Pharmacokinetics

Absorption Distribution Metabolism Excretion Special Population Other Details

Absorption (for reference: overseas data)

In the healthy adult foreign males, imidafenacin was absorbed almost 100% from the gastrointestinal tract, with an absolute bioavailability of 57.8%.

Plasma Concentrations

  1. Single administration

Effect of meal

After single oral administration of 0.1 mg of imidafenacin to healthy adult males (n=12) at the fasting state, plasma concentration reached the peak (Cmax: 471 pg/mL) at 1.5 hours, and decreased with a half-life of 2.9 hours. Cmax and AUC 0-12 at the fed state were about 1.3 and 1.2 times higher than those at the fasting state, respectively.

Dosing state Tmax (hr) Cmax (pg/mL) AUC0-12  (pg ∙ hr/mL) T1/2  (hr)
Fasting 1.5 471±107 2230±540 2.9±0.2
Fed 1.3 611±113 2690±470 2.9±0.2
Mean± SD for Cmax, AUC0_12, and T1I2; median for Tmax

 

2. Repeated administration

After repeated oral administration of 0.25 mg of imidafenacin twice daily for 5 days to the healthy adult males (n=5), the time-course of plasma concentration and pharmacokinetic parameters after the final dosing were comparable to those after the initial dosing, indicating no accumulation of imidafenacin after repeated administration.

Cmax (ng/mL) AUC0-α a) (ng ∙ hr/mL) Tmax (hr) t 1/2 (hr)
Single dose 26.8 ± 9.2 143.9 ± 57.1 2.2 ± 0.5 6.9 ± 3.1
Repeated dose 28.7 ± 7.6 134.3 ± 39.0 2.0 ± 0.0 10.4 ± 4.6

Note: The approved dosage is 0.2 mg/day, and if the efficacy is insufficient, the dosage may be increased up to 0.4 mg/day.


Distribution

Protein Binding

The protein binding ratio of imidafenacin ranged from 87.1 to 88.8%. Major binding proteins were albumin and α1-acid glycoprotein.

Distribution in animals (in rats)

After single oral administration of imidafenacin to rats, concentration in the bladder reached maximum at 1 hour after administration, and decreased with a half-life of 1.8 hours, more slowly than in the serum. Cmax and AUC0-12 in the bladder were 10. 7 and 25.4 times higher than those in the serum, respectively.


Metabolism

After oral administration, about 40% of imidafenacin was subjected to first-pass effect in the liver. Major plasma metabolites included M-2 (oxidized metabolite on the imidazole ring of imidafenacin), M-4 (ring-cleaved metabolite of M-2), and M-9 (N-glucuronide of imidafenacin). Metabolism to M-2 and M-4 was primarily catalyzed by CYP3A4, and that to M-9 was by UGT1A4. In addition, imidafenacin and its major metabolites, M-2,M-4, and M-9, did not inhibit human CYP species in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4).


Excretion

After single oral administration of 14C-imidafenacin to healthy adult foreign males (n=6) at a dose of 0.25 mg at the fasting state, 95% of the dose was recovered in the urine and feces until 192 hours after administration (65.6% in the urine, and 29.4% in the feces). Less than 10% of the dose was excreted unchanged in the urine, and none of the dose was excreted unchanged in the feces.

Note) The approved dosage is 0.2 mg/day, and if the efficacy is insufficient, the dosage may be increased up to 0.4 mg/day.


Special Population

The elderly

After single oral administration of 0.1 mg of imidafenacin to the healthy non-elderly adult males (n=6) and the elderly males aged 65 years or more (n=9) at the fasting state, Cmax in the elderly was about 1.2 times higher than that in the non-elderly, while AUC0-∞ was comparable between the two groups.

Tmax (hr) Cmax (pg/mL) AUC0-12 (pg∙hr/ml) T1/2 (hr)
Non – Elderly 1.5 382 ± 106 2,010 ± 1,050 2.6±0.7
Elderly 1.0 445 ± 136 2,140 ± 480 3. 1±0.4

 

Population pharmacokinetic (PPK) analysis

A two-compartment model involving primary absorption with a lag time in absorption was used for the analysis of population pharmacokinetics by NONMEM. Plasma concentration of imidafenacin was determined at a total of 3,168 points in 852 patients with overactive bladder aged 20 to 85 years (including 101 patients with mild hepatic dysfunction, 116 patients with mild renal dysfunction, and 14 patients with moderate renal dysfunction) and 90 healthy adults aged 20 to 75 years in the long-term study and long-term ascending-dose study. The relationship of clearance (CL/F) of imidafenacin to the following covariates was assessed: body weight, age, gender, drinking habit, smoking habit, indices for hepatic function (AST [GOT], ALT [GPT], y-GTP, ALP, lactate dehydrogenase, and total bilirubin), indices for renal function (serum creatinine, and blood urea nitrogen), and albumin. CL/F in the patients with mild abnormality in ALP was lower than that in the normal patients by 4%. CL/F in the elderly was lower than that in the non-elderly by 14%. The other covariates including indices for renal function (serum creatinine, blood urea nitrogen) did not affect CL/F.

Population Parameter Estimate (95% Cl) Inter individual variability
Total body clearance (L/hr) 23.1 (21.2 to 25.0) 32.40%
Volume of distribution for the
central compartment (L)
109 (102 to 116) 23.30%
Inter-compartmental
clearance (L/hr)
3.50 (2.95 to 4.05)
Volume of distribution for the
peripheral compartment (L)
44.3 (33.8 to 54.8)
Rate constant for absorption
(1/hr)
3.07 (2.55 to 3.59) 136.70%
Absorption lag time (hr) 0.436 (0.422 to 0.450)
Intra-individual variability 37.30%

Other details

Drug Interactions

Itraconazole

After 0.1 mg of imidafenacin was orally co-administered to healthy adult males (n=10) treated with 200 mg of itraconazole once daily for 9 days, Cmax and AUC0-∞ of imidafenacin increased to 1.3 and 1.8 times those after imidafenacin was administered alone, respectively.