Effect of Opicapone Tablets on Levodopa and 3-O-Methyldopa Pharmacokinetics in Healthy Japanese Subjects: Phase 1 Study.

This study evaluated the effect of a small-tablet formulation of opicapone for use in clinical trials in Japan on the pharmacokinetics of levodopa (l-dopa) and 3-O-methyldopa (3-OMD). In an open-label, 3-period, single-sequence crossover phase 1 study in 80 healthy Japanese males (aged 20-45 years; body mass index, 18.5 to <30.0 kg/m2 ), 10 mg of l-dopa/carbidopa 100 was administered 3 times daily on day 0 (period 1) and day 12 (period 3), and opicapone tablets (5, 10, 25, or 50 mg; n = 20 each group) were administered once daily for 11 days (period 2). During periods 1 and 3, plasma concentrations of l-dopa and 3-OMD were measured and pharmacokinetic parameters (maximum observed plasma concentration, time at which maximum concentration was observed, area under the plasma concentration-time curve from time 0 to 5 hours [AUC5h ] and from time 0 to 24 hours [AUC24h ] following each dose, terminal half-life) of plasma l-dopa and 3-OMD were determined along with the geometric mean ratio (period 3/period 1) of AUC24h for l-dopa and 3-OMD. Maximum concentration of l-dopa for the first, second, or third doses of l-dopa/carbidopa did not significantly increase with increasing opicapone dose. The AUC of l-dopa increased with increasing opicapone dose but tended toward a peak plateau with opicapone doses of 25 mg and higher. Geometric mean ratios (90% confidence intervals) of AUC24h were 5 mg, 1.16 (1.10-1.21); 10 mg, 1.26 (1.23-1.30); 25 mg, 1.51 (1.44-1.57); 50 mg, 1.60 (1.54-1.66). Opicapone tablets were well tolerated. In Japanese healthy subjects, increases in plasma exposure to l-dopa appear to level off with opicapone doses of 25 mg and higher, which may be relevant for optimal dosing among Japanese patients with Parkinson disease.

Pharmacokinetic Comparison of Capsule and Tablet Formulations of Opicapone in Healthy Japanese Subjects: Phase 1 Study.

Opicapone, a peripheral, long-acting catechol-O-methyltransferase inhibitor has been shown to improve wearing-off phenomenon in randomized, double-blind studies. This study compared the pharmacokinetic characteristics of opicapone small-tablet and size 1 capsule formulations after single oral administration to healthy Japanese subjects. In this open-label, randomized, 2-way and 2-period crossover phase 1 study, 48 healthy male subjects (aged 20 to 45 years; body mass index, 18.5 to <30.0 kg/m2 ) were randomly assigned to 2 cohorts (n = 24 each), which were administered opicapone 25 or 50 mg in a tablet-capsule or capsule-tablet sequence under fasted conditions. Blood samples were collected for pharmacokinetic analysis before opicapone capsule/tablet administration and at regular intervals over 24 hours after administration. Compared with capsules, tablets were associated with higher Cmax and AUClast/0-∞ values. However, t1/2 and tmax values were similar with opicapone 25- and 50-mg capsules/tablets. Geometric mean ratios (tablets/capsules) of Cmax , AUClast , and AUC0-∞ were 1.24, 1.18, and 1.19, respectively, for the 25-mg dose and 1.42, 1.28, and 1.27, respectively, for the 50-mg dose. Opicapone was well tolerated, and no serious adverse events occurred. A small tablet formulation of opicapone proposed for use in Japanese clinical trials was associated with apparent greater exposure compared with the existing hard capsule formulation, which should be considered when developing opicapone for Japanese patients.

Scale-up of in vitro permeation assay data to human intestinal permeability using pore theory.

The aim of this study is to establish a theoretical method for the prediction of human intestinal permeability from in vitro permeation assay. Pore radius and porosity/length and ion selectivity of the paracellular pathway were calculated using the Renkin function using permeabilities of mannitol and urea and potential difference study to evaluate paracellular permeability in Caco-2 cell monolayer; they were calculated to be 5.91 Å, 7.51 cm(-1) and 2.75, respectively. These values in the human epithelium were calculated from the reported intestinal permeability. The area factor, which can correct the difference in the transcellular permeability between Caco-2 cell monolayer and human epithelium, was obtained using the ratio of permeability of high lipophilicity compounds (human/Caco-2) and was calculated to be 13.3. Paracellular and transcellular permeabilities of 9 compounds in human epithelium were estimated on the basis of the characteristics of the paracellular pathway using physicochemical properties of compounds and the area factor, respectively. Human intestinal permeabilities were predicted by the sum of estimated transcellular and paracellular permeabilities. A linear correlation whose slope and intercept were nearly 1 and 0, respectively, was observed between predicted and reported human intestinal permeabilities. We successfully predicted human intestinal permeability from in vitro data.