Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes

Imeglimin is an orally administered first‐in‐class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.73 m² were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration‐time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15–45 ml/min/1.73 m², and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Imeglimin is a first‐in‐class oral agent for the treatment of type 2 diabetes (T2DM) and is excreted unchanged into urine. A Japanese phase IIb study found that 1000 mg b.i.d. was optimal in Japanese population, and phase III studies confirmed significant glucose lowering effect. A Western phase IIb study found an optimal dose of 1500 mg b.i.d.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed the key determinants of imeglimin pharmacokinetics (PKs), recommended doses for patients with renal impairment, and what drives the different optimal doses between Japanese and Western patients with T2DM.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Renal function significantly impacts imeglimin PKs. Recommended doses for patients with renal impairment have been proposed for exposure matching. Differences in estimated glomerular filtration rate (eGFR) comprised the key driver for different optimal doses at which estimated exposures were similar between Japanese and Western patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Doses of imeglimin could be reduced based on eGFR. Exposure responses seemed similar between Japanese and Western patients.     

New Echocardiographic Techniques in the Evaluation of Left Ventricular Mechanics in Subclinical Thyroid Dysfunction

The new echocardiographic techniques for the study of physiopathological intramyocardial phenomena include video densitometry (VD), integrated backscatter (IBS), and color Doppler myocardial imaging (CDMI). Being more independent from cardiac load and from rotational and translational heart motion, these new sensible, noninvasive techniques such as CDMI and IBS show a real incremental value in comparison with conventional echocardiography and allow to detect subtle functional and textural abnormalities of intramural myocardium, partially undetectable by conventional two-dimensional Doppler echocardiography. Subclinical thyroid dysfunction (STD), both in its hypo- and hyperthyroidism form, has a relatively high prevalence in general population (9–15% with a lower percentage of adult males), hence it could be very useful to study more deeply heart involvement in these physiopathological conditions and understand the complex relationship between thyroid and heart. The use of these new ultrasonic techniques in subclinical hypothyroidism helps to detect the early simultaneous involvement of both cardiac cycle phases, which causes a decrease of intramyocardial contractility and an impairment of both active and passive phases of diastole. In subclinical hyperthyroidism, these new ultrasonic techniques permitted to discover more complex and different early cardiac abnormalities of both systolic and diastolic phases.     

Protective effect of silymarin in antigen challenge- and histamine-induced bronchoconstriction in in vivo guinea-pigs

The effects of silymarin on bronchoconstriction induced by antigen challenge and on post-antigen challenge hyperresponsiveness to substance P were evaluated in sensitized guinea-pigs. Silymarin significantly decreased the bronchoconstriction due to antigen administration in the early phase of the response. In contrast, the dose-response curve for substance P recorded 1 h after antigen challenge was not modified by pretreatment with silymarin. The influence of the flavonoid on hyperresponsiveness to histamine in propranolol- and PAF (platelet-activating factor)-treated animals was also assessed. Silymarin did not affect hyperresponsiveness to histamine induced by either propranolol or PAF although it had inhibitory activity on the bronchial contractile response to the autacoid. These results suggest that silymarin has a protective effect in the early phase of allergic asthma, an effect, which may be related to a negative influence of the flavonoid on bronchial responsiveness to histamine.     

Plasma long-chain polyunsaturated fatty acids and neurodevelopment through the first 12 months of life in phenylketonuria

The aims of the study were to examine the relationship between long-chain polyunsaturated fatty acid (LCPUFA) status at diagnosis of phenylketonuria (PKU) and neurodevelopment through the first 12 months of life, and to assess whether any difference exists between infants breastfed and bottlefed in the first days of life on the basis of LCPUFA status. Twenty infants with PKU were prospectively examined through the first year of life. Plasma fatty acids were measured in infants at diagnosis. Plasma phenylalanine levels were determined monthly. Main outcome measures were the Bayley Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) at 5 and 12 months of age, and the visual function at 12 months, evaluated by P100 wave latencies with visual evoked potentials. A higher PDI score was associated with higher plasma arachidonic acid at diagnosis (adjusted correlation coefficient of PDI at 5 months, r=0.38, p=0.05). P100 wave latency at 15 minutes of arc (15') was associated with the early plasma arachidonic acid (adjusted r=-0.56, p=0.02) and phenylalanine levels at 12 months (adjusted r=0.22, p=0.05). No association was found between MDI score and any essential fatty acids. Breastfed infants exhibited higher plasma arachidonic acid (mean difference, delta, =3.4%; 95% confidence interval [CI]=1.2-5.6%) and shorter P100 wave latency at 15' (delta=-21 ms, 95%CI=-30 to -12) than bottlefed infants. Within the population of this study, a weak positive association has been found between plasma LCPUFAs at diagnosis (higher in breastfed infants) and neurodevelopmental indices through the first year of life.     

HIV prevention and adolescents: a sample survey on Italian high school students

This article resulted from a survey carried out by some researchers of the Telefono Verde AIDS (TVA-National AIDS Help-Line) of the Istituto Superiore di Sanità, with the collaboration of some colleagues of the Segreteria per le Attività Culturali. It is also a summary of strategies of intervention against HIV/AIDS for young people implemented by the Italian Ministry of Health. The study was developed within the context of the workshops on HIV/AIDS education carried out since 1995 by some researchers of TVA. These workshops fall within some other initiatives arranged by the Segreteria per le Attività Culturali for the diffusion of scientific and technological information. Our study aimed at assessing the level of knowledge on HIV/AIDS among some different high-school students. Data processing points out a widespread and quite good level of knowledge on HIV/AIDS in general and particularly on ways of transmission and prevention measures. Results obtained could not be generalized because the sample involved in the survey represented a privileged target, already sensitive to the issues concerning HIV infection and AIDS dealt with in the context of specific teaching programmes.     

Targeted delivery of tumor necrosis factor-alpha to tumor vessels induces a therapeutic T cell-mediated immune response that protects the host against syngeneic tumors of different histologic origin.

PURPOSE: We sought to demonstrate that a single systemic administration of L19mTNFalpha (a fusion protein constituted by the scFv L19 specific for the oncofetal ED-B domain of fibronectin and tumor necrosis factor alpha, TNFalpha) in combination with melphalan induced complete and long-lasting tumor eradication in tumor-bearing mice and triggered the generation of a specific T cell-based immune response that protects the animals from a second tumor challenge, as well as from challenges with syngeneic tumor cells of different histologic origin. Experimental Design and RESULTS: Treatment with L19mTNFalpha, in combination with melphalan, induced complete tumor regression in 83% of BALB/c mice with WEHI-164 fibrosarcoma and 33% of animals with C51 colon carcinoma. All cured mice rejected challenges with the same tumor cells and, in a very high percentage of animals, also rejected challenges with syngeneic tumor cells of different histologic origin. In adoptive immunity transfer experiments, the splenocytes from tumor-cured mice protected naive mice both from C51 colon carcinoma and from WEHI-164 fibrosarcoma. Similar results were also obtained in adoptive immunity transfer experiments using severely immunodepressed mice. Experiments using depleted splenocytes showed that T cells play a major role in tumor rejection. CONCLUSIONS: The results show that the selective targeting of mTNFalpha to the tumor enhances its immunostimulatory properties to the point of generating a therapeutic immune response against different histologically unrelated syngeneic tumors. These findings predicate treatment approaches for cancer patients based on the targeted delivery of TNFalpha to the tumor vasculature.