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.

Improved cardiometabolic risk factors in Japanese patients with type 2 diabetes treated with ipragliflozin: a pooled analysis of six randomized, placebo-controlled trials.

To examine differential improvements among cardiovascular risk factors in response to treatment with ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients, we conducted a pooled analysis of six randomized, double-blind trials of Japanese T2DM patients who received ipragliflozin 50 mg/day or placebo and had patient-level data for cardiometabolic risk parameters. Risk factors included glycated hemoglobin (HbA1c), body weight, homeostatic model assessment for insulin resistance and beta-cell function (HOMA-R and HOMA-beta, respectively), systolic blood pressure, fasting serum insulin concentrations, and the concentration of uric acid, lipids, and liver enzymes from baseline to end of treatment (EOT; 12-24 weeks). The primary endpoint of each trial was the change in HbA1c from baseline to EOT. Changes in risk factors from baseline to EOT were compared between ipragliflozin-treated and placebo groups, and between two subgroups (high- and low-risk groups for each parameter). All parameters, except low-density lipoprotein cholesterol (LDL-C) and non high-density lipoprotein cholesterol (non HDL-C), improved significantly in the ipragliflozin group. Subgroup analysis revealed a significantly greater improvement in the high-risk group versus low-risk group in HbA1c, HOMA-R, HOMA-beta, aspartate transaminase, alanine transaminase, and gamma-glutamyltransferase, but not in any of the lipid parameters or blood pressure. Liver function improvement in the ipragliflozin group was significantly correlated with changes in body weight, HbA1c, HOMA-beta, and HOMA-R. This analysis demonstrated that, in Japanese T2DM patients, ipragliflozin 50 mg/day was associated with improvements in cardiometabolic risk factors, except for LDL-C and non HDL-C.

Analysis of Pediatric Drug Approval Lag in Japan.

BACKGROUND: Drugs should be made available to all patients in a timely manner regardless of whether they are adults or children. In contrast to the United States (US) and the European Union (EU), no laws mandating pediatric drug development have been established in Japan. The objective of this study was to examine the current status and characteristics of pediatric drug development in Japan using information on the approval lag for pediatric indications between Japan and the EU. METHODS: Drugs approved for pediatric indications between January 2007 and December 2018 in Japan were studied. The approval lag for pediatric indications between Japan and the EU was calculated and analyzed by approval time and the Anatomical Therapeutic Chemical (ATC) classification. Factors potentially affecting the approval lag, such as orphan drug status, company nationality, and clinical data package, were examined. RESULTS: The median approval lag for 105 drugs with pediatric indications in both Japan and the EU was 1017 days (Japan was behind). The lag for ATC category B improved significantly after 2011, and for category L after 2015; the medians were less than half a year. The lag for drugs developed globally via multi-regional clinical trials was significantly shorter compared with drugs developed regionally. CONCLUSION: Global clinical trials are the most effective means of shortening approval lag time in pediatric drug development. Global development is making rapid progress for many adult diseases, thereby creating an environment for proactive participation in global clinical trials even for pediatric drugs. For further improvement, more active drug development for pediatric indication is recommended in tandem with the US and the EU.

Pediatric Drug Development in Japan: A Comparison of the Current Situation and Characteristics Between Japan and Europe.

BACKGROUND: In contrast to the European Union and the USA, no laws or regulations mandating pediatric drug development have been established in Japan. Based on the information on drugs approved for pediatric indications in Europe and Japan, we evaluated the recent status of pediatric drug approvals and their characteristics in Japan in comparison with those of Europe. METHODS: Drugs approved for pediatric indications between 2007 and 2015 in both regions were included in the study. The proportion of drugs with pediatric indications was calculated by the Anatomical Therapeutic Chemical (ATC) classification, and the status of pediatric formulation development was examined. The time from adult to pediatric indication approval was determined. RESULTS: A total of 135 drugs were approved for pediatric indications in Europe, with 208 approved in Japan. The proportion of drugs with pediatric indications in Japan among those approved for pediatric indications in Europe was lower among those with ATC classifications of N (Nervous system) and J (Antiinfectives for systemic use) and those with the development of pediatric formulations than among others. Excepting drugs for which adult and pediatric indications were simultaneously approved, the most commonly observed period from the adult indication approval to the pediatric indication approval was more than 12 years in Japan and 3-6 years in Europe. CONCLUSION: The present findings suggested that pediatric development is indeed being promoted in Japan. However, the period from adult to pediatric indication approval was longer in Japan than in Europe, and the development of pediatric drugs for certain diseases has been sluggish, indicating room for further improvement.

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.

Effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus: a pooled analysis of six randomized, placebo-controlled clinical trials.

Our aim was to examine the effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus (T2DM). We conducted a pooled analysis of double-blind trials of Japanese T2DM patients, randomized to 50 mg ipragliflozin or placebo, with patient-level data for the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to end of treatment (12-24 weeks). Data from six trials were analyzed: ipragliflozin was administered as monotherapy in two; in combination with metformin, pioglitazone, or sulfonylurea in one each; and in combination with prior therapy in patients with renal impairment in one. Overall, 628 and 368 patients were treated with ipragliflozin and placebo, respectively. The placebo-adjusted mean changes (95 % confidence interval) in SBP and DBP (mmHg) were -2.8 (-4.4, -1.3, P < 0.001) and -1.6 (-2.7, -0.6, P < 0.002), respectively, in all patients. The reductions in SBP and DBP were significantly greater in patients with baseline SBP ≥140 mmHg [-5.5 (-9.1, -1.8) and -2.9 (-5.3, -0.5), respectively] than in patients with SBP <140 mmHg [-2.1 (-3.8, -0.4) and -1.3 (-2.5, -0.1), respectively]. The reductions in SBP and DBP were also significantly greater in the ipragliflozin group than in the placebo group in patients treated with [-2.8 (-5.1, -0.4) and -2.4 (-4.0, -0.8), respectively] or without [-3.0 (-5.0, -1.0) and -1.0 (-2.4, 0.4), respectively] concomitant antihypertensive therapy. In conclusion, this pooled analysis showed that ipragliflozin was associated with significant reductions in SBP and DBP compared with placebo.

Efficacy and safety of ipragliflozin in Japanese patients with type 2 diabetes stratified by body mass index: A subgroup analysis of five randomized clinical trials.

AIMS/INTRODUCTION: The influence of overweight/obesity on the clinical efficacy and safety of sodium-glucose co-transporter 2 inhibitors is unclear. We carried out a pooled analysis to examine the impact of body mass index on the efficacy and safety of ipragliflozin. MATERIALS AND METHODS: Patient-level data were pooled for five Japanese double-blind trials (NCT00621868, NCT01057628, NCT01135433, NCT01225081 and NCT01242215) in which patients were randomized to ipragliflozin or a placebo as monotherapy, or in combination with metformin, pioglitazone or a sulfonylurea. Outcomes included the changes in hemoglobin A1c, fasting plasma glucose, bodyweight and treatment-emergent adverse events. Patients were divided into four body mass index categories. RESULTS: Hemoglobin A1c, fasting plasma glucose and bodyweight decreased significantly in the ipragliflozin group compared with the placebo group in all body mass index categories, and in the total cohort (all P < 0.001). Hemoglobin A1c did not improve in 11.2 and 69.2% of patients in the ipragliflozin and placebo groups, respectively. The change in hemoglobin A1c was weakly correlated with the change in bodyweight in all patients (r = 0.136, P = 0.002). Regarding laboratory variables, the placebo-subtracted difference tended to be greater in patients with higher body mass index for aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase and uric acid. The incidences of treatment-emergent adverse events were similar between the ipragliflozin and placebo groups in all patients combined and in the four body mass index categories. CONCLUSIONS: These results show that the efficacy and safety of ipragliflozin are not influenced by obesity/overweight in Japanese patients.

Realistic prediction of solid pharmaceutical oxidation products by using a novel forced oxidation system.

This study investigated a novel solid-state-based forced oxidation system to enable a realistic prediction of pharmaceutical product oxidation, a key consideration in drug development and manufacture. Polysorbate 80 and ferric(III) acetylacetonate were used as an organic hydroperoxide source and a transition metal catalyst, respectively. Homogeneous solutions of target compounds and these reagents were prepared in a mixed organic solvent. The organic solvent was removed rapidly under reduced pressure, and the oxidation of the resulting dried solid was investigated. Analysis of the oxidation products generated in test compounds by this proposed forced oxidation system using HPLC showed a high similarity with those generated during more prolonged naturalistic drug oxidation. The proposed system provided a better predictive performance in prediction of realistic oxidative degradants of the drugs tested than did other established methods. Another advantage of this system was that the generation of undesired products of hydrolysis, solvolysis, and thermolysis was prevented because efficient oxidation was achieved under mild conditions. The results of this study suggest that this system is suitable for a realistic prediction of oxidative degradation of solid pharmaceuticals.

Mechanistic study of the oxidative degradation of the triazole antifungal agent CS-758 in an amorphous form.

In this study, the degradates generated from a pharmaceutical solid were characterized, and a mechanistic pathway underlying their formation was proposed. The chemical stability of a novel triazole antifungal drug, CS-758, deteriorated significantly when the crystal was disordered, and characteristic degradates were generated. A total of eight degradates in solution and nine degradates in a solid state were isolated by preparative liquid chromatography. Degradates were characterized using high-performance liquid chromatography-photodiode array, mass spectrometry, and nuclear magnetic resonance. Radical-mediated oxidation is proposed as the main degradation pathway in the solid state. The initiation step of this pathway is hydrogen atom abstraction from a methine carbon that is adjacent to a dien moiety and the formation of a delocalized vinylic radical intermediate. Molecular oxygen is then added to the radical position to form hydroperoxides. There are three potential oxidation routes based on the proposed autoxidation pathway that lead to the generation of the dioxane ring-opening hydroxyl form, the 9,10-epoxide form, or the 11,12-epoxide form, depending on the substituted position of the added molecular oxygen. The epimer compound generated via the vinylic radical intermediate and sulfoxides was characterized. This degradation mechanism provides the scientific foundation for an oxidative stressing system currently under investigation.

Mechanistic study on degradation of azelnidipine solution under radical initiator-based oxidative conditions.

We identified four degradants (Dg-A, Dg-B, Dg-C, Dg-D) of azelnidipine to be generated under radical initiator-based oxidative conditions and proposed the mechanistic pathway for their formation. 2,2'-Azobisisobutyronitrile was used as a radical initiator. There appeared to be two major pathways in the oxidation of the 1,4-dihydropyridine moiety. One was initiated by hydrogen abstraction from the C-4 position of the dihydropyridine ring, followed by hydrogen abstraction from the N-1 position, leading to aromatization of the dihydropyridine ring and Dg-A generation. The other was initiated by hydrogen abstraction from the N-1 position of the dihydropyridine ring followed by oxidation and hydrolysis to yield Dg-B. Furthermore, Dg-B was subjected to hydrolysis to generate Dg-C and Dg-D. It has been revealed that the rate of the Dg-B degradation was predominantly governed by the water content of the solvent used. Water participation in Dg-B degradation was proved by monitoring the incorporation of heavy oxygen atom ((18)O) into the structure with LC-MS, in which the experiment was carried out in a medium prepared with heavy oxygen water to label (18)O during the hydrolysis.