Abstract
This review highlights the design and development of fesoterodine (Toviaz®) as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine, for the treatment of overactive bladder (OAB). Tolterodine and 5-HMT are both potent antimuscarinic agents. A prodrug approach was necessary for systemic bioavailability of 5-HMT after oral administration. Fesoterodine was selected amongst a series of ester analogues of 5-HMT to develop an advanced OAB treatment with an optimum biopharmaceutics profile, while maintaining a pharmacological link to tolterodine. While tolterodine and 5-HMT have similar antimuscarinic activity, the logD value, a determinant of lipophilicity and permeability across biological interfaces such as the gut wall and blood-brain barrier, is considerably lower for 5-HMT (0.74) versus tolterodine (1.83). In contrast to the cytochrome P450 (CYP) 2D6-mediated metabolism of tolterodine, 5- HMT formation from fesoterodine occurs via ubiquitous nonspecific esterases. Consequently, treatment with fesoterodine results in consistent, genotype-independent exposure to a singular active moiety (5-HMT); treatment with tolterodine results in CYP2D6 genotype-dependent exposure to varying proportions of two active moieties (5-HMT and tolterodine). At least partially due to the avoidance of variations in pharmacokinetic exposures observed with tolterodine, it was possible to develop fesoterodine with the flexibility of two efficacious and well-tolerated dosage regimens of 4 and 8 mg daily.
Keywords: Fesoterodine, prodrug, 5-HMT, tolterodine, metabolite, lipophilicity, CNS
Current Medicinal Chemistry
Title: The Design and Development of Fesoterodine as a Prodrug of 5- Hydroxymethyl Tolterodine (5-HMT), the Active Metabolite of Tolterodine
Volume: 16 Issue: 33
Author(s): B. Malhotra, K. Gandelman, R. Sachse, N. Wood and M. C. Michel
Affiliation:
Keywords: Fesoterodine, prodrug, 5-HMT, tolterodine, metabolite, lipophilicity, CNS
Abstract: This review highlights the design and development of fesoterodine (Toviaz®) as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), which is also the active metabolite of tolterodine, for the treatment of overactive bladder (OAB). Tolterodine and 5-HMT are both potent antimuscarinic agents. A prodrug approach was necessary for systemic bioavailability of 5-HMT after oral administration. Fesoterodine was selected amongst a series of ester analogues of 5-HMT to develop an advanced OAB treatment with an optimum biopharmaceutics profile, while maintaining a pharmacological link to tolterodine. While tolterodine and 5-HMT have similar antimuscarinic activity, the logD value, a determinant of lipophilicity and permeability across biological interfaces such as the gut wall and blood-brain barrier, is considerably lower for 5-HMT (0.74) versus tolterodine (1.83). In contrast to the cytochrome P450 (CYP) 2D6-mediated metabolism of tolterodine, 5- HMT formation from fesoterodine occurs via ubiquitous nonspecific esterases. Consequently, treatment with fesoterodine results in consistent, genotype-independent exposure to a singular active moiety (5-HMT); treatment with tolterodine results in CYP2D6 genotype-dependent exposure to varying proportions of two active moieties (5-HMT and tolterodine). At least partially due to the avoidance of variations in pharmacokinetic exposures observed with tolterodine, it was possible to develop fesoterodine with the flexibility of two efficacious and well-tolerated dosage regimens of 4 and 8 mg daily.
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Cite this article as:
Malhotra B., Gandelman K., Sachse R., Wood N. and Michel C. M., The Design and Development of Fesoterodine as a Prodrug of 5- Hydroxymethyl Tolterodine (5-HMT), the Active Metabolite of Tolterodine, Current Medicinal Chemistry 2009; 16 (33) . https://dx.doi.org/10.2174/092986709789712835
DOI https://dx.doi.org/10.2174/092986709789712835 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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