pnu-200577 and fesoterodine

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.

Topics: Benzhydryl Compounds; Cresols; Drug Design; Muscarinic Antagonists; Phenylpropanolamine; Prodrugs; Tolterodine Tartrate

This analysis was conducted to investigate factors that affect 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics after administration of fesoterodine sustained release tablets to Westerners and East Asians. Ten pharmacokinetic studies and three efficacy/safety studies in overactive bladder (OAB) patients were pooled for the population pharmacokinetic analysis. The plasma 5-HMT concentration data were described by a 1-compartment model with first order absorption and a lag time. Creatinine clearance (CLCR), hepatic impairment, CYP2D6 genotype, and concomitant medication with CYP3A inhibitor/inducer were identified as influential covariates. It was estimated that decreasing of CLCR from 80 to 15 mL/min resulted in a 39.5% reduction in 5-HMT apparent oral clearance (CL/F). Hepatic impairment, CYP2D6 poor metabolizer, and CYP3A inhibitor were estimated to reduce CL/F by about 60%, 40%, and 50%, respectively. CYP3A inducer resulted in about fourfold increase in CL/F. Although sex and Japanese ethnicity were selected as covariates on CL/F, each resulted in only about 10% decrease and increase of CL/F, respectively. Of the influential covariates of 5-HMT CL/F, CLCR, hepatic impairment, CYP2D6 genotype, and concomitant medication with CYP3A inhibitor/inducer were of significance, whereas sex and Japanese ethnicity covariates were considered not to have clinically significant impact on exposures of 5-HMT.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Benzhydryl Compounds; Creatinine; Cresols; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Delayed-Action Preparations; Female; Genotype; Humans; Ketoconazole; Liver Diseases; Male; Middle Aged; Models, Biological; Muscarinic Antagonists; Rifampin; Tablets; Urinary Bladder, Overactive; Urological Agents; White People; Young Adult

Fesoterodine is a non-selective muscarinic-receptor antagonist, used in the treatment of overactive bladder syndrome. A highly sensitive, selective and rapid method has been developed for the simultaneous determination of fesoterodine and its active metabolite, 5-hydroxymethyl tolterodine (5-HMT) in human plasma by liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS). Due to rapid conversion of parent drug to 5-HMT, ex vivo stability of fesoterodine in human plasma was extensively studied to optimize the extraction protocol. The analytes and their deuterated analogs were quantitatively extracted from 100μL human plasma by liquid-liquid extraction in methyl tert-butyl ether: n-hexane. The chromatographic separation of analytes was achieved on a Kromasil C18 (100mm×4.6mm, 5μm) column under isocratic conditions. The method was validated over a dynamic concentration range of 0.01-10ng/mL for both the analytes. Ion-suppression effects were investigated by post-column infusion of analytes. The precision (% CV) values for the calculated slopes of calibration curves, which would reflect the relative matrix effect, were less than 1.5% for both the analytes. The intra-batch and inter-batch precision (% CV) across quality control levels varied from 1.82 to 3.73% and the mean extraction recovery was >96% for both the analytes. The method was successfully applied to a bioequivalence study of 8mg fesoterodine tablet formulation (test and reference) in 12 healthy Indian subjects under fasted and fed condition. The assay reproducibility estimated by reanalysis of incurred samples showed a change of ±12.0%.

Topics: Adult; Benzhydryl Compounds; Chromatography, Liquid; Cresols; Cross-Over Studies; Drug Stability; Humans; Linear Models; Male; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry; Therapeutic Equivalency

Fesoterodine, a new antimuscarinic for the treatment of overactive bladder, is rapidly and extensively hydrolyzed by nonspecific esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The elimination of 5-HMT involves metabolism and renal excretion. The plasma and urinary pharmacokinetics of 5-HMT and its inactive carboxy (SPM 5509), N-desisopropyl (SPM 7789), and carboxy-N-desisopropyl (SPM 7790) metabolites were investigated after a single oral dose of 8 mg of fesoterodine in 8 male subjects with moderate hepatic cirrhosis (Child-Turcotte-Pugh class B) and 8 matched healthy controls. The estimated mean ratios (95% confidence interval) of the area under the curve extrapolated to infinity after dosing (AUC(0-∞)), cumulative urinary excretion up to 48 hours after dosing (Ae(0-48)), maximum observed concentration (C(max)), and apparent terminal disposition half-life (t(1/2)) of 5-HMT for cirrhotic and healthy subjects were 2.2 (1.5-3.1), 2.5 (1.7-3.8), 1.4 (1.0-1.9), and 1.1 (0.8-1.3), respectively. In subjects with hepatic cirrhosis, AUC(0-∞) and Ae(0-48) of 5-HMT increased approximately 2-fold; the increase in C(max) was smaller, and t(1/2) was unaffected. AUC and C(max) of the inactive carboxy metabolites, SPM 5509 and SPM 7790, were reduced reciprocally by about 50%, whereas exposure to the dealkylated metabolite, SPM 7789, increased about 2-fold. Fesoterodine 8 mg was equally well tolerated in both groups. The results indicate that moderate hepatic cirrhosis reduces 5-HMT clearance, with an apparent effect on the carboxylation pathway and not on dealkylation.

Topics: Adolescent; Adult; Aged; Benzhydryl Compounds; Biotransformation; Cresols; Half-Life; Hepatic Insufficiency; Humans; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; Muscarinic Antagonists; Prodrugs; Severity of Illness Index; Urinary Bladder, Overactive; Young Adult

Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. The formation of 5-HMT from tolterodine occurs via CYP2D6, and some subjects are poor metabolizers CYP2D6. On the other hand, the formation of 5-HMT from fesoterodine occurs via ubiquitous esterases. Cross-study comparisons of data from phase 1 studies suggest that active moiety exposures are considerably more variable following tolterodine extended release vs. fesoterodine.. This head-to-head study confirmed the findings of reduced pharmacokinetic variability of fesoterodine and further delineates that tolterodine, and not 5-HMT, was the principal source of variability after administration of tolterodine extended release. The data suggest that fesoterodine delivers 5-HMT consistently, regardless of CYP2D6 status, with up to 40% higher bioavailability compared with tolterodine.. Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. Formation of 5-HMT from fesoterodine and tolterodine occurs via esterases and CYP2D6 respectively. This randomized, crossover, open-label, multiple-dose study in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) compared the pharmacokinetics of fesoterodine vs. tolterodine extended release (ER).. Subjects received fesoterodine and tolterodine ER with a ≥3-day washout period. Treatment comprised 4-mg once daily doses for 5 days escalated to 8-mg once daily for 5 days. Pharmacokinetics of active moieties were compared by drug, dose and genotype.. Active moiety exposures following fesoterodine and tolterodine ER increased proportional to dose in EMs and PMs. In EMs only, coefficients of variation for AUC and C(max) following fesoterodine (up to 46% and 48% respectively) were lower than those following tolterodine ER (up to 87% and 87% respectively). Following fesoterodine and tolterodine ER administration, active moiety exposures ranged up to sevenfold and 40-fold respectively. Mean urinary excretion of 5-HMT following fesoterodine 4 and 8 mg, respectively, was 0.44 and 0.89 mg in EMs and 0.60 and 1.32 mg in PMs. Following tolterodine ER 4 and 8 mg, it was 0.38 and 0.71 mg respectively (EMs only). Renal clearance was similar regardless of administered drug, dose or genotype.. Tolterodine, not 5-HMT, was the principal source of variability after tolterodine ER administration. Fesoterodine delivers 5-HMT with less variability than tolterodine, regardless of CYP2D6 status, with up to 40% higher bioavailability. The pharmacokinetics of fesoterodine were considerably less variable than TER.

Topics: Administration, Oral; Adult; Area Under Curve; Benzhydryl Compounds; Biological Availability; Cresols; Cross-Over Studies; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Double-Blind Method; Female; Genotype; Humans; Male; Middle Aged; Muscarinic Antagonists; Phenylpropanolamine; Tolterodine Tartrate

Diurnal variation can affect drug pharmacokinetics. Fesoterodine is a new antimuscarinic drug for the treatment of overactive bladder (OAB). We estimated the relative bioavailability of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine, following nighttime and daytime administration.. In this randomized, open-label, two-period, two-treatment crossover, single-dose study, healthy subjects received daytime and nighttime oral dosing of fesoterodine 8-mg sustained-release tablets, separated by a minimum 60-h washout period. Blood samples for 5-HMT PK determination were collected before dosing and at specified intervals up to 48 h postdose. Safety was assessed by adverse event (AE) reports.. Fourteen subjects completed the study. Plasma concentration versus time profiles (AUC) of 5-HMT were similar for daytime and nighttime dosing. Mean AUC(infinity) 5-HMT values were 47.9 and 51.4 ng h/mL for nighttime and daytime dosing, respectively; the mean time to reach maximum concentration (C(max)) values were 3.9 and 5.0 ng/mL, respectively. Nighttime versus daytime AUC(infinity) and C(max) ratios of 5-HMT were 93 and 79%, respectively; 90% confidence intervals (CIs) indicated equivalence for AUC(infinity) but not for C(max). The median time to reach maximum concentration (T(max)) was 5.0 h for both dosing regimens, and the mean terminal elimination half-life (T((1/2))) was 5.9 and 5.7 h for nighttime and daytime dosing, respectively. Seven treatment-related AEs, most commonly headache, occurred in five subjects.. The AUC values for daytime and nighttime administration of fesoterodine were equivalent. The 21% reduction in the C(max) for nighttime dosing is unlikely to be clinically relevant. No safety issues were apparent. These results support both daytime and nighttime administration of fesoterodine for OAB treatment.

Topics: Adolescent; Adult; Benzhydryl Compounds; Biological Availability; Body Mass Index; Cresols; Cross-Over Studies; Cytochrome P-450 CYP2D6; Delayed-Action Preparations; Drug Chronotherapy; Female; Genotype; Half-Life; Headache; Humans; Male; Middle Aged; Muscarinic Antagonists; Statistics as Topic; Young Adult

Fesoterodine is a new antimuscarinic agent for the treatment of overactive bladder. Following oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active moiety: 5-hydroxymethyl tolterodine (5-HMT). The cytochrome P450 (CYP) enzymes are not involved in the formation of 5-HMT; however, CYP2D6 and CYP3A4 provide 2 alternative pathways for further metabolism and inactivation of 5-HMT.. Single oral doses of 4 mg, 8 mg or 12 mg of fesoterodine sustained-release tablets in the fasted state and 8 mg in a fed state.. This single-center, open-label, randomized, crossover study investigated the effects of fesoterodine in healthy volunteers comprised of CYP2D6 extensive metabolizers (EMs; n = 16) and CYP2D6 poor metabolizers (PMs; n = 8) after either an overnight fast or a high-fat and high-calorie breakfast. Adverse events, vital signs, ECG recordings and laboratory tests were monitored for safety assessment.. For the principal active moiety, 5-HMT, the maximum plasma concentration (Cmax), area under the concentration-time curve from time zero to time of last measurable concentration (AUC0-t) and amount excreted in urine (Ae) increased proportionally with dose in both EM and PM subjects. The mean Cmax and AUC0-t in PMs were approximately twice those observed in EMs. CYP2D6 status had no effect on time to reach Cmax (5 h), renal clearance (approximately 250 ml/min), or half-life (approximately 8 h). Fesoterodine was well tolerated at all doses. While the incidence of dry mouth increased from 8 - 12 mg, all occurrences were mild-to-moderate.. Fesoterodine demonstrated a pharmacokinetic (PK) profile that was favorable for once-daily dosing. The systemic exposure to 5-HMT increased proportionally with dose and was about 2-fold higher in PMs compared with EMs. There was no clinically relevant effect of food on the PK of fesoterodine. Fesoterodine was well tolerated at all dose levels studied.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Benzhydryl Compounds; Cresols; Cross-Over Studies; Cytochrome P-450 CYP2D6; Fasting; Half-Life; Humans; Linear Models; Male; Metabolic Clearance Rate; Middle Aged; Young Adult

To examine the effect of combining a nonselective muscarinic receptor antagonist, 5-hydroxymethyl tolterodine (an active metabolite of fesoterodine), with a β3 adrenoceptor agonist, mirabegron, in a rat model of pelvic congestion.. The rat pelvic congestion model used female Sprague-Dawley rats with their bilateral common iliac and uterine veins ligated. Expressions of M2 and M3 receptor subtypes in the urothelium and detrusor were detected by real-time polymerase chain reaction assays. The effects of both drugs were investigated on isolated bladder strips contracted by electrical field stimulation. in vivo single cystometry was used to assess the effects of 5-hydroxymethyl tolterodine and mirabegron independently or in combination on bladder capacity, micturition pressure, and threshold pressure.. Pelvic congestion rats showed decreased bladder capacity compared with controls, but micturition pressure and threshold pressure were unchanged. Pelvic congestion model rats also demonstrated an approximately two-fold increase in expression of both M2 and M3 receptor subtypes in the urothelium. Additive relaxant effects of 5-hydroxymethyl tolterodine and mirabegron were observed in vitro in the electrical field stimulation-induced contractions of bladder strips from pelvic congestion rats. In vivo, bladder capacity was increased significantly by a combination of 5-hydroxymethyl tolterodine and mirabegron, with the combined effect exceeding the sum of the effects of monotherapies. Micturition pressure and threshold pressure did not significantly differ between groups.. The combination of 5-hydroxymethyl tolterodine with mirabegron suggests the potential of synergistic effects in a rat pelvic congestion model.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Benzhydryl Compounds; Cresols; Disease Models, Animal; Drug Monitoring; Drug Therapy, Combination; Female; Muscarinic Antagonists; Rats; Rats, Sprague-Dawley; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive

5-Hydroxymethyl tolterodine (5-HMT; the active fesoterodine metabolite) is metabolized via the cytochrome P450 (CYP) 2D6 and CYP3A pathways. Mirabegron is a moderate CYP2D6 inhibitor and weak CYP3A inhibitor. Potential drug-drug interactions (DDIs) following coadministration of these 2 overactive bladder treatments were estimated using physiologically based pharmacokinetic models, developed and verified by comparing predicted and observed pharmacokinetic profiles from clinical studies. Models predicted and verified mirabegron and desipramine (CYP2D6 substrate) and 5-HMT and ketoconazole (strong CYP3A inhibitor) DDIs. Mirabegron model-predicted mean steady-state AUC and C

Topics: Acetanilides; Adult; Benzhydryl Compounds; Cresols; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Humans; Ketoconazole; Male; Middle Aged; Rifampin; Thiazoles; Urinary Bladder, Overactive

The present study aimed to characterize muscarinic receptor binding of fesoterodine, 5-hydroxymethyl tolterodine (5-HMT), and tolterodine in bladder and other tissues of rats after their oral, intravenous, or intravesical administration. Muscarinic receptors in tissues were measured by using [N-methyl-

Topics: Administration, Intravenous; Administration, Intravesical; Administration, Oral; Animals; Benzhydryl Compounds; Cresols; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Organ Specificity; Protein Binding; Rats, Sprague-Dawley; Receptors, Muscarinic; Tissue Distribution; Tolterodine Tartrate; Urinary Bladder; Urinary Bladder, Overactive

To comparatively characterize the binding activity of fesoterodine, its active metabolite (5-hydroxymethyl tolterodine [5-HMT]), and tolterodine in the human bladder mucosa, detrusor muscle, and parotid gland.. Muscarinic receptors in the homogenates of human bladder mucosa, detrusor muscle, and parotid gland were measured by a radioligand binding assay using [N-methyl-(3)H] scopolamine methyl chloride.. Fesoterodine, 5-HMT, and tolterodine competed with [N-methyl-(3)H] scopolamine methyl chloride for binding sites in the bladder mucosa, detrusor muscle, and parotid gland in a concentration-dependent manner. The affinity for muscarinic receptors of these agents was significantly greater in the bladder than in the parotid gland, suggesting pharmacologic selectivity for the bladder over the parotid gland. The bladder selectivity was larger for fesoterodine and 5-HMT than for tolterodine. Fesoterodine, 5-HMT, and tolterodine resulted in significantly increased (two- to five-fold) values of the apparent dissociation constant for specific [N-methyl-(3)H] scopolamine methyl chloride binding in the detrusor muscle and parotid gland, with little effect on the corresponding values of the maximal number of binding sites. This finding indicates that these agents bind to the human muscarinic receptors in a competitive and reversible manner.. Fesoterodine and 5-HMT bind to the muscarinic receptors with greater affinity in the human bladder mucosa and detrusor muscle than in the parotid gland in a competitive and reversible manner.

Topics: Adult; Aged; Benzhydryl Compounds; Cresols; Female; Humans; Male; Middle Aged; Mucous Membrane; Muscarinic Antagonists; Muscle, Smooth; Parotid Gland; Phenylpropanolamine; Receptors, Muscarinic; Tolterodine Tartrate; Urinary Bladder

The combination of muscarinic receptor and alpha(1)-adrenoceptor antagonists is increasingly used for benign prostatic hyperplasia related lower urinary tract symptoms. In addition to the well established peripheral site of action, little is known about the central effects of muscarinic receptor antagonists and muscarinic receptor/alpha(1)-adrenoceptor antagonist combinations on bladder function, partly due to poor brain penetration after systemic administration. We assessed the effects of intrathecal 5-hydroxymethyl tolterodine, an active metabolite of fesoterodine, in obstructed and nonobstructed rats, and of combined intrathecal 5-hydroxymethyl tolterodine/doxazosin in a rat model of partial urethral obstruction.. We used 80 male Sprague-Dawley rats to test various doses of intrathecal 5-hydroxymethyl tolterodine and/or intrathecal doxazosin on urodynamic parameters. Urodynamic evaluation without anesthesia was done 3 days after bladder and intrathecal catheterization. Two weeks before urodynamics 40 rats underwent partial urethral obstruction.. Intrathecal 5-hydroxymethyl tolterodine had no urodynamic effects in nonobstructed rats. Compared to controls obstructed rats had increased bladder pressure and weight, and voiding frequency. In obstructed rats 5-hydroxymethyl tolterodine restored urodynamic parameters to those seen in nonobstructed animals. Doxazosin had effects similar to those of intrathecal 5-hydroxymethyl tolterodine. When the 2 drugs were combined, at the doses used only small additional effects were observed.. Urodynamic changes in obstructed rats can be normalized by intrathecal 5-hydroxymethyl tolterodine and by intrathecal doxazosin. The central pathways on which the 2 drugs act seem to be up-regulated with partial urethral obstruction and less relevant under normal conditions.

Topics: Adrenergic alpha-Antagonists; Animals; Benzhydryl Compounds; Cresols; Doxazosin; Drug Therapy, Combination; Male; Rats; Rats, Sprague-Dawley; Spinal Cord; Urethral Obstruction