Detrol
Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice.

Pahlman I, d'Argy R, Nilvebrant L.

Department of Drug Metabolism Research, Pharmacia AB, Stockholm, Sweden. ingrid.pahlman astrazeneca.com

Tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5) is an antimuscarinic agent developed specifically for the treatment of the overactive bladder. In this study, the extent and profile of tissue distribution of 14C-tolterodine, after single and repeat oral dosing, was investigated in the mouse. Overall, distribution of radioactivity in tissues was rapid, and there were no gender-specific differences. The concentration of radioactivity in most tissues was similar to, or exceeded, that in blood. Highest concentrations were measured in gall bladder, urinary bladder, liver, kidneys and lungs, while the lowest concentration (10-times lower than in plasma) was seen in the brain. The distribution pattern after repeat oral dosing was similar to that after a single dose, although the decline in tissue concentrations was slower. Studies in pregnant mice showed that the distribution of radioactivity differed between dams and fetuses. Radioactivity was low and showed homogeneous distribution in the fetus, while a heterogeneous pattern was seen in the dam. Highest concentrations were seen in the fetal liver, brain and spinal cord. Some accumulation was observed in the choroid plexus. Placental concentrations of radioactivity were generally higher than those in the fetus, with some accumulation in the yolk sac. Studies in suckling mouse pups showed low levels of exposure to drug-related radioactivity (around 0.2% of the dose); the milk:plasma concentration ratio was 0.0-0.7. In conclusion, tolterodine and its metabolites are rapidly distributed into tissues following oral administration of radiolabelled drug in the mouse, with many tissues (including the fetus) reaching similar concentrations to that observed in blood. In other tissues, especially the eliminating organs, radioactivity levels were much higher than in blood. Penetration of the central nervous system was low, suggesting that the risk of deleterious effects on cognitive function may be lower with tolterodine than with more lipophilic antimuscarinic drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11258042&dopt=Abstract tolterodine Detrol



Detrol
Pharmacokinetics of tolterodine, a muscarinic receptor antagonist, in mouse, rat and dog. Interspecies relationship comparing with human pharmacokinetics.

Pahlman I, Kankaanranta S, Palmer L.

Department of Drug Metabolism Research, Pharmacia AB, Stockholm, Sweden. ingrid.pahlman astrazeneca.com

Tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5) is an antimuscarinic agent developed specifically for the treatment of the overactive bladder. In this study, the pharmacokinetics of tolterodine were investigated in the mouse, rat and dog, following which allometric scaling was performed to predict oral pharmacokinetics in man. The intestinal absorption of tolterodine after oral dosing was almost complete in all three species, with peak serum concentrations observed within 1 hour post-dose. Bioavailability varied between 2-20% in rodents and 58-63% in the dog. A high volume of distribution in all three species was consistent with extravascular distribution. Tolterodine was extensively metabolised in all the animal models, but the profile of metabolism differed in the rat compared to the mouse and dog, the latter having similar metabolism routes as man. Limitation of metabolism capacity caused a non-linear increase of tolterodine concentrations with dose (repeat-dose study in the mouse), and changed the relative metabolite concentration pattern. The results suggest that the hydroxylation of tolterodine is a high affinity, low capacity pathway, while N-dealkylation follows a low affinity, high capacity pathway. The elimination of tolterodine from serum was rapid, with a half-life of less than 2 h in all species. A very high clearance in the mouse and rat (10-15 l/h.kg), and in the dog (1.4 l/h.kg), indicated additional non-metabolic clearance mechanisms for tolterodine (shown to be attributed to biliary excretion). Urinary excretion of compound-related radioactive substance was around 15%, 45% and 50%, respectively, in the rat, mouse and dog. Allometric scaling allowed a good prediction of clearance and volume of distribution to be extrapolated for comparison with tolterodine pharmacokinetics in man. In conclusion, the pharmacokinetics of tolterodine are similar in the mouse and dog, and correlate with that in man. Although the rat has a different metabolic profile, clearance fits into the allometric relationship between species, enabling prediction of total clearance of tolterodine in man from preclinical data.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11258043&dopt=Abstract tolterodine Detrol



Detrol
Safety profile of tolterodine as used in general practice in England: results of prescription-event monitoring.

Layton D, Pearce GL, Shakir SA.

Drug Safety Research Unit, Southampton, England.

BACKGROUND: Unstable bladder symptoms are a common problem in general practice. Drug therapy with anticholinergic drugs is frequently used in the management of this condition. However such drugs are associated with a high incidence of anticholinergic adverse effects. Tolterodine is a competitive anticholinergic agent, selective for the bladder as opposed to the salivary glands. OBJECTIVE: To monitor the safety of tolterodine as used in general practice patients in England for the treatment of urinary frequency, urgency and incontinence. DESIGN: Prospective observational cohort study. Patients and participants: 14,526 patients [mean age 62.7 (SD 16.4) years; 68.6% female]. METHODS: Patients prescribed tolterodine in general practice, soon after the release of the drug in the UK, were followed up for a minimum of 6 months using the technique of prescription-event monitoring (PEM). RESULTS: The most common adverse events reported were dry mouth, headache, malaise, constipation, dyspepsia, nausea and vomiting and pain in abdomen. We identified some uncommon events as possible adverse drug reactions--notably hallucinations, tachycardia and palpitations. The prevalence of these events was compared with that in patient cohorts for other drugs on the PEM database. The age- and sex-adjusted relative risk of hallucinations on tolterodine compared with 10 drugs of other therapeutic classes, and with terodiline, another drug indicated for bladder instability, was 4.85 [95% confidence interval (CI) 2.72 to 8.66] and 1.25 (95% CI 0.62 to 2.53), respectively. There was no significant difference for tachycardia/palpitation in this comparison. CONCLUSIONS: Tolterodine is well tolerated in general practice at the recommended daily dose. Hallucinations, tachycardia and palpitations are infrequently associated with the drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11522122&dopt=Abstract tolterodine Detrol



Detrol
Cost-Effectiveness of tolterodine for patients with urge incontinence who discontinue initial therapy with oxybutynin: a Canadian perspective.

O'Brien BJ, Goeree R, Bernard L, Rosner A, Williamson T.

Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. obrienb mcmaster.ca

BACKGROUND: Tolterodine is a novel muscarinic receptor antagonist for the treatment of overactive bladder. OBJECTIVE: The purpose of this study was to examine the cost-effectiveness of tolterodine for patients with urge incontinence (UI) who discontinue initial therapy with oxybutynin in a Canadian setting. METHODS: We compared 2 treatment strategies for the management of adult patients with UI: (1) generic oxybutynin with no further treatment for patients who discontinue and (2) generic oxybutynin with switch to tolterodine (2 mg BID) for patients who discontinue. We developed a 1-year Markov model (4-week cycle length) with transitions between disease states of normal, mild, moderate, and severe. Transition probabilities over 12 weeks were obtained from randomized trial data, and drug discontinuation rates were obtained from Quebec prescription claims data. Outcome measures were time in "normal" health state and quality-adjusted life-years (QALYs) using EuroQol-5D utility scores from a survey of Swedish patients with overactive bladder. Costs to the health care payer and patient out-of-pocket costs (in Canadian dollars) were included. RESULTS: For patients who discontinue oxybutynin, the use of tolterodine is associated with approximately 6 months per year in a normal health or mild disease state, compared with approximately 3 months for those who do not receive further drug therapy after discontinuation. Tolterodine use resulted in an annual additional cost per patient of Can $163. The incremental cost per QALY was Can $9,982 and appeared to be robust to alternative model parameter assumptions. CONCLUSION: Use of tolterodine in patients with UI who discontinue initial therapy with generic oxybutynin lies within currently accepted benchmarks for cost-effectiveness.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11813937&dopt=Abstract tolterodine Detrol