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.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Darexaban is an oral direct factor Xa inhibitor developed as an antithrombotic for several indications. Several other new oral anticoagulants are metabolized via CYP3A4 and transported by P-glycoprotein, displaying clinically relevant drug interactions with rifampicin and ketoconazole.• Darexaban is almost entirely metabolized to darexaban glucuronide, which is the main active moiety. In vitro, CYP3A4 metabolism is not involved in the formation or metabolism of darexaban glucuronide; and darexaban, but not darexaban glucuronide, is a P-glycoprotein substrate in vitro. WHAT THIS STUDY ADDS• The study shows that rifampicin does not affect the pharmacokinetic 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.• This study was carried out to confirm the susceptibility of darexaban/darexaban glucuronide to CYP3A4 and P-glycoprotein induction in vivo in humans. AIMSWe 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. METHODSIn 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 (Cmax) and exposure [area under the plasma concentration-time curve from time zero to time of quantifiable measurable concentration; (AUClast) or AUClast extrapolated to infinity (AUC•)] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and Cmax ratios were predefined as 80-125%. RESULTSDarexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUClast with/without rifampicin was 1.08 (1.00, 1.16). The Cmax 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. CONCLUSIONSOverall, 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.
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.
4393 Background: YM150, a potent oral direct factor Xa (FXa) inhibitor, is in development for the prevention of venous thromboembolism after major surgery and of thromboembolic events in subjects with atrial fibrillation. After administration, YM150 is rapidly and extensively metabolized into YM-222714, which predominantly determines antithrombotic effect. Naproxen, a non-steroidal anti-inflammatory drug with antiplatelet properties that inhibits cyclooxygenase (COX)-1 and COX-2 isoenzymes, and similar mode of action drugs will likely be co-prescribed with YM150 in clinical practice. This study assessed the interaction of YM150 and naproxen following co-administration in healthy males. Methods: A Phase I, randomized, open-label, 3-period crossover study (≥14-day washout between periods) compared the pharmacodynamic (PD) and pharmacokinetic (PK) properties of YM150 and naproxen given alone and in combination. Subjects received YM150 60 mg once daily and/or naproxen 500 mg twice daily for 6 and 4 days, respectively. Primary endpoint was change in skin bleeding time (SBT); assessors were blinded to treatment. Change from baseline (BL; pre-dose on Day 1) to 3 h post final dose in SBT was calculated to Day 4 for naproxen alone and Day 6 for YM150 alone and the combination group, thereby reflecting the respective times to achieve steady state (SS). Secondary PD endpoints included minimum FXa activity (FXamin), maximum prothrombin time (PTmax), maximum activated partial thromboplastin time (aPTTmax) and platelet aggregation. Blood and urine PK parameters (maximum concentration [Cmax], time to maximum concentration [tmax], area under the curve [AUC] and renal clearance [CLR]) and safety were also assessed. Blood samples for PK and PD variables were taken at SS on the final day of dosing (pre-dose and up to 24 h post-dose). Data are presented as arithmetic means. Results: 26 subjects were randomized and received treatment (mean age, 30.4 yrs); 6 subjects prematurely discontinued (consent withdrawal, n=3; adverse event [AE], n=2; protocol violation, n=1). Co-administration of YM150 and naproxen did not result in additive increases in SBT (Table). From BL to SS, mean (standard deviation [SD]) SBT (sec) increased from 317 (89.2) to 430 (111) after YM150 alone, from 306 (79.0) to 621 (230) after naproxen alone and from 332 (84.1) to 721 (259) after combination treatment. YM150 inhibited FXa activity and increased PTmax and aPTTmax; co-administration with naproxen did not influence these outcomes (Table). Naproxen decreased collagen-induced platelet aggregation, with no additive effect when co-administered with YM150 (Table). The PK of YM-222714 was generally unchanged when YM150 was administered alone or with naproxen (tmax 1.70 vs 1.45 h; Cmax 1535 vs 1497 ng/mL; AUCtau 11,644 vs 11,369 ng·h/mL; CLR 2.39 vs 3.42 L/h); the PK profile of YM150 itself was similarly unchanged (tmax 1.43 vs 1.17 h; Cmax 7.94 vs 8.23 ng/mL; AUCtau 79.8 vs 66.6 ng·h/mL; CLR 4.91 vs 6.67 L/h). Naproxen PK were also unchanged when co-administered with YM150. Overall, YM150 alone, naproxen alone and combination treatment were safe and well tolerated. Only one subject experienced AEs considered related to treatment (gingival bleeding and epistaxis); combination treatment was discontinued. One other subject discontinued due to an AE unrelated to study drug (gastroenteritis). No clinically relevant changes in laboratory parameters, vital signs or physical assessments were observed. Conclusions: Co-administration of YM150 with naproxen did not result in additive increases in SBT or clinically relevant changes in the PD or PK profiles of either agent; the combination was generally safe and well tolerated. Observed changes in FXa activity, PT and aPTT confirm the antithrombotic potency of YM150 and YM-222714, which was unaltered upon co-administration with naproxen. YM150 has no clinically relevant interaction with naproxen. Disclosures: Heeringa: Astellas Pharma Global Development Europe: Employment. Garcia-Hernandez:Astellas Pharma Global Development Europe: Employment. Kadokura:Astellas Pharma Inc.: Employment. Groenendaal – van de Meent:Astellas Pharma Global Development Europe: Employment. Mol:Astellas Pharma Global Development Europe: Employment. Eltink:Astellas Pharma Global Development Europe: Employment. Heinzerling:Astellas Pharma Global Development Europe: Employment.
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