Population pharmacokinetics and exposure-response relationship of a muscarinic receptor antagonist, imidafenacin.

This study was designed to update the population pharmacokinetic model and investigate the exposure-response (efficacy and safety) and concentration-QT relationships for imidafenacin, a synthetic orally active muscarinic receptor antagonist. The population pharmacokinetic model was updated using data from 90 healthy subjects and 852 patients with an overactive bladder. Plasma concentration data from nine clinical studies were used, including new data from a long-term dose escalation study. The updated population pharmacokinetic model for imidafenacin adequately described the plasma concentration profile. The results were generally consistent with those obtained from the previous population pharmacokinetic analysis, indicating that no new covariates were found to influence the pharmacokinetics of imidafenacin. Exposure-response relationships in the long-term dose escalation study were investigated using a regression analysis with efficacy and safety endpoints as dependent variables. There was no clear relationship between exposure and any endpoint. The concentration-QT relationship was also evaluated to assess whether imidafenacin prolonged the concentration-dependent QT interval. There was no clear relationship between the plasma concentration of imidafenacin and QTc, indicating that concentration-dependent QTc interval prolongation was not observed.

Absolute bioavailability of imidafenacin after oral administration to healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The absolute bioavailability of imidafenacin in rats and dogs is 5.6% and 36.1%, respectively. The pharmacokinetic profiles of imidafenacin after oral administration have been revealed. Imidafenacin is primarily metabolized to metabolites by CYP3A4 and UGT1A4. WHAT THIS STUDY ADDS: The absolute bioavailability of imidafenacin in human is 57.8%. The pharmacokinetic profiles of imidafenacin after intravenous administration are revealed. The formation of metabolites in the plasma is caused mainly by first-pass effects. AIMS: To investigate the absolute bioavailability of imidafenacin, a new muscarinic receptor antagonist, a single oral dose of 0.1 mg imidafenacin was compared with an intravenous (i.v.) infusion dose of 0.028 mg of the drug in healthy subjects. METHODS: Fourteen healthy male subjects, aged 21-45 years, received a single oral dose of 0.1 mg imidafenacin or an i.v. infusion dose of 0.028 mg imidafenacin over 15 min at two treatment sessions separated by a 1-week wash-out period. Plasma concentrations of imidafenacin and the major metabolites M-2 and imidafenacin-N-glucuronide (N-Glu) were determined. The urinary excretion of imidafenacin was also evaluated. Analytes in biological samples were measured by liquid chromatography tandem mass spectrometry. RESULTS: The absolute oral bioavailability of imidafenacin was 57.8% (95% confidence interval 54.1, 61.4) with a total clearance of 29.5 +/- 6.3 l h(-1). The steady-state volume of distribution was 122 +/- 28 l, suggesting that imidafenacin distributes to tissues. Renal clearance after i.v. infusion was 3.44 +/- 1.08 l h(-1), demonstrating that renal clearance plays only a minor role in the elimination of imidafenacin. The ratio of AUC(t) of both M-2 and N-Glu to that of imidafenacin was reduced after i.v. infusion from that seen after oral administration, suggesting that M-2 and N-Glu in plasma after oral administration were generated primarily due to first-pass metabolism. No serious adverse events were reported during the study. CONCLUSIONS: The absolute mean oral bioavailability of imidafenacin was determined to be 57.8%. Imidafenacin was well tolerated following both oral administration and i.v. infusion.

Effect of itraconazole on the pharmacokinetics of imidafenacin in healthy subjects.

The effect of itraconazole, a potent inhibitor of the CYP3A isoenzyme family, on the pharmacokinetics of imidafenacin, a novel synthetic muscarinic receptor antagonist, was investigated. Twelve healthy subjects participated in this open-label, self-controlled study. In period I, subjects received a single oral dose of 0.1 mg imidafenacin. In period II, they received multiple oral doses of 200 mg itraconazole for 9 days and a single oral dose of 0.1 mg imidafenacin on day 8. Plasma concentrations of imidafenacin and M-2, the major metabolite of imidafenacin metabolized by CYP3A4, were determined. Analytes were measured by liquid chromatography tandem mass spectrometry. Following coadministration with itraconazole, the maximum plasma concentration (C(max)) of imidafenacin increased 1.32-fold (90% confidence intervals [CIs]: 1.12-1.56), and the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased 1.78-fold (90% CI: 1.47-2.16). In conclusion, itraconazole increases the plasma concentrations of imidafenacin by inhibiting CYP3A4. Therefore, itraconazole or potent CYP3A4 inhibitors should be carefully added to imidafenacin drug regimens.

Population pharmacokinetic analysis of a novel muscarinic receptor antagonist, imidafenacin, in healthy volunteers and overactive bladder patients.

The objectives of this study were to develop a population pharmacokinetic model of imidafenacin and to explore the factors that affect the pharmacokinetics of imidafenecin. A total of 2406 plasma samples were collected from 90 healthy volunteers and 457 patients with overactive bladder. We determined the plasma concentrations of imidafenacin by liquid chromatography with tandem mass spectrometry; resultant data were analyzed by a population approach using NONMEM software. The imidafenacin plasma concentration time course was described using a two-compartment model with first-order absorption and lag time. The robustness of the population pharmacokinetic model was evaluated by bootstrap resampling. The results of the population pharmacokinetic analysis demonstrated that oral clearance was decreased with advancing age, increasing hepatic function parameters (AST and ALP), food intake, and itraconazole coadministration, while the first-order absorption rate constant was decreased with food intake. All parameter estimates from the final model fell within 20% of the bootstrapped mean. In conclusion, we developed a population pharmacokinetic model for imidafenacin that well-described plasma concentration profiles. We also identified the factors affecting imidafenacin pharmacokinetics.