Tolterodine (Detrol®, Detrol® LA)

Detrol®, Detrol® LA

Classification:
Autonomic Agents

• Anticholinergics
  
  • Antimuscarinics

Genitourinary Agents

• Bladder Antispasmodics

Description: Tolterodine is a antimuscarinic anticholinergic agent administered orally for the treatment of patients with overactive bladder. Tolterodine helps to reduce urinary frequency and urgency, and helps to reduce urge-related incontinence. Tolterodine has been studied extensively in the elderly, and may be preferred in the geriatric population over other antimuscarinic drugs for overactive bladder. Final FDA approval in the United States was granted March 25, 1998; tolterodine was the first new drug approved for this condition in over 20 years. In Europe, the drug is sold by the trade name ‘Detrusitol’. An extended-release dosage form, Detrol® LA, was FDA approved in December 2000.

Mechanism of Action: Tolterodine and its active metabolite, 5-hydroxymethyltolterodine, are competitive muscarinic receptor antagonists. Actions on the bladder include inhibition of bladder contraction, a decrease in detrusor pressure, and an incomplete emptying of the bladder. Antimuscarinic effects on the salivary gland are much less pronounced than the effects on the urinary bladder. Neither tolterodine nor its active metabolite exert clinically significant effects on other neurotransmitter receptors or other pharmacologic targets such as calcium channels.

Tolterodine and its active metabolite have a lipophilicity 30 and > 350 times lower than oxybutynin, respectively, which limits the drugs entry into the CNS and therefore would be expected to limit the drug’s CNS antimuscarinic activity. In healthy volunteers, only minor EEG changes were noted after tolterodine administration. In clinical trials of normal volunteers and patients, QT interval prolongation was not observed at doses up to 4 mg PO twice daily of tolterodine. Higher doses were not evaluated for cardiac conduction changes.

Pharmacokinetics: Tolterodine is administered orally. Tolterodine is rapidly absorbed with peak serum concentrations (Cmax) occurring within 1-2 hours after administration of the immediate-release product. Maximum serum concentrations of tolterodine extended-release capsules are observed 2-6 hours after administration. Approximately 77% of the dose is absorbed. The pharmacokinetics of tolterodine are dose-proportional over the range of 1-4 mg of an immediate-release tablet. The AUC of the 4 mg dose of tolterodine extended-release once daily is equivalent to tolterodine immediate release 2 mg twice per day. Cmax and Cmin levels of tolterodine extended-release are about 75% and 150% of tolterodine immediate-release, respectively. Concomitant administration with food increases the bioavailability of tolterodine immediate-release by roughly 53%, however, the increase does not appear to be clinically significant. There is no effect of food on the pharmacokinetics of tolterodine extended-release capsules. Tolterodine may be administered with food.

Once in the systemic circulation, tolterodine is extensively metabolized by the liver to an active metabolite (5-hydroxymethyltolterodine) which has essentially the same antimuscarinic effects as tolterodine. Tolterodine is highly bound to plasma proteins, primarily to alpha1-acid glycoprotein; the 5-hydroxymethyl metabolite is not extensively protein bound. Neither tolterodine or the active metabolite distributes significantly to erythrocytes. In animal models, tolterodine exhibited greater tissue distribution in the bladder versus the central nervous system. In mice, the highest concentrations of tolterodine were seen in elimination organs, such as the bladder, kidney, gallbladder, and liver. The lowest concentrations of tolterodine were seen in the central nervous system (brain and spinal cord) and skeletal muscles.

The hepatic enzyme responsible for converting tolterodine to its active metabolite is CYP2D6; however, roughly 7% of the Caucasian population is devoid of this isozyme. In this group (referred to as “poor metabolizers"), the drug is metabolized via CYP3A4 to N-dealkylated tolterodine. Pharmacokinetic studies show that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers; this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite. Because of differences in the protein-binding characteristics of tolterodine and the active metabolite, the sum of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite is similar in extensive and poor metabolizers at steady state. The net antimuscarinic activity is expected to be similar in both extensive and poor metabolizers. The 5-hydroxymethyl metabolite is further metabolized to 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites. Approximately 77% of an administered dose is excreted in the urine and 17% in feces, primarily as metabolites.

The elimination half-life of immediate-release tolterodine after multiple dosing ranges from 2-4 hours in extensive metabolizers to 9.6 hours in poor metabolizers. The half life of the extended-release product ranges from 6.9 hours in extensive metabolizers to 18 hours in poor metabolizers.