| pA2 online © Copyright 2004 The British Pharmacological Society |
157P
University of Newcastle Winter Meeting December 2004 |
Pharmacokinetics of darifenacin, an M3 selective receptor antagonist: effects of renal or hepatic impairment Damayanthi Devineni, Andrej Skerjanec, Gerard Greig & Thasia G. Woodworth (introduced by Henry Danahay ). Novartis Pharmaceuticals, East Hanover, New Jersey, USA. |
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Print abstractDarifenacin is an M3 selective receptor antagonist (M3 SRA) for once daily treatment of overactive bladder. The effect of impaired renal or hepatic function on the steady-state pharmacokinetics of darifenacin 15 mg controlled release tablets, administered once daily for 6 days, was determined in 24 and 41 subjects, respectively.
Renal impairment had no clinically relevant effect on the pharmacokinetics of darifenacin (see t able 1 for mean values at day 6) . Regression analysis showed that there was no relationship between darifenacin clearance and renal function. Plasma protein binding of darifenacin was not reduced in subjects with renal impairment.
Table 1:
| aParameter | Creatinine clearance (ml min-1) |
|||
Normal (n = 6) (>80) |
Mild (n = 6) (51–80) |
Moderate (n = 6) (30–50) |
Severe (n = 6) (<30) |
|
| AUC(0,24 h) (ng ml -1 h) | 44.5 |
86.1 |
116 |
52.9 |
Cmax (ng ml-1) |
3.03 |
5.21 |
8.35 |
5.46 |
| CL/F (l h-1) | 337 |
174 |
129 |
284 |
| CLR (l h-1) | 6.66 |
5.65 |
1.46 |
0.65 |
| tmax (h) | 6.3 |
6.7 |
5.2 |
5.4 |
aData expressed as geometric means except for tmax which is the arithmetic mean.
There were no clinically important differences between subjects with mild hepatic impairment (Child Pugh A) and healthy controls. However, darifenacin exposure was increased in subjects with moderate hepatic impairment (Child Pugh B) (see t able 2 ). Following correction for protein binding, subjects with moderate hepatic impairment exhibited a mean 4.7-fold and 4.0-fold increase in unbound darifenacin AUC and Cmax, respectively, compared with healthy controls.
Table 2:
| aParameter | Healthy (n = 12) |
Child Pugh A (n = 13) |
Child Pugh B (n = 11) |
| AUC(0,24 h) (ng ml-1 h) | 101 |
65 |
269 |
| Cmax(ng ml-1) | 6.0 |
4.0 |
14.2 |
| CL/F (l h-1) | 149.1 |
229.4 |
55.7 |
| t max (h) | 10.0 |
9.3 |
11.3 |
aData expressed as geometric means except for tmax which is the arithmetic mean.
The safety profile was similar in healthy patients and patients with varying degrees of renal or hepatic impairment. In conclusion, these findings indicate no need for any specific changes to the proposed dosage regimen (7.5 mg or 15 mg once daily) for patients with renal impairment. While a dose of darifenacin CR 15 mg once daily can be used in mild hepatic impairment, the maximum recommended dose for use in subjects with moderate hepatic impairment is 7.5 mg once daily.