The pharmacokinetics of darexaban (YM150), an oral direct factor Xa inhibitor, are not affected by ketoconazole, a strong inhibitor of CYP3A and P-glycoprotein.

We investigated the effects of ketoconazole on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite darexaban glucuronide (YM-222714) which almost entirely determines the antithrombotic effect. In this open-label, randomized, two-period crossover study, 26 healthy male volunteers received in one treatment period a single dose of darexaban 60 mg, and in the other treatment period, ketoconazole 400 mg once daily on Days 1-9 with a single dose of darexaban 60 mg on Day 4. Washout between periods was at least 1 week. The geometric mean ratio (90% confidence interval) of darexaban glucuronide (darexaban plus ketoconazole versus darexaban) for AUCinf was 1.11 (1.00, 1.23), and for Cmax 1.18 (1.03, 1.35). Darexaban concentrations remained very low (AUClast ∼196-fold lower) in relation to darexaban glucuronide concentrations. In conclusion, the PK of darexaban glucuronide was not affected to a clinically relevant degree by co-administration of the strong CYP3A/P-glycoprotein inhibitor, ketoconazole. The PK of the parent compound darexaban were changed, however, concentrations remained quantitatively insignificant in relation to the main active moiety, darexaban glucuronide.

The pharmacokinetics of darexaban are not affected to a clinically relevant degree by rifampicin, a strong inducer of P-glycoprotein and CYP3A4.

AIMS: We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM-222714), which almost entirely determines the antithrombotic effect. METHODS: In this open-label, single-sequence study, 26 healthy men received one dose of darexaban 60 mg on day 1 and oral rifampicin 600 mg once daily on days 4-14. On day 11, a second dose of darexaban 60 mg was given with rifampicin. Blood and urine were collected after study drug administration on days 1-14. The maximal plasma drug concentration (C(max)) and exposure [area under the plasma concentration-time curve from time zero to time of quantifiable measurable concentration; (AUC(last)) or AUC(last) extrapolated to infinity (AUC(∞))] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and C(max) ratios were predefined as 80-125%. RESULTS: Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUC(last) with/without rifampicin was 1.08 (1.00, 1.16). The C(max) of darexaban glucuronide increased by 54% after rifampicin [ratio 1.54 (1.37, 1.73)]. The plasma concentrations of darexaban were very low (<1% of darexaban glucuronide concentrations) with and without rifampicin. Darexaban alone or in combination with rifampicin was generally safe and well tolerated. CONCLUSIONS: Overall, rifampicin did not affect the PK profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug-drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low.

Pharmacokinetic properties of mirabegron, a ß3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women.

BACKGROUND: Mirabegron (YM178) is a ß(3)-adrenoceptor agonist for the treatment of overactive bladder (OAB). As part of the clinical development program for mirabegron, 2 human volunteer studies were performed to derive detailed data on the multiple-dose pharmacokinetic (PK) properties of mirabegron. OBJECTIVE: Two randomized Phase I studies were conducted to evaluate the PK properties of mirabegron, including metabolic profile and effects of age and sex, following multiple oral doses in healthy subjects. METHODS: In study 1, mirabegron oral controlled absorption system (OCAS) tablets were administered once daily to healthy young subjects (18-55 years) at doses of 50, 100, 200, and 300 mg and in elderly subjects (65-80 years) at 50 and 200 mg in a double-blind placebo-controlled, parallel-group design. In study 2, mirabegron OCAS was administered once daily to healthy young (18-45 years) and older (≥55 years) subjects at doses of 25, 50, and 100 mg in an open-label crossover design. Blood samples were collected up to 72 hours (study 1) and 168 hours (study 2) after the last dose. Urine samples were collected up to 24 hours after the last dose. Plasma and urine concentrations of mirabegron and its metabolites (study 2 only) were analyzed by LC-MS/MS. PK parameters were determined using noncompartmental methods. Tolerability assessments included physical examinations, supine blood pressure and pulse rate, orthostatic stress testing (study 1), resting 12-lead ECGs, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse-events (AE) monitoring using investigators' questionnaires and subjects' spontaneous reports. RESULTS: Thirty-two young male (mean age, 30.3 years; mean weight, 77.1 kg), 32 young female (27.6 years; 64.6 kg), 16 elderly male (69.8 years; 79.3 kg), and 16 elderly female (68.1 years; 67.4 kg) subjects were enrolled in study 1. Eighteen young male (mean age, 28.6 years; mean weight, 68.9 kg), 18 young female (28.7 years; 58.8 kg), 21 older male (63.4 years; 72.6 kg), and 18 older female (65.1 years; 62.3 kg) subjects were enrolled in study 2. Most of the subjects were white (91% in study 1 and 88% in study 2). Mirabegron plasma concentrations peaked at ∼3 to 5 hours and declined multiexponentially with a t of ∼32 hours in study 1 and 60 hours in study 2. Steady state was achieved within 7 days of once daily administration, with an accumulation ratio of ∼2. Mirabegron and its metabolites demonstrated a greater-than-dose-proportional increase in C(max) and AUC(0-τ) after multiple-dose administration. Two major circulating metabolites were observed, representing 17% and 10% of total drug-related AUC(0-τ). Excretion of unchanged mirabegron in urine over the 24-hour dosing interval (Ae(0-τ)%) increased from approximately 7% at 25 mg to 18% at 300 mg once daily in young subjects. Renal clearance (CL(R)) of mirabegron was independent of dose and averaged ∼13 L/h. Mirabegron C(max) and AUC(0-τ) were similar in older and young subjects. Women exhibited ∼40% higher mirabegron C(max) and AUC(0-τ) than men; weight-corrected values were ∼20% higher in women. Mirabegron was generally well tolerated up to 300 mg once daily. No clear trends for increased incidence of AEs occurred with higher doses of mirabegron. The AE with the highest incidence was headache. CONCLUSION: Oral mirabegron exhibited a greater-than-dose-proportional increase in exposure. Sex but not age significantly affected mirabegron exposure. ClinicalTrials.gov identifier: NCT01478503 (Study 1) and NCT01285596 (Study 2).

Single dose pharmacokinetics and absolute bioavailability of mirabegron, a ß3-adrenoceptor agonist for treatment of overactive bladder.

BACKGROUND AND OBJECTIVES: Mirabegron is a potent and selective ß3-adrenoceptor agonist in development for treatment of overactive bladder. METHODS: Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91). RESULTS: After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F. CONCLUSIONS: Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.