Tomoya Ohno

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 (Cmax) 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 (AUC0‐∞) 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.

Modeling and simulation of bone mineral density response from a phase 2 study of ONO-5334, a new cathepsin K inhibitor, to support dose selection in osteoporosis.

ONO‐5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure–response (E–R) models to relate ONO‐5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO‐5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT. The exposure metrics at steady state were estimated by post hoc Bayesian prediction using the final population PK model. E–R models were developed using dose‐ranging data with only IRT from postmenopausal females with osteoporosis. Based on the developed model, lumbar spine and total hip BMD after administration of ONO‐5334 SRT as well as IRT were simulated. The simulation results showed that ONO‐5334 SRT should provide comparable BMD responses at a lower dose relative to IRT (a finding consistent with the results from a previous population PK–PD modeling study with bone resorption markers).

Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO-5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females.

ONO‐5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic–pharmacodynamic (PK–PD) models for ONO‐5334 using dose‐ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK–PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK–PD models were developed for each formulation for post‐dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO‐5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO‐5334. There was no significant difference in PK and pharmacodynamic potency (IC50) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO‐5334 IRT or SRT were simulated, and the results showed that ONO‐5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [11C]PBR28

ONO‐2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO‐specific PET radioligand [11 C]PBR28 to confirm binding of ONO‐2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO‐2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO‐2952 (n = 4 per dose). Two PET scans with [11 C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO‐2952 administration. [11 C]PBR28 regional distribution volume (VT) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (VND) was obtained on an individual basis for each subject using linear regression as the x‐intercept of the Lassen plot. The binding potential relative to VND (BPND) was derived as the difference between VT in the ROI (VT ROI) and VND, normalized to VND; BPND = (VT ROI – VND)/VND. TSPO occupancy was calculated as the change in BPND (ΔBPND) from individuals baseline scan to the on‐medication scan to the baseline BPND value. TSPO occupancy by ONO‐2952 was dose dependent between 20–200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated Ki values ranged from 24.1 to 72.2 nM. This open‐label, single‐center, single‐dose study demonstrated engagement of ONO‐2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO‐2952 could potentially modulate neurosteroid production by binding to brain TSPO.