Abstract | BACKGROUND: OBJECTIVE: This study set out to identify and characterize the influence of a number of intrinsic characteristics on the pharmacokinetics of the anticholinergic agent trospium chloride (Sanctura(®)) 60 mg extended release (XR), and to evaluate the correlation between trospium chloride exposure and key efficacy and safety outcomes in subjects and patients. STUDY DESIGN: Pharmacokinetic data were obtained from three studies in which a total of 349 subjects received trospium chloride XR for up to 12 weeks. Plasma trospium chloride concentration data were pooled and a population pharmacokinetic model was derived using non-linear mixed-effects modelling. Demographic factors were assessed for influence on the model. The correlation between trospium chloride exposure and key efficacy variables was evaluated. Correlations between exposure and safety outcomes were also assessed. INTERVENTION: RESULTS: The best population pharmacokinetic model was determined to be a two-compartment model with zero-order release into the depot compartment and first-order absorption. Body surface area (BSA) was the only covariate to significantly (P < 0.05) impact trospium chloride 60 mg XR pharmacokinetics. Significant relationships (P < 0.05) were observed between exposure [maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve from time zero to 24 h (AUC(24))] and efficacy outcomes in the <65-year age group for change in average number of voids/day, change in number of incontinence episodes, and change in urgency severity, and in the ≥65-year age group statistical significance (P < 0.05) was achieved for C(max), but not for AUC(24), for these same three efficacy measures. Statistically significant relationships (P < 0.004) were also observed between exposure and both dry mouth and constipation, with increased benefit and increased incidence of adverse events (AEs) associated with higher concentrations; the correlation coefficients were low against the aggregate of AEs of interest (0.19 for AUC(24) and 0.18 for C(max)), indicating only mild strength of association. CONCLUSION: This population pharmacokinetic analysis demonstrated that the only demographic characteristic associated with trospium chloride pharmacokinetics was BSA. Thus, treatment of most patients with overactive bladder with once-daily trospium chloride 60 mg XR should not require consideration of key intrinsic demographic parameters. Furthermore, while efficacy and tolerability outcomes were found to be correlated with trospium chloride exposure, the strength of the association was modest in this study.
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Authors | Mark D Harnett, James Shipley, Laura MacLean, Ute Schwiderski, Bobby W Sandage Jr |
Journal | Clinical drug investigation
(Clin Drug Investig)
Vol. 33
Issue 2
Pg. 133-41
(Feb 2013)
ISSN: 1179-1918 [Electronic] New Zealand |
PMID | 23203138
(Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't)
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Chemical References |
- Benzilates
- Delayed-Action Preparations
- Muscarinic Antagonists
- Nortropanes
- trospium chloride
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Topics |
- Adolescent
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Area Under Curve
- Benzilates
(administration & dosage, pharmacokinetics, therapeutic use)
- Body Surface Area
- Case-Control Studies
- Clinical Trials, Phase I as Topic
- Clinical Trials, Phase II as Topic
- Clinical Trials, Phase III as Topic
- Delayed-Action Preparations
- Female
- Humans
- Male
- Middle Aged
- Models, Biological
- Muscarinic Antagonists
(administration & dosage, pharmacokinetics, therapeutic use)
- Nonlinear Dynamics
- Nortropanes
(administration & dosage, pharmacokinetics, therapeutic use)
- Time Factors
- Urinary Bladder, Overactive
(drug therapy)
- Young Adult
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