The clinical pharmacokinetics of darifenacin.
Darifenacin hydrobromide is a selective muscarinic M(3) receptor antagonist that is indicated for use in treatment of overactive bladder disorder. Darifenacin was found to have a short terminal elimination half-life after intravenous and immediate-release oral dosage forms (3-4 hours) but this increased with a prolonged-release (PR) formulation (14-16 hours). The absolute bioavailability of darifenacin from 7.5 and 15 mg PR tablets was estimated to be 15.4% and 18.6%, respectively. With repeated once-daily oral administration of the PR formulation, peak plasma concentrations of darifenacin are achieved approximately 7 hours post-dose. After oral administration, darifenacin is well absorbed from the gastrointestinal tract and very little unchanged drug (<2%) is recovered in the faeces. Steady state is achieved after 6 days of once-daily administration of the PR formulation. As expected, values of peak plasma concentration (C(max)) and area under the plasma concentration-time curve are dose dependent, although the increase in plasma concentrations is proportionally greater than the increase in dose owing to saturation of presystemic metabolism. From intravenous administration, it has been established that darifenacin possesses a moderate-to-high hepatic extraction ratio, with high plasma clearance (36-52 L/h) and a volume of distribution (165-276L) that exceeds total body water. It is highly protein bound (98%), primarily to alpha(1)-acid glycoprotein. Darifenacin is subject to extensive hepatic metabolism, with 3% of unchanged drug excreted in urine and faeces. Metabolism is mediated by hepatic cytochrome P450 2D6 and 3A4, the main metabolic routes being monohydroxylation in the dihydrobenzfuran ring, dihydrobenzfuran ring opening, and N-dealkylation of the pyrrolidine nitrogen. Several possibly important drug-drug interactions have been identified with darifenacin, including ketoconazole, erythromycin and fluconazole, each of which increases darifenacin mean C(max) by 9.52-, 2.28- and 1.88-fold, respectively. When given with imipramine, darifenacin causes 1.6-fold higher plasma concentrations of the antidepressant and its major metabolite. Moderate hepatic impairment, but not renal insufficiency, has been shown to increase plasma concentrations of the drug. The pharmacokinetic profile of darifenacin is not affected by food.
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA. andrej.skerjanec@novartis.com
Andrej
A
Skerjanec
D001572:Benzofurans / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D006801:Humans; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011759:Pyrrolidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors; D014549:Urinary Incontinence / Q000188:drug therapy / Q000378:metabolism*
D001572:Benzofurans; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D043587:Receptor, Muscarinic M3; C101207:darifenacin