Darifenacin

The daily dose of darifenacin should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Darifenacin has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population

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The systemic exposure of darifenacin from darifenacin extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of darifenacin should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil)

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Subjects with severe hepatic impairment (Child-Pugh C) have not been studied, therefore darifenacin is not recommended for use in these patients

. The daily dose of darifenacin should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child-Pugh B). 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. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A).

After oral administration of darifenacin 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 darifenacin 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1.

A summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of darifenacin 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 Darifenacin 7.5 mg and 15 mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 Phenotype

Darifenacin 7.5 mg (N = 68 EM, 5 PM)						Darifenacin 15 mg (N = 102 EM, 17 PM)
	AUC24 ( ng • h / mL )	Cmax ( ng / mL )	Cavg ( ng / mL )	Tmax ( h )	t1 / 2 ( h )	AUC24 ( ng • h / mL )	Cmax ( ng / mL )	Cavg ( ng / mL )	Tmax ( h )	t1 / 2 ( h )
EM	29.24 (15.47)	2.01 (1.04)	1.22 (0.64)	6.49 (4.19)	12.43 (5.64)a	88.90 (67.87)	5.76 (4.24)	3.70 (2.83)	7.61 (5.06)	12.05 (12.37)b
PM	67.56 (13.13)	4.27 (0.98)	2.81 (0.55)	5.20 (1.79)	19.95c -	157.71 (77.08)	9.99 (5.09)	6.58 (3.22)	6.71 (3.58)	7.40d -
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; t1/2= Terminal elimination half-life. Regarding EM and PM [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Variability in Metabolism (12.3)].

The mean oral bioavailability of darifenacin in EMs at steady-state is estimated to be 15 percent and 19 percent for mg and 15 mg tablets, respectively.

Following single dose administration of darifenacin with food, the AUC of darifenacin was not affected, while the C_maxwas increased by 22 percent and T_maxwas shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from darifenacin.

Darifenacin is approximately 98 percent bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (V_ss) is estimated to be 163 L.

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:

(i)                 monohydroxylation in the dihydrobenzofuran ring;

(ii)               dihydrobenzofuran ring opening;

(iii)             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.

A subset of individuals (approximately 7 percent Caucasians and 2 percent 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 C_maxand AUC following darifenacin 15 mg once daily at steady-state were 1.9 and 1.7, respectively.

Following administration of an oral dose of¹⁴C-darifenacin solution to healthy volunteers, approximately 60 percent of the radioactivity was recovered in the urine and 40 percent in the feces. Only a small percentage of the excreted dose was unchanged darifenacin (3 percent). 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.

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

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In a drug interaction study, when a 7.5 mg once daily dose of darifenacin 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 ngh/mL for EMs and for one PM subject, respectively. When a 15 mg daily dose of darifenacin 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 1,110 and 931 ngh/mL for EMs and for one PM subject, respectively.

The mean C_maxand AUC of darifenacin following 30 mg once daily dosing at steady-state were 128 percent and 95 percent 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 C_maxand AUC by 88 percent and 84 percent, respectively

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The mean C_maxand AUC of darifenacin following 30 mg once daily at steady-state were 42 percent and 34 percent higher, respectively, in the presence of cimetidine, a mixed CYP P450 enzyme inhibitor.

Darifenacin exposure following 30 mg once daily at steady-state was 33 percent higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg.

Based onhuman microsomal studies, darifenacin is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations.

The potential for clinical doses of darifenacin to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies.

The mean C_maxand AUC of imipramine, a CYP2D6 substrate, were increased by 57 percent and 70 percent, respectively, in the presence of steady-state darifenacin 30 mg once daily. The mean C_maxand AUC of desipramine, the active metabolite of imipramine, were increased by 260 percent.

Darifenacin (30 mg daily) co-administered with a single oral dose of midazolam 7.5 mg resulted in a 17 percent increase in midazolam exposure.

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).

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.

Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in a 16 percent increase in digoxin exposure.

A population pharmacokinetic analysis of patient data indicated a trend for clearance of darifenacin to decrease with age (6 percent per decade relative to a median age of 44). Following administration of darifenacin 15 mg once daily, darifenacin exposure at steady-state was approximately 12 percent to 19 percent higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years

The pharmacokinetics of darifenacin has not been studied in the pediatric population.

PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin C_maxand AUC at steady-state were approximately 57 percent to 79 percent and 61 percent to 73 percent higher in females than in males, respectively.

A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) given darifenacin 15 mg once daily to steady-state demonstrated no clear relationship between renal function and darifenacin clearance.

Darifenacin pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given darifenacin 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.