New strategies to improve clinical outcomes for diabetic kidney disease

BACKGROUND: Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. MAIN BODY: This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. CONCLUSION: With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes

Impact of Impaired Renal Function on the Pharmacokinetics of the Antiepileptic Drug Lacosamide

Background and Objective The antiepileptic drug lacosamide is eliminated predominantly via the kidneys. Therefore, an evaluation of the impact of renal impairment on its pharmacokinetic profile is an important component of its safety assessment. The objective of this study was to evaluate the pharmacokinetic profile of lacosamide among individuals with renal impairment (mild, moderate, or severe) and among patients with end-stage renal disease (ESRD), including those on hemodialysis. Methods This was an open-label, Phase I trial. The pharmacokinetics of a single oral 100-mg lacosamide dose were evaluated in five groups of participants: healthy controls, patients with mild, moderate, or severe renal impairment, and patients with ESRD (with and without hemodialysis). Results Forty participants completed the trial, eight in each group. In healthy volunteers, renal clearance accounted for approximately 30 % of total body clearance [geometric mean 0.5897 l/h (coefficient of variation 37.9 %) vs 2.13 l/h (20.8 %)]. With severe renal impairment, renal clearance was approximately 11 % of total body clearance [0.1428 l/h (31.8 %) vs 1.34 l/h (26.9 %)]. Terminal half-life and systemic exposure were increased with renal impairment, while total body clearance, renal clearance, and urinary excretion were decreased. Strong positive correlations between creatinine clearance, renal clearance, and urinary excretion were observed. Among patients with ESRD, approximately 50 % of lacosamide was cleared from systemic circulation by 4-h hemodialysis. In patients with essentially no renal clearance, nonrenal clearance was still present (1.1 l/h). Lacosamide was well tolerated by healthy volunteers and patients. Conclusions In patients with mild-to-moderate renal impairment, lacosamide dose adjustment is not necessary, because total body clearance decreased by only approximately 20 %. Dose adjustment, however, is required for patients with severe renal impairment. Hemodialysis removes approximately 50 % of lacosamide from plasma; therefore, dose supplementation following hemodialysis should be considered

Pharmacokinetics of Serelaxin in Patients with Severe Renal Impairment or End-Stage Renal Disease Requiring Hemodialysis: A Single-dose, Open-label, Parallel-group Study

Serelaxin, a recombinant human relaxin-2, is currently in clinical development for treating acute heart failure. This open-label parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-h intravenous infusion (10μg/kg) in patients with severe renal impairment (n=6) or end-stage renal disease (ESRD) requiring hemodialysis (with PK on the day of dialysis [n=6] or during dialysis-free interval [n=6]) compared with healthy subjects (n=18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with a mean terminal elimination half-life of 6.5–8.8h. Compared to healthy subjects, a moderate decrease in serelaxin systemic clearance (37%–52%) and increase in its exposure (30%–115%) were observed in all patients. During the 4-h hemodialysis in ESRD patients, serelaxin was partially removed (30%) from blood with dialysis clearance constituting approximately 52% of total systemic clearance. Anti-serelaxin antibodies were not detected in any participant, and serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. The observed serelaxin PK differences in patients with severe renal impairment compared with matched healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients

Pharmacokinetics of serelaxin in patients with hepatic impairment: A single-dose, open-label, parallel-group study

Summary AIMS Serelaxin is a recombinant form of human relaxin-2 in development for the treatment of acute heart failure. The present study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included the evaluation of immunogenicity, safety and tolerability of serelaxin. METHODS This was an open-label, parallel-group study (NCT01433458) comparing the PK of serelaxin following a single 24-hour intravenous infusion (30 μg/kg/day) between patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C, respectively), and healthy matched controls. Blood sampling and standard safety assessments were conducted. The primary non-compartmental PK parameters [including area under the plasma concentration-time curve (AUC)0-48h and AUCinf, and serum concentration at 24 hours post-dose (C24h)] were compared between each hepatic impairment group and healthy controls. RESULTS A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 hours and then declined following completion of the infusion with a mean terminal half-life of 7-8 hours. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to an adverse event or deaths were reported. No serelaxin-treatment-related antibodies developed during this study. CONCLUSIONS The PK and safety profile of serelaxin were not affected by hepatic impairment, indicating that dose adjustments are unlikely to be required for such patients

Pharmacokinetics of serelaxin in patients with hepatic impairment: A single-dose, open-label, parallel-group study

AIMS Serelaxin is a recombinant form of human relaxin-2 in development for the treatment of acute heart failure. The present study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included the evaluation of immunogenicity, safety and tolerability of serelaxin. METHODS This was an open-label, parallel-group study (NCT01433458) comparing the PK of serelaxin following a single 24-hour intravenous (IV) infusion (30 μg/kg/day) between patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C, respectively), and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve (AUC)0-48h and AUCinf, and serum concentration at 24 hours post-dose (C24h)] were compared between each hepatic impairment group and healthy controls. RESULTS A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 hours and then declined following completion of the infusion with a mean terminal half-life of 7-8 hours. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to an adverse event or deaths were reported. No serelaxin-treatment-related antibodies developed during this study. CONCLUSIONS The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48-hr IV infusion in patients with hepatic impairment