drug interactions or possible conception. The present study was therefore performed to investigate the influence of tolterodine on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive containing ethinyl estradiol and levonorgestrel. Overall, our findings demonstrate no clinically significant interaction between tolterodine given at the clinically relevant dosage of 2 mg BID and a typical combination oral contraceptive. Plasma concentrations of ethinyl estradiol and levonorgestrel were similar both in the presence and absence of tolterodine, and were corn1886
parable to those observed in a previous study. ~7The absence of a pharmacokinetic interaction was confirmed by FreI values for the pharmacokinetic parameters of ethinyl estradiol and levonorgestrel, which indicated equivalence for both steroid hormones throughout the 2 treatment periods. These findings are in accordance with those of an earlier probe-drug study, 18 in which tolterodine had no effect on CYP3A4-mediated metabolism. It is therefore reasonable to assume that interactions between tolterodine and the estrogen and progestin components of other oral contraceptive formulations are unlikely to occur. In addition to performing pharmacokinetic assessments of ethinyl estradiol and levonorgestrel in the present study, we measured levels of endogenous hormones as an index of contraceptive efficacy. Overall, no differences in ovarian function were apparent between the 2 treatment periods, with follicular activity being completely suppressed in the majority of subjects in each cycle. Although some follicular activity was seen, similar observations have been reported in women using low-dose combination oral contraceptives, w,2° Furthermore, no change in ovarian function type, as described using the method of Landgren and Diczfalusy, 12 was observed for any subject in the presence or absence of tolterodine. Thus, contraceptive efficacy is not likely to be impaired during coadministration of tolterodine and combination oral contraceptives. It is well established that CYP2D6 is the major metabolic pathway for tolterodine. 3'4 Since this isozyme is polymorphically distributed, 6 subjects can be clearly identified as poor or extensive metabolizers of the drug. However, this difference
B. OLSSON AND B.-M. LANDGREN
is of minor importance to the antimuscarinic effect) In the present study, 3 subjects were deficient in CYP2D6. Serum concentrations of tolterodine in these individuals, along with concentrations of tolterodine and 5-HM in extensive metabolizers, were in accordance with previously published pharmacokinetic data on tolterodine. 3 Such findings indicate that coadministration of tolterodine with combination oral contraceptives does not affect the metabolic disposition of tolterodine. This is an important finding for poor metabolizers of tolterodine, in whom the CYP3A4-catalyzed N-dealkylation pathway is the major route of metabolism. 3'7 A more significant finding, however, is that a poor-metabolizer phenotype does not appear to predispose an individual to a significant drug-drug interaction between tolterodine and combination oral contraceptives. Theoretically, these individuals would be expected to be at greatest risk for interaction, as the steroid components of combination oral contraceptives are also metabolized by CYP3A4. 8 However, plasma concentrations of ethinyl estradiol and levonorgestrel in poor metabolizers were similar both in the presence and absence of tolterodine, which is consistent with there being no apparent interaction in these individuals. There was also no evidence to suggest that concomitant treatment with tolterodine compromised contraceptive efficacy in poor metabolizers. CONCLUSIONS This study found no evidence of clinically relevant pharmacokinetic or pharmacodynamic interactions between tolterodine and a representative combination oral con-
traceptive containing ethinyl estradiol and levonorgestrel in a selected population of healthy volunteers. Neither did the oral contraceptive show any relevant pharmacokinetic interaction with tolterodine. Coadministration of tolterodine at therapeutically relevant dosages is therefore unlikely to affect the contraceptive efficacy of combination oral contraceptives. ACKNOWLEDGMENTS This study was supported by Pharmacia Corporation, Peapack, New Jersey. The authors wish to thank Helena Engfeldt-Jansson (midwife), Margaretha Strtm (midwife), Eva Rosendahl (assistant nurse), and Mia Karlsson (laboratory assistant) for their technical assistance and Lena Palm& and Johan Szamosi for their useful comments during the writing of this manuscript. REFERENCES 1. Shenfield GM. Oral contraceptives: Are drug interactions of clinical significance? Drug Saf 1993;9:21-37. 2. Versi E, for the Study Group. Screening initiative confirms widespread prevalence of overactive bladder in American adults. lnt Urogynecol J Pelvic Floor Dysfunct. 2001;12:S13. Abstract. 3. Brynne N, Daltn P, AlvAn G, et al. Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of tolterodine. Clin Pharmacol Ther. 1998; 63:529-539. 4. Postlind H, Danielson /~, Lindgren A, Andersson SHG. Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab Dispos. 1998;26:289-293. 1887
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5. Nilvebrant L, Gillberg PG, Sparf B. Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol. 1997;81: 169-172. 6. Alvfin G, Bechtel P, Iselius L, GundertRemy U, Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol. 1990;39:533-537. 7. Brynne N, Forslund C, Hallrn B, et al. Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity. Br J Clin Pharmacol. 1999;48:564-572. 8. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet. 1996;31:198-214. 9. Evans DA, Mahgoub A, Sloan TP, et al. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. JMed Genet. 1980;17:102-105. 10. Lennard MS, Silas JH, Smith AJ, Tucker GT. Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flameionization and nitrogen-selective detection. J Chromatogr 1977;133:161-166. 11. Palmrr L, Andersson L, Andersson T, Stenberg U. Determination of tolterodine and the 5-hydroxymethyl metabolite in plasma, serum and urine using gas chromatography-mass spectrometry. J Pharm Biomed Anal. 1997;16:155-165. 12. Landgren B-M, Diczfalusy E. Hormonal effects of the 300 txg norethisterone (NET) minipill. I. Daily steroid levels in 43 subjects during a pretreatment cycle and during the second month of NET administration. Contraception. 1980;2l:87-113.
13. Clemett D, Jarvis B. Tolterodine: A review of its use in the treatment of overactive bladder. Drugs Aging. 2001 ; 18:277-304. 14. Guidance for Industry: In Vivo Drug Metabolism~Drug Interaction Studies-Study Design, Data Analysis, and Recommendations for Dosing and Labeling. Rockville, Md: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; November 1999. 15. Note for Guidance on the Investigation of Drug Interactions. London: Committee for Proprietary Medicinal Products; December 1997 (CPMP/EWP/560/95), 16. Larsson G, Hallrn B, Nilvebrant L. Tolterodine in the treatment of overactive bladder: Analysis of the pooled phase II efficacy and safety data. Urology. 1999;53: 990-998. 17. Kuhnz W, al-Yacoub G, Fuhrmeister A. Pharmacokinetics of levonorgestrel in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation. Contraception. 1992;46:455--469. 18. Brynne N, Brttiger Y, Hall~n B, Bertilsson L. Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole. Br J Clin Pharmacol. 1999;47:145-150. 19. Wang E, Shi S, Cekan SZ, et al, Hormonal consequences of "~missing the pill." Contraception. 1982;26:545-566. 20. Landgren B-M, Diczfalusy E. Hormonal consequences of missing the pill during the first two days of three consecutive artificial cycles. Contraception. 1984;29:437-446.
Address correspondence to: Birgitta Olsson, MSc, Experimental Medicine, Biovitrum AB, SE-112 76 Stockholm, Sweden. E-mail: [email protected]
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