Takeshi Kadokura

Effect of Ipragliflozin (ASP1941), a Novel Selective Sodium-Dependent Glucose Co-Transporter 2 Inhibitor, on Urinary Glucose Excretion in Healthy Subjects

AbstractBackground: Hyperglycaemia is associated with serious complications, significant morbidity and death. Despite the availability of a wide range of therapeutic options, many patients with diabetes mellitus fail to achieve or maintain recommended glycaemic goals. Ipragliflozin (ASP1941) is a novel, selective inhibitor of the sodium-dependent glucose co-transporter 2, which is highly expressed in the proximal tubules of the kidneys. It suppresses renal glucose reabsorption and increases urinary glucose excretion (UGE), potentially providing an insulin-independent treatment option for type 2 diabetes. Methods: This multiple ascending-dose study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of ipragliflozin in healthy subjects after single doses and multiple once-daily doses for 10 days (dose levels: 5–600 mg). Results: Ipragliflozin was well tolerated following single and multiple once-daily oral dosing. Ipragliflozin was rapidly absorbed with a median time to reach the maximum plasma concentration of 1.3 hours after the last dose. The area under the plasma concentration-time curve increased proportionally with increasing dose. The mean elimination half-life was 12 hours following the last dose. Ipragliflozin dose dependently increased UGE up to a maximum of approximately 59 g (327 mmol) of glucose excreted over 24 hours following multiple doses, without affecting plasma glucose levels in healthy subjects. Conclusion: Administration of ipragliflozin was well tolerated and resulted in a rapid, dose-dependent increase in glucosuria. Pharmacodynamic and pharmacokinetic data suggest that ipragliflozin is suitable for prolonged once-daily oral treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01288898.

Renal Glucose Handling: Impact of chronic kidney disease and sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes

OBJECTIVE Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, stimulates glycosuria and lowers glycemia in patients with type 2 diabetes (T2DM). The objective of this study was to assess the pharmacodynamics of ipragliflozin in T2DM patients with impaired renal function. RESEARCH DESIGN AND METHODS Glycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 ± 9 years, fasting glucose 133 ± 39 mg/dL, mean ± SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR1 ≥90 mL · min–1 · 1.73 m−2), mild (eGFR2 ≥60 to <90), moderate (eGFR3 ≥30 to <60), or severe reduction in eGFR (eGFR4 ≤15 to <30). RESULTS Ipragliflozin significantly increased urinary glucose excretion in each eGFR class (P < 0.0001). However, ipragliflozin-induced glycosuria declined (median [IQR]) across eGFR class (from 46 mg/min [33] in eGFR1 to 8 mg/min [7] in eGFR4, P < 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P < 0.0001 for both, r2 = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia. CONCLUSIONS In T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment.

Discovery of N-[2-Hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (Darexaban, YM150) as a Potent and Orally Available Factor Xa Inhibitor

Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.

No pharmacokinetic interaction between ipragliflozin and sitagliptin, pioglitazone, or glimepiride in healthy subjects.

To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa in healthy subjects.

Combination Treatment With Ipragliflozin and Metformin: A Randomized, Double-Blind, Placebo-Controlled Study in Patients With Type 2 Diabetes Mellitus

BACKGROUND Ipragliflozin (ASP1941) is a selective sodium glucose cotransporter 2 inhibitor in clinical development for the treatment of patients with type 2 diabetes mellitus (T2DM). OBJECTIVES The primary objective was to evaluate the safety profile and tolerability of ipragliflozin as a glucose-lowering agent in combination with stable metformin therapy in patients with T2DM. A secondary objective was to evaluate the effect of ipragliflozin on the pharmacokinetic (PK) properties of metformin. METHODS Thirty-six patients with T2DM stable on metformin therapy (850, 1000, or 1500 mg bid) were randomized in a double-blind manner to receive ipragliflozin (300 mg qd; n = 18) or matching placebo (n = 18) for 14 days. Safety profiles, including monitoring of hypoglycemic events, treatment-emergent adverse events (TEAEs), laboratory measurements, and vital signs were assessed throughout the study. The PK properties of metformin and ipragliflozin were determined in plasma. The geometric mean ratio and its 90% CI for the maximum plasma concentration and AUC(0-10) were calculated for metformin + ipragliflozin (day 14) versus metformin alone (day -1). Pharmacodynamic properties were assessed by measurement of urinary glucose excretion over 24 hours (UGE(0-24)). RESULTS All the TEAEs, except 1, were mild. Fifteen TEAEs were observed in the ipragliflozin group (7 of 18 patients [38.9%]), and 19 TEAEs were observed in the placebo group in (8 of 18 patients [44.4%]). Treatment-related TEAEs were reported by 3 of 18 patients (16.7%) receiving metformin + ipragliflozin and by 5 of 18 patients (27.8%) receiving metformin + placebo. No hypoglycemic events (blood glucose level <54 mg/L [to convert to millimoles per liter, multiply by 0.0555]) were observed. The geometric mean ratios for C(max) and AUC(0-10) of metformin + ipragliflozin versus metformin alone were 1.11 (90% CI, 1.03-1.19) and 1.18 (90% CI, 1.08-1.28), respectively. After ipragliflozin treatment, UGE(0-24) on day 14 (74.9 g) was significantly higher than that in the placebo group (3.6 g) and at baseline (3.3 g). CONCLUSIONS Combination treatment for 14 days with ipragliflozin and metformin was well tolerated in patients withT2DM without hypoglycemia. The addition of ipragliflozin (300 mg qd) to metformin therapy did not result in a clinically relevant change in the PK properties of metformin. ClinicalTrials.gov identifier: NCT01302145.

Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study

AIMS Ipragliflozin is a novel and highly selective sodium-glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM. METHODS In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50mg or 100mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days -1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0-3h (AUC0-3h) and 0-24h (AUC0-24h). Pharmacokinetic characteristics included AUC0-24h, maximum ipragliflozin concentration (Cmax), and time to maximum plasma ipragliflozin concentration (tmax). RESULTS Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC0-3h and AUC0-24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC0-24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. Cmax and AUC0-24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group. CONCLUSIONS Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.

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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

Ipragliflozin Does Not Prolong QTc Interval in Healthy Male and Female Subjects: A Phase I Study

BACKGROUND Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agents effects on the QT/QTc interval. OBJECTIVE The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects. METHODS This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericias correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms. RESULTS A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms). CONCLUSIONS No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413.

Clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban, an oral direct factor Xa inhibitor, in healthy Caucasian and Japanese subjects

Background. Darexaban (YM150) is a potent direct factor Xa (FXa) inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This drug is rapidly and extensively metabolized to darexaban glucuronide (YM‐222714), which is a pharmacologically active metabolite. The objective of the present study was to evaluate the clinical pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of ascending multiple oral doses of darexaban in healthy non‐elderly Caucasian and Japanese subjects. Methods. A randomized, double‐blind, placebo‐controlled, single and multiple dose‐escalating study of healthy Caucasian and Japanese male and female subjects was performed. The tested doses were 20, 60, 120 and 240 mg of darexaban. Results. Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose‐dependently after both single and repeated doses in both Caucasians and Japanese. Cmax was about 17%–19% lower in Caucasians than in Japanese, although AUC appeared to be similar. The time‐profiles of prothrombin time reported as the international normalized ratio (PT‐INR), activated partial thromboplastin time (aPTT) and FXa activity closely followed the time–concentration profile of darexaban glucuronide, and no clear differences were observed in ethnicity. Overall, 38 of the 82 enrolled subjects reported a total of 57 treatment‐emergent adverse events (TEAEs). Fifty‐five TEAEs were of mild intensity and two were of moderate intensity. Conclusion. It is concluded that single and multiple doses of darexaban are safe and well tolerated up to 240 mg with predictable PK and PD profiles in both Caucasians and Japanese, and that ethnicity does not affect its PK, PD or tolerability. Copyright

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.