Effect of duloxetine on tolterodine pharmacokinetics in healthy volunteers

Abstract

Aim

To investigate the effect of duloxetine on the pharmacokinetics and tolerability of tolterodine and its active 5-hydroxymethyl metabolite (5-HM).

Methods

Sixteen healthy subjects received two 5-day treatment regimens in a randomized, double-blinded, crossover fashion: tolterodine (2 mg, BID) +duloxetine (40 mg, BID), tolterodine (2 mg, BID) +duloxetine placebo (BID). Plasma concentrations of tolterodine and 5-HM were measured on day 5. Adverse events, clinical safety laboratory data and vital signs were assessed during the study.

Results

Duloxetine increased the AUC_τ,ss of tolterodine by 71%[geometric mean, 95% confidence interval (CI) 31, 123], and its C_max,ss by 64% (CI 30, 106), and prolonged its t_1/2 by 14% (CI 1, 28). Duloxetine did not affect the plasma concentrations or t_1/2 of 5-HM. Laboratory data and vital signs did not reveal any clinically significant changes or abnormalities.

Conclusions

Duloxetine exhibited minor inhibitory effects on the pharmacokinetics of tolterodine but not 5-HM. Coadministration of these drugs was well tolerated and demonstrated no significant safety findings in the studied population. These findings suggest that there should not be a need for routine adjustment of tolterodine dosage in the presence of duloxetine.

Introduction

Duloxetine [LY248686, (+) - (S) - N - methyl - 3 - (1 -naphthalenyloxy)-2-thiophenepropanamine], a potent dual inhibitor of both serotonin and norepinephrine re-uptake (SNRI) [1], is being developed for the treatment of stress urinary incontinence [2], and depression [3]. Tolterodine [(R) - N,N - diisopropyl - 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, molecular weight 325.5] is a muscarinic receptor antagonist indicated for urge incontinence [4, 5]. In clinical practice many incontinent women report both stress and urge incontinence, but urodynamic validation of the symptoms often only reveals stress incontinence [6]. Duloxetine and tolterodine may therefore be considered by some physicians for coadministration when these two conditions coexist. In humans, tolterodine is mainly eliminated by hydroxylation, catalysed by cytochrome P4502D6 (CYP2D6), and N-dealkylation, catalysed by CYP3A4 [7]. Duloxetine may alter the pharmacokinetics of tolterodine by inhibiting CYP2D6 activity [8]. The aim of this study was to investigate the effect of duloxetine on the pharmacokinetics of tolterodine and its active 5-hydroxymethyl metabolite (5-HM) and the safety and tolerability of coadministration of duloxetine and tolterodine.

Methods

Study subjects

Study subjects were healthy men and healthy nonpregnant women as determined by medical history, physical examination, clinical laboratory tests, vital signs and electrocardiogram (ECG). Their ages ranged between 21 and 65 years, and their body mass index (BMI) between 19 and 32 kg m⁻². Only subjects who were ascertained to be CYP2D6 extensive metabolizers by genotyping for the CYP2D6*3, *4, *5, *6, *7, *8, *10, *2 and *2XN alleles using a commercially available method (PPGx, Inc. Morrisville, NC, USA) were eligible to participate. Subjects taking medications or other substances that might interfere with the pharmacokinetics of tolterodine were excluded. Subjects who showed evidence of uncontrolled narrow-angle glaucoma and significant active neuropsychiatric disease, had a history of clinically significant bladder outflow obstruction, and known allergies to duloxetine, tolterodine or related compounds, were also excluded. All subjects provided written informed consents.

Study design

This was a double-blind, randomized, two-period crossover study. It was approved by the Research and Ethics Committee of the National University Hospital in Singapore and was performed in accordance with the Declaration of Helsinki.

Duloxetine (20-mg capsules) and placebo capsules, identical to those containing active drug, were supplied by Eli Lilly and Co. (Indianapolis, IN, USA). Tolterodine (1-mg tablets) was obtained as tolterodine l-tartrate (Detrol® Pharmacia & Upjohn). Subjects received two treatments in a randomized, crossover fashion: (i) tolterodine 2 mg twice daily (BID) and placebo BID, and (ii) tolterodine 2 mg BID and duloxetine 40 mg BID. Each treatment lasted 5 days with only the morning dose given on day 5. There was a 7-day washout period between the two treatments. This dosing regimen for duloxetine is that recommended for the treatment of SUI. The study drugs were administered together and taken with approximately 200 ml of water. The first dose (day 1) and last dose (day 5) of each period were administered in the Clinical Research Unit (CRU). Other than occasions when they were attending the CRU, subjects were allowed to self-administer the medication, as instructed by the investigator.

Prior to dosing on day 5 of both periods, subjects fasted from approximately midnight the previous evening until at least 3 h after dosing. Blood samples were collected for the assay of tolterodine and 5-HM on day 5 of each period at 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 h after drug administration. Blood samples were collected for the assay of duloxetine on day 5 of each period at 0 (predose) and 12 h after duloxetine administration.

Standard laboratory tests (haematology, clinical chemistry and urinalysis) were performed at initial screening, at admission to each study phase, and at follow-up. A serum pregnancy test was performed at screening and at admission to each study phase, where appropriate. Blood pressure, heart rate and oral temperature were measured at screening, admission, at the end of each study period, and at the follow-up visit. In addition, blood pressure and heart rate were measured on day 1 (predose and 2 h after dosing) and day 5 (predose, 2, 6 and 12 h after dosing) of period 1 and period 2. Adverse events were monitored throughout the study.

Analytical methods

Plasma samples were assayed for tolterodine and 5-HM using a validated high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS) method (Advion BioSciences Inc., Ithaca, NY, USA). A stable isotope analogue of tolterodine was used as the internal standard. Plasma samples were prepared using a 96-well Isolute CBA solid-phase extraction procedure. Following dilution, the extracts were analysed by turbo ion spray LC/MS/MS in the positive ion mode. The analytes were separated on a Zorbax Eclispe XDB-C₈ column with mobile phase composed of methanol and water containing 0.1% formic acid. The lower limit of quantification was 0.2 ng ml⁻¹ for both tolterodine (0.6 nm) and 5-HM (0.59 nm) with the upper calibration range of 50 ng ml⁻¹ for both tolterodine (153.6 nm) and 5-HM (146.4 nm). Accuracy expressed as the absolute percentage (%) error was ≤10.8% for tolterodine and ≤12.3% for 5-HM. The precision of the assay expressed as the % coefficient of variation (CV) was ≤12.7% for tolterodine and ≤12.5% for 5-HM.

Plasma concentrations of duloxetine were determined using a validated LC/MS/MS method (Prevalere Research Services Inc., Whitesboro, NY, USA). Duloxetine and its stable-isotope labelled internal standard were extracted from plasma using Spec Plus C₈ solid-phase extraction columns. The compounds were separated chromatographically on Phenomenex Luna C₁₈ columns with a mobile phase consisting of 55% acetonitrile/45% 10 mm ammonium acetate, pH 5 (v/v). The extracts were analysed using turbo ionspray. Standard curves and quality control samples were analysed along with the samples. The validated range for the assay was 0.5–100 ng ml⁻¹ (i.e. 1.7 nm to 337 nm). The accuracy of the assay expressed as the absolute percentage error was ≤3.58% and its precision expressed as the % CV was ≤4.32%.

Pharmacokinetic analysis

Noncompartmental pharmacokinetic parameters for tolterodine and 5-HM were derived using actual sampling times (WinNonlin Professional ver 3.1). The following parameters were determined: maximum observed plasma concentrations at steady state (C_max,ss), time to reach C_max,ss (t_max,ss), apparent clearance (CL/F), half-life (t_1/2) and the area under the plasma concentration--time curve during a steady-state dosing interval (AUC_τ,ss) calculated using the log-linear trapezoidal rule. The metabolic ratio was calculated as the ratio of tolterodine AUC_τ,ss to 5-HM AUC_τ,ss. Plasma concentrations of duloxetine on day 5 were used to determine whether steady state had been attained. No formal pharmacokinetic analyses were performed on the duloxetine data.

Statistical analysis

Sixteen subjects were enrolled to allow for dropouts with a view to at least 12 subjects completing the study. This number provides 80% power, at a 5% level of significance, to detect a 100% or more increase in tolterodine AUC₀₋₁₂ in the presence of duloxetine.

Tolterodine and 5-HM pharmacokinetic parameters except t_max,ss were log-transformed and analysed using the PROC MIXED software in SAS® for Windows. Geometric means for both treatments, the ratio of geometric means with 95% confidence intervals, and P-values were calculated. The analysis of t_max was based on Wilcoxon signed rank test. Medians and ranges for both treatments, the median of the difference between treatments, and the P-values are presented.

Results

Sixteen subjects were enrolled and 14 subjects (three males, 11 females; two Asian Indians, 11 Chinese and one Caucasian) completed the study. They were all determined to be CYP2D6 extensive metabolizers by genotype. Subjects had an average age of 40 years (range 21–54), and a BMI of 23.9 ± 3.0 kg m⁻² (mean ± SD). All subjects were nonsmokers except for one who had a 2-year smoking history.

The geometric mean (CV%) of trough duloxetine concentrations was 132 nmol l⁻¹ (68.4%) for the predose measurement and 143 nmol l⁻¹ (57.5%) at 12 h after dosing with duloxetine on day 5.

Figure 1 illustrates the mean (+ SD) steady-state plasma concentration-time profiles for tolterodine and 5-HM in the presence and absence of duloxetine dosed to steady-state. The summary statistics and associated P-values and confidence intervals for the derived pharmacokinetic parameters are summarized in Table 1. There were 64% (CI 30, 106), 71% (CI 31, 123) and 14% (CI 1, 28) increases in the geometric mean C_max,ss, AUC_τ,ss, and t_1/2, respectively, when the drug was coadministered with duloxetine, compared with when it was given alone. Correspondingly, the apparent clearance of tolterodine was 42% (CI 24, 55) lower. All these differences were statistically significant, but the magnitude of effect of duloxetine on the pharmacokinetics of tolterodine varied among individual subjects as indicated by the wide confidence intervals. The median t_max,ss for tolterodine was 1 h during both treatments.

Figure 1.

Arithmetic mean (+ SD) plasma concentration-time profiles of (a) tolterodine (2 mg BID) and (b) its 5-hydroxymethyl metabolite in the absence and presence of duloxetine under steady state condition (N = 14 subjects). Tolterodine + placebo (•); tolterodine + duloxetine (○)

Table 1.

Comparisons of the pharmacokinetic parameters of tolterodine and its 5-hydroxymethyl metabolite in the absence and presence of duloxetine

		Geometric mean
Parameter		Tolterodine + duloxetine	Tolterodine − duloxetine	Ratio of geometric mean	95% CI for the ratio of geometric mean	P-value for difference in means
Cmax,ss (nmol l−1)	Tolterodine	10.1	16.6	1.64	(1.30, 2.06)	< 0.001
	5-HM	7.45	7.31	0.98	(0.88, 1.10)	0.717
AUCτ,ss (nmol h−1 l−1)	Tolterodine	43.2	73.9	1.71	(1.31, 2.23)	0.001
	5-HM	42.41	41.99	0.99	(0.88, 1.12)	0.863
t½ (h)	Tolterodine	2.84	3.23	1.14	(1.01, 1.28)	0.031
	5-HM	3.90	4.21	1.08	(0.97, 1.20)	0.148
CL/F (l h−1)	Tolterodine	97.5	57.0	0.58	(0.45, 0.76)	0.001

		Median (min, max)
		Tolterodine + placebo	Tolterodine + duloxetine	Median of differencea	P-value for Wilcoxon signed rank test
Tmax,ss (h)	Tolterodine	1.00 (0.75, 1.50)	1.00 (0.50, 2.00)	0.00	0.588
	5-HM	1.00 (0.75, 2.00)	0.75 (0.50, 4.00)	−0.25	0.319

CI, Confidence interval.

^aMedian value from the list of differences between individual subject T_max,ss values.

In contrast to the parent drug, the changes in the mean C_max,ss, AUC_τ,ss, and t_1/2 for 5-HM after coadministration of duloxetine were less than 8%. The mean ratio of drug : metabolite was approximately 85% higher when duloxetine was given with tolterodine (1.86] CV 47.5%) compared with tolterodine alone (1.27] CV 70.1%).

The most common adverse event reported during treatment with tolterodine and placebo was fatigue whilst the most common adverse events during combined treatment with tolterodine and duloxetine were somnolence, fatigue and headache. Two subjects discontinued the study during their first dosing period of combined treatment. These were a 50-year-old woman with a previous history of dizziness who reported neck stiffness, jerky movement and dizziness (no hypotension or other abnormal findings were recorded for this subject) and a 54-year-old woman who experienced difficulty swallowing, which abated on discontinuation. Difficulty in micturition was reported by one 54-year-old male subject on the first 2 days, and by a 53-year-old female subject on the third day of the study. There were no reports of acute urinary retention. Laboratory data (haematology, clinical biochemistry and urinalysis) and vital signs (oral temperature, supine heart rate and blood pressure) did not reveal any clinically significant changes or abnormalities.

Discussion

This study has demonstrated that on average duloxetine decreases the CL/F of tolterodine by 42%, increases its AUC_τ,ss and C_max,ss by 71% and 64%, respectively, and prolongs its t_1/2 by 14%. Duloxetine did not affect the plasma concentrations or t_1/2 of 5-HM. Two women discontinued the study, one suffering dizziness, a known adverse effect of tolterodine. Vital signs and laboratory data did not raise any safety concerns.

Brynne et al.[9] reported that coadministration of fluoxetine, a SSRI (selective serotonin reuptake inhibitor) antidepressant known to be a potent inhibitor of CYP2D6 activity, increased the AUC_τ,ss and C_max,ss of tolterodine by 385% and 260%, respectively, but decreased those of 5-HM by 21% and 52%, respectively, in extensive metabolizers. Despite these pharmacokinetic changes, the authors concluded that the effect of CYP2D6 inhibition by fluoxetine was not clinically important since the therapeutic effect, which correlates with the unbound concentrations of tolterodine and 5-HM, was expected to be within normal variation. The prescribing information for tolterodine [10] states that no dose adjustment is required for coadminstration with fluoxetine. Our results indicate that duloxetine coadministration results in quantitative changes in tolterodine pharmacokinetics, but to a much lesser extent than when the SSRI fluoxetine is coadministered [9].

Inhibition of CYP2D6 activity would be expected to decrease the systemic exposure to a metabolite formed by this enzyme. However, for 5-HM, the mean C_max,ss and AUC_τ,ss were virtually unaltered by duloxetine. This may be partly explained by a CYP2D6-dependent clearance of the metabolite itself, as suggested by Brynne et al.[9]. Assuming this, the systemic exposure to 5-HM could increase, decrease or stay unaltered, depending upon the relative magnitude of inhibition of CYP2D6 activity on the formation and elimination of 5-HM. In the present work, the lack of effect of duloxetine on plasma concentrations of 5-HM may reflect similar changes in the formation and elimination of this metabolite.

All subjects were genotyped as CYP2D6‘extensive metabolizers’. Whereas it is recognized that some CYP2D6 genotypes may confer a decreased metabolic capacity, there was no pattern to suggest that genotype was a significant contributor to the findings of the present study.

The adverse events reported during treatment with tolterodine alone did not appear to differ from historical data on tolterodine [7]. Whereas a greater number of adverse events were reported during the combined treatment of duloxetine and tolterodine, they were qualitatively similar to those reported previously for tolterodine [10] or duloxetine [8]. During the combined treatment of tolterodine and duloxetine, the most common adverse events, somnolence, fatigue and headache, were reported mainly during the first 3 days of treatment. This included the two subjects with micturition difficulties. In addition, less common adverse events were also reported during the first 2 days. These observations suggest the possibility that tolerance may occur with continued dosing. The present study was performed in a small group of healthy CYP2D6 extensive metabolizer subjects. Thus, extrapolation of these data to the relevant patient group and to CYP2D6 poor metabolizers should be made with caution.

In conclusion, duloxetine exhibited minor inhibitory effects on the pharmacokinetics of tolterodine but not 5-HM, and changes in exposure of tolterodine are expected to be within the variation of pharmacokinetics seen in the general population. Coadministration of both drugs is well tolerated and demonstracted no significant safety findings in the studied population. These findings suggest that there should not be a need for routine adjustment of tolterodine dosage in the presence of duloxetine.