CLINICAL PHARMACOLOGY
Mechanism Of Action
Darifenacin is a competitive muscarinic receptor
antagonist. Muscarinic receptors play an important role in several major
cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion.
In vitro studies using human recombinant muscarinic
receptor subtypes show that darifenacin has greater affinity for the M3 receptor
than for the other known muscarinic receptors (9- and 12-fold greater affinity
for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3
compared to both M2 and M4). M3 receptors are involved in contraction of human
bladder and gastrointestinal smooth muscle, saliva production, and iris
sphincter function. Adverse drug effects such as dry mouth, constipation and
abnormal vision may be mediated through effects on M3 receptors in these
organs.
Pharmacodynamics
In three cystometric studies performed in patients with
involuntary detrusor contractions, increased bladder capacity was demonstrated
by an increased volume threshold for unstable contractions and diminished
frequency of unstable detrusor contractions after Enablex treatment. These
findings are consistent with an antimuscarinic action on the urinary bladder.
Electrophysiology
The effect of a six-day treatment of 15 mg and 75 mg
Enablex on QT/QTc interval was evaluated in a multiple-dose, double-blind,
randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm
design study in 179 healthy adults (44% male, 56% female) aged 18 to 65.
Subjects included 18% poor metabolizers (PMs) and 82% extensive metabolizers
(EMs). The QT interval was measured over a 24-hour period both predosing and at
steady-state. The 75 mg Enablex dose was chosen because this achieves exposure
similar to that observed in CYP2D6 poor metabolizers administered the highest
recommended dose (15 mg) of darifenacin in the presence of a potent CYP3A4
inhibitor. At the doses studied, Enablex did not result in QT/QTc interval
prolongation at any time during the steady-state, while moxifloxacin treatment
resulted in a mean increase from baseline QTcF of about 7.0 msec when compared
to placebo. In this study, darifenacin 15 mg and 75 mg doses demonstrated a
mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to
placebo. However, in the clinical efficacy and safety studies, the change in
median HR following treatment with Enablex was no different from placebo.
Pharmacokinetics
Absorption
After oral administration of Enablex to healthy
volunteers, peak plasma concentrations of darifenacin are reached approximately
seven hours after multiple dosing and steady-state plasma concentrations are
achieved by the sixth day of dosing. The mean (SD) steady-state time course of
Enablex 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1.
Figure 1 : Mean (SD) Steady-State Darifenacin Plasma
Concentration-Time Profiles for Enablex 7.5 mg and 15 mg in Healthy Volunteers
Including Both CYP2D6 EMs and PMs*
*Includes 95 EMs and 6 PMs for
7.5 mg; 104 EMs and 10 PMs for 15 mg.
A summary of mean (standard deviation, SD) steady-state
pharmacokinetic parameters of Enablex 7.5 mg and 15 mg extended-release tablets
in EMs and PMs of CYP2D6 is provided in Table 3.
Table 3: Mean (SD) Steady-State Pharmacokinetic
Parameters from Enablex 7.5 mg and 15 mg Extended-Release Tablets Based on
Pooled Data by Predicted CYP2D6 Phenotype
|
AUC24 (ng•h/mL) |
Cmax (ng/mL) |
Cavg (ng/mL) |
Tmax (h) |
t½(h) |
AUC24 (ng•h/mL) |
Cmax (ng/mL) |
Cavg (ng/mL) |
Tmax (h) |
t½(h) |
EM |
29.24 |
2.01 |
1.22 |
6.49 |
12.43 |
88.90 |
5.76 |
3.70 |
7.61 |
12.05 |
(15.47) |
(1.04) |
(0.64) |
(4.19) |
(5.64)a |
(67.87) |
(4.24) |
(2.83) |
(5.06) |
(12.37) b |
PM |
67.56 |
4.27 |
2.81 |
5.20 |
19.95c |
157.71 |
9.99 |
6.58 |
6.71 |
7.40d |
(13.13) |
(0.98) |
(0.55) |
(1.79) |
- |
(77.08) |
(5.09) |
(3.22) |
(3.58) |
- |
aN = 25; bN = 8; cN = 2; dN = 1; AUC24 = Area under the plasma concentration versus time curve for 24h;
Cmax = Maximum observed plasma concentration; Cavg = Average plasma
concentration at steady-state;
Tmax = Time of occurrence of Cmax; t½ = Terminal elimination half-life.
Regarding EM and PM [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Variability in Metabolism]. |
The mean oral bioavailability of Enablex in EMs at
steady-state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets,
respectively.
Effect of Food
Following single dose administration of Enablex with
food, the AUC of darifenacin was not affected, while the Cmax was increased by
22% and Tmax was shortened by 3.3 hours. There is no effect of food on
multiple-dose pharmacokinetics from Enablex.
Distribution
Darifenacin is approximately 98% bound to plasma proteins
(primarily to alpha-1-acid-glycoprotein). The steady-state volume of
distribution (Vss) is estimated to be 163 L.
Metabolism
Darifenacin is extensively metabolized by the liver
following oral dosing.
Metabolism is mediated by cytochrome P450 enzymes CYP2D6
and CYP3A4. The three main metabolic routes are as follows:
- monohydroxylation in the dihydrobenzofuran ring;
- dihydrobenzofuran ring opening;
- N-dealkylation of the pyrrolidine nitrogen.
The initial products of the hydroxylation and
N-dealkylation pathways are the major circulating metabolites but they are
unlikely to contribute significantly to the overall clinical effect of
darifenacin.
Variability in Metabolism
A subset of individuals (approximately 7% Caucasians and
2% African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs.
Individuals with normal CYP2D6 activity are referred to as extensive
metabolizers (EMs). The metabolism of darifenacin in PMs will be principally
mediated via CYP3A4. The darifenacin ratios (PM versus EM) for Cmax and AUC
following darifenacin 15 mg once daily at steady-state were 1.9 and 1.7,
respectively.
Excretion
Following administration of an oral dose of 14C-darifenacin
solution to healthy volunteers, approximately 60% of the radioactivity was
recovered in the urine and 40% in the feces. Only a small percentage of the
excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance
is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of darifenacin
following chronic dosing is approximately 13 to 19 hours.
Drug-Drug Interactions
Effects of Other Drugs on Darifenacin
Darifenacin metabolism is primarily mediated by the
cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or
inhibitors of either of these enzymes may alter darifenacin pharmacokinetics [see
DRUG INTERACTIONS].
CYP3A4 Inhibitors: In a drug interaction study,
when a 7.5 mg once daily dose of Enablex was given to steady-state and
co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean
darifenacin Cmax increased to 11.2 ng/mL for EMs (n = 10) and 55.4 ng/mL for
one PM subject (n = 1). Mean AUC increased to 143 and 939 ng•h/mL for EMs and
for one PM subject, respectively. When a 15 mg daily dose of Enablex was given
with ketoconazole, mean darifenacin Cmax increased to 67.6 ng/mL and 58.9 ng/mL
for EMs (n = 3) and one PM subject (n = 1), respectively. Mean AUC increased to
1110 and 931 ng•h/mL for EMs and for one PM subject, respectively [see DOSAGE
AND ADMINISTRATION and DRUG INTERACTIONS].
The mean Cmax and AUC of darifenacin following 30 mg once
daily dosing at steady-state were 128% and 95% higher, respectively, in the
presence of a moderate CYP3A4 inhibitor, erythromycin. Co-administration of
fluconazole, a moderate CYP3A4 inhibitor and darifenacin 30 mg once daily at
steady-state increased darifenacin Cmax and AUC by 88% and 84%, respectively [see
DRUG INTERACTIONS].
The mean Cmax and AUC of darifenacin following 30 mg once
daily at steady-state were 42% and 34% higher, respectively, in the presence of
cimetidine, a mixed CYP P450 enzyme inhibitor.
CYP2D6 Inhibitors: Darifenacin exposure following
30 mg once daily at steady-state was 33% higher in the presence of the potent
CYP2D6 inhibitor paroxetine 20 mg [see DRUG INTERACTIONS].
Effects of Darifenacin on Other Drugs
In Vitro Studies: Based on in vitro human
microsomal studies, Enablex is not expected to inhibit CYP1A2 or CYP2C9 at
clinically relevant concentrations.
In Vivo Studies: The potential for clinical doses
of Enablex to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated
in specific drug interaction studies.
CYP2D6 Substrates: The mean Cmax and AUC of
imipramine, a CYP2D6 substrate, were increased by 57% and 70%, respectively, in
the presence of steady-state darifenacin 30 mg once daily. The mean Cmax and
AUC of desipramine, the active metabolite of imipramine, were increased by 260%
[see DRUG INTERACTIONS].
CYP3A4 Substrates: Darifenacin (30 mg daily)
co-administered with a single oral dose of midazolam 7.5 mg resulted in a 17%
increase in midazolam exposure.
Combination Oral Contraceptives: Darifenacin (10
mg three times daily) had no effect on the pharmacokinetics of a combination
oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol
(0.03 mg).
Warfarin: Darifenacin had no significant effect on
prothrombin time when a single dose of warfarin 30 mg was co-administered with
darifenacin (30 mg daily) at steady-state [see DRUG INTERACTIONS].
Digoxin: Darifenacin (30 mg daily) co-administered
with digoxin (0.25 mg) at steady-state resulted in a 16% increase in digoxin
exposure [see DRUG INTERACTIONS].
Pharmacokinetics in Special Populations
Age: A population pharmacokinetic analysis of
patient data indicated a trend for clearance of darifenacin to decrease with
age (6% per decade relative to a median age of 44). Following administration of
Enablex 15 mg once daily, darifenacin exposure at steady-state was
approximately 12% to 19% higher in volunteers between 45 and 65 years of age
compared to younger volunteers aged 18 to 44 years [see Use in Specific
Populations].
Pediatric: The pharmacokinetics of Enablex has not
been studied in the pediatric population [see Use in Specific Populations].
Gender: PK parameters were calculated for 22 male
and 25 female healthy volunteers. Darifenacin Cmax and AUC at steady-state were
approximately 57% to 79% and 61% to 73% higher in females than in males,
respectively [see Use in Specific Populations].
Renal Impairment: A study of subjects with varying
degrees of renal impairment (creatinine clearance between 10 and 136 mL/min)
given Enablex 15 mg once daily to steady-state demonstrated no clear
relationship between renal function and darifenacin clearance [see Use in
Specific Populations].
Hepatic Impairment: Enablex pharmacokinetics were
investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B)
impairment of hepatic function given Enablex 15 mg once daily to steady-state.
Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin.
However, protein binding of darifenacin was affected by moderate hepatic
impairment. After adjusting for plasma protein binding, unbound darifenacin
exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment
than subjects with normal hepatic function. Subjects with severe hepatic
impairment (Child-Pugh C) have not been studied [see DOSAGE AND
ADMINISTRATION, WARNINGS AND PRECAUTIONS and Use in Specific
Population].
Clinical Studies
Enablex extended-release tablets were evaluated for the
treatment of patients with overactive bladder with symptoms of urgency, urge
urinary incontinence, and increased urinary frequency in three randomized,
fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies
(Studies 1, 2 and 3) and one randomized, double-blind, placebo-controlled,
multicenter, dose-titration study (Study 4). For study eligibility in all four
studies, patients with symptoms of overactive bladder for at least six months
were required to demonstrate at least eight micturitions and at least one
episode of urinary urgency per day, and at least five episodes of urge urinary
incontinence per week. The majority of patients were white (94%) and female
(84%), with a mean age of 58 years, range 19 to 93 years. Thirty-three percent
of patients were greater than or equal to 65 years of age. These
characteristics were well balanced across treatment groups. The study
population was inclusive of both naïve patients who had not received prior
pharmacotherapy for overactive bladder (60%) and those who had (40%).
Table 4 shows the efficacy data collected from 7- or
14-day voiding diaries in the three fixed-dose placebo-controlled studies of
1,059 patients treated with placebo, 7.5 mg or 15 mg once daily Enablex for 12
weeks. A significant decrease in the primary endpoint, change from baseline in
average weekly urge urinary incontinence episodes was observed in all three
studies. Data is also shown for two secondary endpoints, change from baseline
in the average number of micturitions per day (urinary frequency) and change
from baseline in the average volume voided per micturition.
Table 4: Difference Between Enablex (7.5 mg, 15 mg)
and Placebo for the Week 12 Change from Baseline (Studies 1, 2 and 3)
|
Study 1 |
Study 2 |
Study 3 |
Enablex 7.5 mg |
Enablex 15 mg |
Placebo |
Enablex 7.5 mg |
Enablex 15 mg |
Placebo |
Enablex 15 mg |
Placebo |
No. of Patients Entered |
229 |
115 |
164 |
108 |
107 |
109 |
112 |
115 |
Urge Incontinence Episodes per Week |
Median Baseline |
16.3 |
17.0 |
16.6 |
14.0 |
17.3 |
1 6.1 |
16.2 |
15.5 |
Median Change from Baseline |
-9.0 |
-10.4 |
-7.6 |
-8.1 |
-10.4 |
-5.9 |
-11.4 |
-9.0 |
Median Difference to Placebo |
-1.5* |
-2.1* |
- |
-2.8* |
-4.3* |
- |
-2.4* |
- |
Micturitions per Day |
Median Baseline |
10.1 |
10.1 |
10.1 |
10.3 |
11.0 |
10.1 |
10.5 |
10.4 |
Median Change from Baseline |
-1.6 |
-1.7 |
-0.8 |
-1.7 |
-1.9 |
-1.1 |
-1.9 |
-1.2 |
Median Difference to Placebo |
-0.8* |
-0.9* |
- |
-0.5 |
-0.7* |
- |
-0.5 |
- |
|
|
|
|
|
|
|
|
|
Volume of Urine Passed per Void (mL) |
|
|
|
|
|
|
|
|
|
Median Baseline |
160.2 |
151.8 |
162.4 |
161.7 |
157.3 |
162.2 |
155.0 |
147.1 |
Median Change from Baseline |
14.9 |
30.9 |
7.6 |
16.8 |
23.6 |
7.1 |
26.7 |
4.6 |
Median Difference to Placebo |
9.1* |
20.7* |
- |
9.2 |
16.6* |
- |
20.1* |
- |
*Indicates statistically significant difference versus
placebo (p less than 0.05, Wilcoxon rank-sum test) |
Table 5 shows the efficacy data from the dose-titration
study in 395 patients who initially received 7.5 mg Enablex or placebo daily
with the option to increase to 15 mg Enablex or placebo daily after two weeks.
Table 5: Difference between Enablex (7.5 mg/15 mg) and
Placebo for the Week 12 Change from Baseline (Study 4)
|
Enablex 7.5 mg /15 mg |
Placebo |
|
|
|
No. of Patients T reated |
268 |
127 |
Urge Incontinence Episodes per Week |
Median Baseline |
16.0 |
14.0 |
Median Change from Baseline |
-8.2 |
-6.0 |
Median Difference to Placebo |
-1.4* |
- |
Micturitions per Day |
Median Baseline |
9.9 |
10.4 |
Median Change from Baseline |
-1.9 |
-1.0 |
Median Difference to Placebo |
* .8 0. - |
- |
Volume of Urine Passed per Void (mL) |
Median Baseline |
173.7 |
177.2 |
Median Change from Baseline |
18.8 |
6.6 |
Median Difference to Placebo |
13.3 * |
- |
*Indicates statistically significant difference versus
placebo (p less than 0.05, Wilcoxon rank-sum test) |
As seen in Figures 2 a, 2b and 2c, reductions in the
number of urge incontinence episodes per week were observed within the first
two weeks in patients treated with Enablex 7.5 mg and 15 mg once daily compared
to placebo. Further, these effects were sustained throughout the 12-week
treatment period.
Figures 2a, 2b, 2c. Median Change from Baseline at
Weeks 2, 6, 12 for Number of Urge Incontinence Episodes per Week (Studies 1, 2
and 3)