Single- and Multiple-dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP1128, a Novel Peroxisome Proliferator-activated Receptor δ Modulator, in Healthy Participants.

Peroxisome proliferator-activated receptor δ (PPARδ) plays a central role in modulating mitochondrial function in ischemia-reperfusion injury. ASP1128, a potent and selective modulator of PPARδ, is currently under investigation for treating acute kidney injury. This randomized, first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ASP1128 administered intravenously in healthy participants. Forty-nine participants received a single dose of ASP1128 0.3-10 mg (n = 37) or placebo (n = 12) and 53 received daily (7 days) doses of ASP1128 3-100 mg (n = 39) or placebo (n = 14), including a cohort aged ≥65 years (ASP1128 100 mg, n = 3; placebo, n = 2). Treatment-emergent adverse events occurred in 37.8%, 59.0%, and 33.3%-35.7% of participants in the single ASP1128, multiple ASP1128, and placebo groups, respectively. All were mild in severity, and the frequency of adverse events did not appear to be dose-related. One participant (multiple ASP1128 3 mg group) withdrew with an infusion site erythema, possibly related to study drug. Exposure was roughly dose-proportional, and elimination was generally consistent across doses (mean t½ 14.6-17.4 hours in the 10, 30, and 100 mg groups on day 7). There was little accumulation in plasma following multiple dosing; steady state was reached after ∼4 days. ASP1128 treatment led to rapid and dose-related upregulation of six fatty acid oxidation-related PPARδ target genes at ≥10 mg, which lasted >24 hours postdose. In conclusion, single and multiple intravenous doses of ASP1128 were generally well tolerated, with dose-dependent pharmacokinetics and target gene engagement in healthy participants.

Horizontal distribution of surface microplastic concentrations and water-column microplastic inventories in the Chukchi Sea, western Arctic Ocean.

The recent influx of microplastics into the Arctic Ocean may increase environmental stress on the western Arctic marine ecosystem, which is experiencing significant sea-ice loss due to global warming. Quantitative data on microplastics in the western Arctic Ocean are very limited, and the microplastic budget of the water column is completely unknown. To fill in gaps in our knowledge of Arctic microplastics, we observed surface concentrations (number of particles per unit volume of seawater) of meso- and microplastics using a neuston net, and we observed wind speeds and significant wave heights in the Chukchi Sea, Bering Strait, and Bering Sea. From these observations, we estimated the total number (particle inventory) and mass (mass inventory) of microplastics in the entire water column by taking into account the effect of vertical mixing. The particle inventory of microplastics in the Chukchi Sea ranged from 0 to 18,815 pieces km-2 with a mean and standard deviation of 5236 ± 6127 pieces km-2. The mass inventory ranged from 0 to 445 g km-2 with a mean and standard deviation of 124 ± 145 g km-2. Mean particle inventories for the Chukchi Sea were one-thirtieth of those for the Arctic Ocean on the Atlantic side and less than one-tenth of the average for the global ocean, suggesting that the Chukchi Sea is less polluted. However, the annual flux of microplastics from the Pacific Ocean into the Chukchi Sea, estimated from microplastic concentrations in the Bering Strait, was about 5.5 times greater than the total amount of microplastic in the entire Chukchi Sea water. This suggests that microplastic inflows from the Pacific Ocean are accumulating in large amounts in reservoirs other than the Chukchi Sea water (e.g., sea ice and seafloor sediments) or in the downstream regions of the Pacific-origin water.

Exposure-response modeling of peficitinib efficacy in patients with rheumatoid arthritis.

The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure-response models. The analysis incorporated results from three multicenter, placebo-controlled, double-blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28-CRP measurements were modeled by a non-linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure-response models of effect of peficitinib on duration-dependent increase in ACR20 response rate and decrease in DAS28-CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal Emax saturable of drug exposure in RA patients. The significant covariates were DAS28-CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28-CRP model. The covariate effects were highly consistent between the two models. Our exposure-response models of peficitinib in RA patients satisfactorily described duration-dependent improvements in ACR20 response rates and DAS28-CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment. CLINICAL TRIAL REGISTRATION: NCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).

Safety and Antitumor Activity of Repeated ASP3026 Administration in Japanese Patients with Solid Tumors: A Phase I Study.

BACKGROUND AND OBJECTIVE: Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required. METHODS: This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts. RESULTS: Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group). CONCLUSION: ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile. CLINICAL TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.

Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis.

AIMS: To analyse the population pharmacokinetics (PK) of peficitinib in patients with rheumatoid arthritis (RA) and assess the potential PK covariates to identify the requirement for dose adjustment in RA patients. METHODS: The analysis incorporated 2464 observations from 98 healthy volunteers and 4919 observations from 989 RA patients. A population PK model for peficitinib in RA patients was constructed by a nonlinear mixed effect model using NONMEM with prior information from a healthy volunteer model. RESULTS: A 2-compartment model with sequential zero- and first-order absorption and lag time was constructed for RA patients. Covariate exploration in the RA patient model revealed that estimated glomerular filtration rate (eGFR) and lymphocyte count had a significant effect on apparent total systemic clearance (CL), which was 91.7 L/h (2.3% relative standard error). Compared with the mean population CL, the model predicted mean changes in CL of 12.3 and -10.7% in patients with observed minimum and maximum lymphocyte count of 500 and 4600 106 /L, respectively, and mean changes in CL of -17.8 and 16.7% in patients with minimum and maximum eGFR of 36.4 and 188 mL/min/1.73m2 , respectively. The simulated population mean area under plasma concentration-time curve for 24 hours after dosing showed a 1.35-fold increase in patients with severe renal impairment (eGFR 22.5 mL/min/1.73m2 ) compared with patients with reference eGFR (91.5 mL/min/1.73m2 ). CONCLUSION: The population PK model identified eGFR and lymphocyte count as covariates for CL. The magnitude of changes was not considered clinically relevant, indicating no requirement for dose adjustment.

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150-mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150-mg tablet formulation of peficitinib was bioequivalent to the developmental 150-mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation.

Comparison of the Pharmacokinetic and Pharmacodynamic Relationship of Ipragliflozin Between Patients With Type 1 and Type 2 Diabetes Mellitus.

PURPOSE: To characterize the pharmacokinetic and pharmacodynamic (PK/PD) relationship of ipragliflozin in Japanese patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and to determine the appropriate dose regimen for a Phase III study of ipragliflozin in Japanese patients with T1DM. METHODS: The PK (AUC24h of plasma ipragliflozin) and PD (renal glucose clearance) properties in patients with T1DM and T2DM were assessed in 2 independent clinical pharmacologic studies of ipragliflozin. The same maximum efficacy (Emax) model described the PK/PD relationship in patients with T1DM and T2DM. Changes in fasting plasma glucose (FPG) in T1DM patients were simulated by applying a previously established FPG model for ipragliflozin in patients with T2DM. FINDINGS: Data from 42 patients with T1DM and 28 patients with T2DM were used. Comparable AUC24h of plasma ipragliflozin and similar dose dependency were observed on day 14 between patients with T1DM and those with T2DM. Decreases in renal glucose clearance were comparable regardless of the ipragliflozin dose in both groups of patients. The estimated mean Emax and AUC24h producing 50% of Emax (EX50) were 45.1 mL/min (95% CI, 37.0-53.2 mL/min) and 2160 ng·h/mL (95% CI, 929-3390 ng·h/mL), respectively, in all patients with T1DM and T2DM. Observed FPG in patients with T1DM was reproduced well by the simulation from the previously established FPG model. IMPLICATIONS: The PK/PD properties for ipragliflozin were comparable between patients with T1DM and T2DM, suggesting no substantial difference in PK/PD relationships in both patient populations. The dose regimen used for patients with T2DM was also recommended for a Phase III study in Japanese patients with T1DM. ClinicalTrials.gov identifiers: NCT01023945 and NCT02529449.

A drug-drug interaction study to evaluate the impact of peficitinib on OCT1- and MATE1-mediated transport of metformin in healthy volunteers.

PURPOSE: Peficitinib is an oral pan-Janus kinase inhibitor for the treatment of rheumatoid arthritis. Co-administration of peficitinib with metformin, a type 2 diabetes therapy, can occur in clinical practice. Hepatic and renal uptake of metformin is mediated by organic cation transporter 1 (OCT1) and OCT2, respectively, and its renal excretion by multidrug and toxin extrusion 1 (MATE1) and MATE2-K. This study investigated the effect of peficitinib on metformin pharmacokinetics in vitro and in healthy volunteers. METHODS: Inhibitory effects of peficitinib and its metabolite H2 on metformin uptake into human OCT1/2- and MATE1/2-K-expressing cells were assessed in vitro. In an open-label, drug-drug interaction study, 24 healthy volunteers received a single dose of metformin 750 mg on Days 1 and 10, and a single dose of peficitinib 150 mg on Days 3 and 5-11. Blood and urine samples were collected pre-dose on Days 1 and 10, and at intervals ≤ 48 h post-dose. Metformin concentration was determined by liquid chromatography-tandem mass spectrometry and its pharmacokinetic parameters calculated. RESULTS: Peficitinib, but not H2, inhibited metformin uptake into OCT1- and MATE1/2-K-expressing cells. Repeated-dose administration of peficitinib reduced metformin area under the concentration-time curve from 0 h extrapolated to infinity (AUCinf) by 17.4%, maximum plasma concentration (Cmax) by 17.0%, and renal clearance (CLR) by 12.9%. Co-administration of peficitinib with metformin was generally well tolerated. CONCLUSION: Slight changes in AUCinf, Cmax and CLR of metformin were observed when co-administered with peficitinib; however, these changes were considered not clinically relevant.

Pharmacokinetics, Pharmacodynamics, and Safety of Peficitinib (ASP015K) in Healthy Male Caucasian and Japanese Subjects.

BACKGROUND AND OBJECTIVE: Peficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects. METHODS: In this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received a single oral dose of peficitinib (20, 60, or 200 mg) or placebo. Another cohort of Japanese men (n = 24) received peficitinib (10, 30, or 100 mg) or placebo twice daily for 7 days. Pharmacokinetic and pharmacodynamic parameters were assessed, and adverse events (AEs) monitored throughout. RESULTS: Dose proportionality of maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUCinf) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized Cmax was 45.7-98.8% higher and AUCinf was 33.8-66.4% higher in Japanese versus Caucasian subjects. Mean peak inhibition of STAT5 phosphorylation was higher in Japanese than Caucasian subjects for a given peficitinib dose, but inhibition was comparable across ethnicities for a given plasma peficitinib concentration. In the multiple-dose study, plasma peficitinib concentrations were similar on day 1 and day 7. All AEs were mild, and none resulted in study discontinuation. CONCLUSIONS: Peficitinib was well tolerated at doses up to 200 mg daily for 7 days in healthy Japanese subjects. Dose-proportional exposure was demonstrated across the single-dose range of 20-200 mg, with greater peficitinib exposure in Japanese compared with Caucasian subjects. The pharmacokinetic/pharmacodynamic relationships were considered comparable between these populations. CLINICALTRIALS. GOV IDENTIFIER: NCT01225224.

Model-based Prediction of the Long-term Glucose-Lowering Effects of Ipragliflozin, a Selective Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor, in Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: Sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors inhibit the reabsorption of glucose from the kidneys and increase urinary glucose excretion (UGE), thereby lowering the blood glucose concentration in people suffering from type 1 and type 2 diabetes mellitus (T2DM). In a previous study, we reported a pharmacokinetics/pharmacodynamics model to estimate individual change in UGE (ΔUGE), which is a direct pharmacological effect of SGLT2 inhibitors. In this study, we report our enhancement of the previous model to predict the long-term effects of ipragliflozin on clinical outcomes in patients with T2DM. METHODS: The time course of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) in patients with T2DM following ipragliflozin treatment that had been observed in earlier clinical trials was modeled using empirical models combined with the maximum drug effect (Emax) model and disease progression model. As a predictive factor of drug effect, estimated ΔUGE was introduced into the Emax model, instead of ipragliflozin exposure. The developed models were used to simulate the time course of FPG and HbA1c following once-daily treatment with placebo or ipragliflozin at doses of 12.5, 25, 50 and 100 mg, and the changes at 52 weeks at the approved dose of 50 mg were summarized by renal function category. RESULTS: The developed models that included UGE as a dependent variable of response were found to well describe observed time courses in FPG and HbA1c. Baseline blood glucose level and renal function had significant effects on the glucose-lowering effect of ipragliflozin, and these models enabled quantification of these impacts on clinical outcomes. Simulated median changes in HbA1c in T2DM patients with mild and moderate renal impairment were 25 and 63% lower, respectively, than those in T2DM patients with normal renal function. These results are consistent with the observed clinical data from a previous renal impairment study. CONCLUSIONS: Empirical models established based on the effect of UGE well predicted the renal function-dependent long-term glucose-lowering effects of ipragliflozin in patients with T2DM.

Long-term (52-week) efficacy and safety of ipragliflozin add-on therapy to insulin in Japanese patients with type 1 diabetes mellitus: An uncontrolled, open-label extension of a phase III study.

INTRODUCTION: The aim of the present study was to assess the long-term (52-week) efficacy and safety of ipragliflozin in insulin-treated Japanese patients with type 1 diabetes mellitus and inadequate glycemic control. MATERIALS AND METHODS: In this 28-week, open-label extension of a multicenter, randomized, placebo-controlled, 24-week phase III study, ipragliflozin recipients continued treatment (50 mg, once daily), and placebo recipients were switched to once-daily 50 mg ipragliflozin at the start of the extension period. The ipragliflozin dose could be increased to 100 mg if warranted. The primary end-point was change in glycated hemoglobin; secondary end-points were change in insulin dose and bodyweight. Safety outcomes were monitored as treatment-emergent adverse events. RESULTS: A total of 53 (placebo switched to ipragliflozin) and 108 (ipragliflozin) patients completed the open-label extension (treatment period 2), with 24 and 44 patients, respectively, receiving dose increases. From baseline to end of treatment, the overall mean change (standard deviation [SD]) in glycated hemoglobin was -0.33% (0.72; -3.7 mmol/mol [7.9]), with changes in basal, bolus and total insulin doses of -3.76 IU (SD 3.85 IU), -2.51 IU (SD 7.08 IU) and -6.27 IU (SD 8.16 IU), respectively. No serious drug-related treatment-emergent adverse events or deaths were reported. Treatment-emergent adverse events leading to study discontinuation occurred in zero and three (2.6%) patients in the placebo switched to ipragliflozin and ipragliflozin groups, respectively; all were considered drug-related. There were no cases of severe hypoglycemia or diabetic ketoacidosis, and no safety concerns related to dose increase. CONCLUSIONS: The efficacy and safety of 50 mg, once-daily ipragliflozin in insulin-treated type 1 diabetes mellitus patients were confirmed in this long-term, open-label extension study. No safety concerns were attributed to a dose increase to 100 mg.

Pharmacokinetics and Safety of a Single Oral Dose of Peficitinib (ASP015K) in Japanese Subjects With Normal and Impaired Hepatic Function.

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non-RA subjects (n = 24) in an open-label, parallel-group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma-concentration-time curve from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUCinf and Cmax , were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment-emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment.

Efficacy and safety of ipragliflozin add-on therapy to insulin in Japanese patients with type 1 diabetes mellitus: A randomized, double-blind, phase 3 trial.

AIM: To assess the efficacy and safety of once-daily ipragliflozin 50 mg versus placebo in Japanese people with type 1 diabetes mellitus (T1DM) inadequately controlled with insulin. MATERIALS AND METHODS: We conducted a multicentre, double-blind, parallel-group, placebo-controlled phase 3 study. Participants (N = 175) were randomized (2:1) to receive once-daily ipragliflozin 50 mg (n = 115) or placebo (n = 60), combined with insulin, for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c); key secondary endpoints included change in insulin dose and body weight. Treatment-emergent adverse events (TEAEs) were evaluated. RESULTS: The ipragliflozin group demonstrated a significant decrease in HbA1c from baseline to end of treatment versus the placebo group: adjusted mean difference (AMD) -3.8 mmol/mol (95% confidence interval [CI] -6.2, -1.5) or - 0.36% (95% CI -0.57, -0.14; P = 0.001). Significant reductions in total daily insulin dose (AMD -7.35 IU [95% CI -9.09, -5.61]; P < 0.001) and body weight (AMD -2.87 kg [95% CI -3.58, -2.16]; P < 0.001) were observed for the ipragliflozin group versus placebo. Two serious TEAEs occurred (major hypoglycaemia and abdominal abscess); both were in the placebo group. All other TEAEs were mild or moderate in severity. Four cases of study discontinuation occurred; three in the placebo group and one in the ipragliflozin group. No diabetic ketoacidosis was reported for any participant in this study. CONCLUSIONS: Daily ipragliflozin 50 mg in combination with insulin significantly reduced HbA1c, daily insulin dose and body weight versus placebo in people with T1DM. No safety concerns were identified after 24 weeks of treatment. Overall, once-daily ipragliflozin 50 mg was both efficacious and well tolerated.

Pharmacokinetic and pharmacodynamic modelling for renal function dependent urinary glucose excretion effect of ipragliflozin, a selective sodium-glucose cotransporter 2 inhibitor, both in healthy subjects and patients with type 2 diabetes mellitus.

AIMS: To provide a model-based prediction of individual urinary glucose excretion (UGE) effect of ipragliflozin, we constructed a pharmacokinetic/pharmacodynamic (PK/PD) model and a population PK model using pooled data of clinical studies. METHODS: A PK/PD model for the change from baseline in UGE for 24 hours (ΔUGE24h ) with area under the concentration-time curve from time of dosing to 24 h after administration (AUC24h ) of ipragliflozin was described by a maximum effect model. A population PK model was also constructed using rich PK sampling data obtained from 2 clinical pharmacology studies and sparse data from 4 late-phase studies by the NONMEM $PRIOR subroutine. Finally, we simulated how the PK/PD of ipragliflozin changes in response to dose regime as well as patients' renal function using the developed model. RESULTS: The estimated individual maximum effect were dependent on fasting plasma glucose and renal function, except in patients who had significant UGE before treatment. The PK of ipragliflozin in type 2 diabetes mellitus (T2DM) patients was accurately described by a 2-compartment model with first order absorption. The population mean oral clearance was 9.47 L/h and was increased in patients with higher glomerular filtration rates and body surface area. Simulation suggested that medians (95% prediction intervals) of AUC24h and ΔUGE24h were 5417 (3229-8775) ng·h/mL and 85 (51-145) g, respectively. The simulation also suggested a 1.17-fold increase in AUC24h of ipragliflozin and a 0.76-fold in ΔUGE24h in T2DM patients with moderate renal impairment compared to those with normal renal function. CONCLUSIONS: The developed models described the clinical data well, and the simulation suggested mechanism-based weaker antidiabetic effect in T2DM patients with renal impairment.

Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: A phase 2, randomized, placebo-controlled trial.

AIM: To evaluate the pharmacodynamics, pharmacokinetics, and safety of the novel oral sodium-glucose co-transporter-2 inhibitor, ipragliflozin, in Japanese patients with type 1 diabetes mellitus. MATERIALS AND METHODS: We conducted a multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive 25, 50, or 100 mg/day ipragliflozin or placebo for 2 weeks. Key pharmacokinetic endpoints included area under the concentration-time curve 24 hours postdose (AUC24h ), maximum plasma concentration (Cmax ), and renal clearance. Key pharmacodynamic endpoints included 24-hour urinary glucose excretion, mean plasma glucose AUC0-24h , and mean renal glucose clearance. Changes in total, basal, and bolus insulin dosages were recorded. Adverse events (AEs) were monitored for safety. RESULTS: Dose-dependent increases were observed in AUC24h and Cmax on days 1 and 14 for 25-, 50-, and 100-mg ipragliflozin. The mean plasma glucose AUC0-24h was lower than that of placebo and the mean renal glucose clearance increased in a dose-dependent manner from baseline, but remained unchanged in the placebo group. The mean (standard deviation) change from baseline in total daily insulin dose was greater in the ipragliflozin 25-, 50-, and 100-mg groups (-14.77 ± 14.04%, -18.40 ± 12.49% and -19.25 ± 16.77%, respectively), than placebo (-4.51 ± 16.28%). Most AEs were mild in severity; no patients discontinued the study because of treatment-emergent AEs. CONCLUSIONS: The pharmacokinetic and pharmacodynamic properties of ipragliflozin in Japanese patients with type 1 diabetes mellitus were confirmed. Increases in urinary glucose excretion lead to dose-dependent decreases in plasma glucose. Concomitant insulin dose decreased with ipragliflozin treatment. No clinically relevant safety concerns were identified.

Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan.

We assessed the efficacy and safety of fidaxomicin, a narrow-spectrum macrocyclic antibiotic, for treating inpatients with Clostridioides (Clostridium) difficile infection (CDI) in Japan. The objective was to demonstrate the non-inferior efficacy of fidaxomicin versus vancomycin. This Phase III, vancomycin-controlled, double-blind, parallel-group study enrolled adults with CDI. Patients were randomly assigned to receive fidaxomicin (200 mg twice daily, orally) or vancomycin (125 mg four-times daily, orally) for 10 days. The primary endpoint was global cure rate of CDI (proportion of patients cured at end of treatment with no recurrence during 28-day follow-up). Non-inferiority margin of 10% was pre-specified. Two-hundred and twelve patients were randomized and received treatment at 82 hospitals. Global cure rate was 67.3% (70/104) with fidaxomicin and 65.7% (71/108) with vancomycin: difference 1.2% [95% confidence interval (CI) -11.3-13.7]. Non-inferiority was not demonstrated. Post-hoc analysis in full analysis set patients who received at least 3 days' treatment revealed a higher global cure rate for fidaxomicin [70/97 (72.2%)] than vancomycin [71/106 (67.0%)]: difference 4.6% (95% CI -7.9-17.1). Recurrence rate in the full analysis set for recurrence was lower in fidaxomicin- [17/87 (19.5%)] than vancomycin-treated [24/95 (25.3%)] patients. Adverse event incidences and profiles were similar for both treatments. Though non-inferiority was not demonstrated for fidaxomicin versus vancomycin, global cure rate was numerically higher and recurrence rate lower for fidaxomicin than vancomycin. Fidaxomicin could be an option for the treatment of CDI in an era of reduced antibiotic susceptibility, and to reduce the incidence of recurrence in Japanese patients. CLINICALTRIALS. GOV IDENTIFIER: NCT02179658.

Pharmacokinetic drug interaction study between overactive bladder drugs mirabegron and tolterodine in Japanese healthy postmenopausal females.

Mirabegron, the first selective ß3-adrenoceptor agonist for the treatment of overactive bladder (OAB), inhibits cytochrome P450 isozyme CYP2D6. This study was performed in Japanese healthy postmenopausal female volunteers to assess any pharmacokinetic drug interaction between mirabegron and tolterodine, another OAB drug and a sensitive substrate of CYP2D6. Tolterodine 4 mg was orally administered from Days 1-7 and co-administered with mirabegron 50 mg from Days 8-14. Mirabegron 50 mg increased maximum concentration (Cmax) and area under the concentration-time curve from zero to 24 h after dosing (AUC24h) of tolterodine by 2.06-fold (90% confidence interval [CI] 1.81, 2.34) and 1.86-fold (90% CI 1.60, 2.16), respectively, and increased Cmax and AUC24h of the metabolite 5-hydroxymethyl tolterodine by 1.36-fold (90% CI 1.26, 1.47) and 1.25-fold (90% CI 1.15, 1.37), respectively. This suggested a weak pharmacokinetic drug interaction between mirabegron and tolterodine. Mean change from baseline of Fridericia's QT correction formula (ΔQTcF) was slightly higher on Day 14 than on Day 7. No subject had QTcF >480 msec or ΔQTcF >60 msec. All the treatment-emergent adverse events were mild. Mirabegron 50 mg was considered to be safe and well tolerated when coadministered with tolterodine 4 mg in healthy postmenopausal female volunteers.

Investigation of the role of transporters on the hepatic elimination of an LAT1 selective inhibitor JPH203.

JPH203 has been developed as an anticancer drug that inhibits L-type amino acid transporter 1-mediated essential amino acid uptake into tumor cells. This study sought to elucidate which drug transporters may be involved in JPH203 hepatic elimination, and to estimate human hepatic clearance. In Sprague-Dawley rats, JPH203 total body clearance approached blood flow rate. JPH203 biotransformation via phase II metabolism produces N-acetyl-JPH203 (NAc-JPH203). NAc-JPH203 accumulates in the bile, and NAc-JPH203 canalicular efflux was significantly decreased in Mrp2-deficient mutant rats (Eisai hyperbilirubinemic rats). JPH203 and NAc-JPH203 are organic anion transporters [organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, and OAT3] substrates. In human cryopreserved hepatocytes, JPH203 uptake was saturable and inhibited by rifampicin, a prototypical OATP inhibitor. JPH203 metabolic clearance was larger than influx clearance and eventually passive clearance; JPH203 uptake appears to be the rate-determining process in overall hepatic elimination. Furthermore, unlike rats, the human hepatic clearance was predicted to be intrinsic clearance rate limited. These results suggest that the hepatic uptake transporters are determinant factors to determine JPH203 systemic exposure.

Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney.

Cimetidine, an H2 receptor antagonist, has been used to investigate the tubular secretion of organic cations in human kidney. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 (hOCT1) and hOCT2 and human multidrug and toxin extrusion 1 (hMATE1) and hMATE2-K, respectively]. Inhibition constants (K(i)) of cimetidine were determined by using five substrates [tetraethylammonium (TEA), metformin, 1-methyl-4-phenylpyridinium, 4-(4-(dimethylamino)styryl)-N-methylpyridinium, and m-iodobenzylguanidine]. They were 95 to 146 µM for hOCT2, providing at most 10% inhibition based on its clinically reported plasma unbound concentrations (3.6-7.8 µM). In contrast, cimetidine is a potent inhibitor of MATE1 and MATE2-K with K(i) values (µM) of 1.1 to 3.8 and 2.1 to 6.9, respectively. The same tendency was observed for mouse Oct1 (mOct1), mOct2, and mouse Mate1. Cimetidine showed a negligible effect on the uptake of metformin by mouse kidney slices at 20 µM. Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of 21.6 µM to examine its effect on the renal disposition of Mate1 probes (metformin, TEA, and cephalexin) in vivo. The kidney- and liver-to-plasma ratios of metformin both were increased 2.4-fold by cimetidine, whereas the renal clearance was not changed. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8.0- and 3.3-fold compared with a control and decreased the renal clearance from 49 to 23 and 11 to 6.6 ml/min/kg, respectively. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.