HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus-Based In Vivo Prediction in Humans: Part I.

Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (van't Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δd = 17.88, δp = 4.0, and δh = 8.8 of PEG400) and comparable to the drug (δd = 17.6, δp = 2.4, and δh = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (xe = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δp and δh interacting forces. The activity coefficient (ϒi) was found to be increased with temperature. The higher values of r2 (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated "xe" data for crystalline TOTA and the explored models (modified Apelblat and van't Hoff models). TOTA solubility in "PEG400 + water mixture" was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.

Genotype-based enrichment study design for minimizing the sample size in bioequivalence studies using tolterodine and CYP2D6 genotype
.

OBJECTIVE: The objective of this study was to explore a pharmacogenomic information-based enrichment study design for reducing the sample size in bioequivalence (BE) studies using tolterodine and CYP2D6 genotypes. MATERIALS AND METHODS: A BE study of tolterodine was performed in a randomized, open-label, 2×2 cross-over design. A two one-sided test (TOST) was executed for pharmacokinetic (PK) parameters of tolterodine, and their geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were estimated. The coefficient of variation (CV) was calculated for each cytochrome P450 (CYP) 2D6 genotype group, and the sample size required to meet the power of an equivalence test was estimated, based on TOST in genotype stratified groups as well as in a conventional group. Replicated simulation datasets of PK parameters for each genotype group were generated using bootstrap resampling technique. RESULTS: The CVs of PK parameters in the conventional dataset were much greater than those in the genotype-based stratified groups. While up to 70 subjects were required for statistical power based on the CV of the area under the concentration-time curve (AUCt) observed in the conventional dataset, only 26 - 44 subjects in extensive metabolizers (EMs) and poor metabolizers (PMs), respectively, were required for the CYP2D6 genotype groups. The 90% CIs for GMR in all simulated datasets appeared to meet the BE criterion (0.8 - 1.25). CONCLUSION: This exploration demonstrated that a drug-metabolizing enzyme genotype-based enrichment strategy can be implemented to minimize the sample size in BE studies of drugs that have high PK variability due to polymorphic metabolizing enzyme(s).

Virtual Thorough QT (TQT) Trial-Extrapolation of In Vitro Cardiac Safety Data to In Vivo Situation Using Multi-Scale Physiologically Based Ventricular Cell-wall Model Exemplified with Tolterodine and Fesoterodine.

QT interval prolongation typically assessed with dedicated clinical trials called thorough QT/QTc (TQT) studies is used as surrogate to identify the proarrhythmic risk of drugs albeit with criticism in terms of cost-effectiveness in establishing the actual risk of torsade de pointes (TdP). Quantitative systems toxicology and safety (QSTS) models have potential to quantitatively translate the in vitro cardiac safety data to clinical level including simulation of TQT trials. Virtual TQT simulations have been exemplified with use of two related drugs tolterodine and fesoterodine. The impact of bio-relevant concentration in plasma versus estimated heart tissue exposure on predictions was also assessed. Tolterodine and its therapeutically equipotent metabolite formed via CYP2D6 pathway, 5-HMT, inhibit multiple cardiac ion currents (IKr, INa, ICaL). The QSTS model was able to accurately simulate the QT prolongation at therapeutic and supra-therapeutic dose levels of tolterodine well within 95% confidence interval limits of observed data. The model was able to predict the QT prolongation difference between CYP2D6 extensive and poor metaboliser subject groups at both dose levels thus confirming the ability of the model to account for electrophysiologically active metabolite. The QSTS model was able to simulate the negligible QT prolongation observed with fesoterodine establishing that the 5-HMT does not prolong QT interval even though it is a blocker of hERG channel. With examples of TOL and FESO, we demonstrated the utility of the QSTS approaches to simulate virtual TQT trials, which in turn could complement and reduce the clinical studies or help optimise clinical trial designs.

Plasma concentration profile of tolterodine and 5-hydroxymethyl tolterodine following transdermal administration of tolterodine in rats.

In this study, the plasma concentration profiles of tolterodine and its active metabolite, 5-hydroxymethyl tolterodine (5-HM tolterodine) were investigated in rats with tolterodine transdermal patches using liquid chromatography-tandem mass spectrometry. The plasma samples were extracted by a liquid-liquid extraction method, with an n-hexane/isopropyl alcohol mixture (9:1, v/v). Tiropramide was used as an internal standard (IS). Chromatographic separation was achieved using a C18 column (2.0 mm × 150 mm, 5 µm), with a mobile phase consisting of 5 mM ammonium acetate in distilled water/acetonitrile (50:50, v/v). The precursor-product ion pairs used for multiple reaction monitoring were m/z 326 → 284 (tolterodine), m/z 342 → 223 (5-HM tolterodine), and m/z 468 → 367 (IS). Subsequently, the plasma concentration levels of tolterodine and 5-HM tolterodine were measured in rat plasma after oral or transdermal administration of tolterodine and the pharmacokinetic parameters were calculated. The Cmax of the patch was less than that of the oral administration but their AUC values were comparable. The resulting data suggested that a transdermal dose of tolterodine 3 times higher (9 mg/12 cm2) could yield comparable efficacy to a 10 mg/kg oral dose in rats. These results would provide useful information on dose optimization of tolterodine transdermal patch for further clinical studies.

Simultaneous determination of tolterodine and its two metabolites, 5-hydroxymethyltolterodine and N-dealkyltolterodine in human plasma using LC-MS/MS and its application to a pharmacokinetic study.

Tolterodine is a nonselective muscarinic antagonist that is indicated for the overactive urinary bladder and other urinary difficulties. We developed and validated a simple, rapid and sensitive high-performance liquid chromatography analytical method utilizing tandem mass spectrometry (LC-MS/MS) for the quantitation of tolterodine and its major metabolites, 5-hydroxymethyltolterodine (5-HMT) and N-dealkyltolterodine (NDT), in human plasma. After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of the three analytes was achieved using a reversed-phase Luna Phenyl-hexyl column (100 × 2.0 mm, 3 µm particles) with a mobile phase of 10 mM ammonium formate buffer (pH 3.5)-methanol (10:90, v/v) and quantified by MS/MS detection in electrospray ionization (ESI) positive ion mode. The retention time of tolterodine, 5-HMT, NDT, and internal standard (IS) were 1.4, 1.24, 1.33, and 1.26 min, respectively. The calibration curves were linear over a range of 0.025-10 ng/ml for tolterodine and 5-HMT, and 0.05-10 ng/ml for NDT. The lower limit of quantifications using 200 µl of human plasma was 0.025 ng/ml for tolterodine and 5-HMT, and 0.05 ng/ml for NDT. The mean accuracy and precision for intra- and inter-run validation of tolterodine, 5-HMT, and NDT were all within acceptable limits. These results showed that a simple, rapid and sensitive LC-MS/MS method for the quantification of tolterodine and its major metabolites in human plasma was developed. This method was successfully applied to a pharmacokinetic study in humans.

Tolterodine Tartrate.

Tolterodine tartrate belongs to the family of muscarinic receptor antagonists and is indicated for the treatment of overactive urinary bladder syndrome. This chapter provides an overview of physical, analytical, and ADME profiles; highlights methods of chemical synthesis; and discusses stability of tolterodine as a free base and/or its l-tartrate salt in solution and in the solid state. The information presented in this chapter is based on the peer-reviewed literature, compendial reports (USP, EP), and authors' data. Patent literature is included only in a few instances.

Pharmacokinetic drug interaction study between overactive bladder drugs mirabegron and tolterodine in Japanese healthy postmenopausal females.

Mirabegron, the first selective ß3-adrenoceptor agonist for the treatment of overactive bladder (OAB), inhibits cytochrome P450 isozyme CYP2D6. This study was performed in Japanese healthy postmenopausal female volunteers to assess any pharmacokinetic drug interaction between mirabegron and tolterodine, another OAB drug and a sensitive substrate of CYP2D6. Tolterodine 4 mg was orally administered from Days 1-7 and co-administered with mirabegron 50 mg from Days 8-14. Mirabegron 50 mg increased maximum concentration (Cmax) and area under the concentration-time curve from zero to 24 h after dosing (AUC24h) of tolterodine by 2.06-fold (90% confidence interval [CI] 1.81, 2.34) and 1.86-fold (90% CI 1.60, 2.16), respectively, and increased Cmax and AUC24h of the metabolite 5-hydroxymethyl tolterodine by 1.36-fold (90% CI 1.26, 1.47) and 1.25-fold (90% CI 1.15, 1.37), respectively. This suggested a weak pharmacokinetic drug interaction between mirabegron and tolterodine. Mean change from baseline of Fridericia's QT correction formula (ΔQTcF) was slightly higher on Day 14 than on Day 7. No subject had QTcF >480 msec or ΔQTcF >60 msec. All the treatment-emergent adverse events were mild. Mirabegron 50 mg was considered to be safe and well tolerated when coadministered with tolterodine 4 mg in healthy postmenopausal female volunteers.

Saliva versus Plasma Relative Bioavailability of Tolterodine in Humans: Validation of Class III Drugs of the Salivary Excretion Classification System.

Relative bioavailability study of tolterodine in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioavailability and bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected up to 16 h after 2 mg oral dose. Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis using Kinetica program V5. Human effective intestinal permeability was optimized by SimCYP program V13. Tolterodine falls into class III (High permeability/Low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A high pearsons correlation coefficient of 0.97 between mean saliva and plasma concentrations, and saliva/plasma concentrations ratio of 0.33 were observed. In addition, correlation coefficients and saliva/plasma ratios of area under curve and maximum concentration were 0.98, 0.95 and 0.42, 0.34 respectively. On the other hand, time to reach maximum concentration was higher in saliva by 2.37 fold. In addition, inter subject variability values in saliva were slightly higher than plasma leading to need for slightly higher number of subjects to be used in saliva studies (55 vs. 48 subjects). Non-invasive saliva sampling instead of invasive plasma sampling method can be used as a surrogate for bioavailability and bioequivalence of SECS class I drugs when adequate sample size is used.