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.