Moderate Renal Impairment Groups Research Articles

Low-dose apatinib in subjects with renal impairment: A pharmacokinetics study

ObjectiveIn patients with renal impairment, we studied apatinib and its major metabolites (M1–1, M1–2, M1–6, and M9–2) for pharmacokinetics. MethodsSubjects with different renal functions were given a single oral dose of apatinib mesylate tablets of 250 mg. Pharmacokinetic samples were collected at 1 hour before dosing,0.25, 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, and 96 h after dosing. The pharmacokinetic parameters of apatinib and its major metabolites were calculated by noncompartmental analysis. ResultsComparing PK parameters of the mild or moderate renal impairment group with the healthy group: the geometric mean ratios of maximum observed drug concentration (Cmax), the area under the plasma drug concentration-time curve from time 0 to the final quantifiable time (AUC0-t), and the area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0–inf) were all about one. No significant effect of mild and moderate renal impairment on apatinib pharmacokinetics was observed. Mild and moderate renal impairment was also not observed to have a significant effect on the pharmacokinetics of metabolites M1–1, M1–2, and M1–6. However, mild and moderate renal impairment had a certain increase in exposure to the metabolite M9–2. Considering that M9–2 has no inhibitory effect on protein tyrosine kinase, it has no clinical significance. In addition, the proportion of cumulative excretion of apatinib and its major metabolites was small and almost negligible in all three groups of subjects. ConclusionPatients with mild and moderate renal impairment do not need to adjust the dose of apatinib when using low dose (250 mg) apatinib.

Association of albumin, globulin and albumin/globulin ratio with renal injury in type 2 diabetic nephropathy patients

BackgroundStudies have shown that albumin/globulin ratio (AGR) can assess the extent of kidney damage in type 2 diabetic nephropathy (T2DN). However, there is a lack of similar clinical data to support this.ObjectivesThis study sought to inquire into the correlation of albumin (ALB), globulin (GLB) and albumin/globulin ratio (AGR) with renal injury in patients with type 2 diabetes mellitus (T2DM).MethodsA retrospective analysis was performed on the clinical data of 82 patients with T2DM (Control group) and 110 patients with type 2 diabetic nephropathy (T2DN) who were admitted to the First Affiliated Hospital of Wannan Medical College from October 2019 to April 2022. T2DN patients were classified into mild renal impairment group (n = 75) and moderate renal impairment group (n = 35) according to urinary albumin excretion rate (UAER). Then, the general data of all groups were compared. Furthermore, Pearson correlation was used to analyze the correlation of serum ALB, GLB and AGR with UAER in the three groups. A receiver operating characteristic curve (ROC) was utilized to evaluate the diagnostic value of ALB, GLB and AGR for moderate renal injury in T2DN patients.ResultsThere were significant differences in course of disease, history of hypertension, levels of fasting plasma glucose and glycosylated hemoglobin among the three groups. Besides, compared with the Control group, the levels of ALB and AGR were lower while GLB levels were higher in the mild and moderate renal impairment group. In particular, ALB and AGR levels were lower in the moderate renal impairment group relative to the mild renal impairment group, but the GLB levels exhibited no significant difference between the two groups. According to the results of Pearson correlation analysis, a negative correlation of ALB and AGR levels with UAER was revealed in T2DN patients. ROC curves displayed the area under the curve (AUC) of ALB (0.88) and AGR (0.71) predicting moderate renal injury in T2DM patients (p < 0.05). However, GLB has no significant diagnostic value for moderate renal injury in patients with T2DN.ConclusionThe course of disease, hypertension and glycemic control may affect the occurrence and development of T2DN. ALB and AGR are of high value in predicting renal injury in patients with T2DN and can serve as the foundation for the clinical diagnosis of the condition.

Effects of Renal Impairment on the Pharmacokinetics, Efficacy, and Safety of Inclisiran: An Analysis of the ORION-7 and ORION-1 Studies

ObjectiveTo investigate the pharmacodynamic properties of inclisiran, a small interfering RNA targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), in individuals with normal renal function and renal impairment (RI). Patients and MethodsThe analysis included participants with normal renal function and mild, moderate, and severe RI from the phase 1 ORION-7 renal study (n=31) and the phase 2 ORION-1 study (n=247) who received 300 mg of inclisiran sodium or placebo. ResultsIn ORION-7, PCSK9 values were reduced at day 60 in the normal renal function group (68.1%±12.4%), mild RI group (74.2%±12.3%), moderate RI group (79.8%±4.9%), and severe RI group (67.9%±16.4%) (P<.001 vs placebo in all groups). Low-density lipoprotein cholesterol levels were significantly reduced versus placebo: normal renal function, 57.6%±10.7%; mild RI, 35.1%±13.5%; moderate RI, 53.1%±21.3%; severe RI, 49.2%±26.6% (P<.001 for all). In ORION-1, PCSK9 level reductions at day 180 were 48.3% to 58.6% in the 300-mg single-dose groups and 67.3% to 73.0% in the 300-mg 2-dose groups (P<.001 vs placebo in all groups). The corresponding low-density lipoprotein cholesterol level reductions were 35.7% to 40.2% in the 300-mg single-dose groups and 50.9% to 58.0% in the 300 mg 2-dose groups (P<.001 vs placebo in all groups). In ORION-7, exposure to inclisiran was proportionally greater in individuals with increasing RI; inclisiran was undetectable in plasma 48 hours after administration in any group. ConclusionThe pharmacodynamic effects and safety profile of inclisiran were similar in study participants with normal and impaired renal function. Dose adjustments of inclisiran are not required in these patients. Trial Registrationclinicaltrials.gov Identifiers: NCT02597127 and NCT03159416

P3849Baseline profile of patients treated for acute venous thromboembolism in routine clinical practice according to age and renal function in the RE-COVERY DVT/PE global cohort study

Abstract Background Observational studies provide the opportunity to evaluate routine practice without the selection and treatment criteria imposed in randomized clinical trials (RCTs). Purpose Using data from the RE-COVERY DVT/PE global observational study (enrolment January 2016 to May 2017), we describe the baseline profile of patients treated for acute venous thromboembolism (VTE) in routine clinical practice according to age and renal function. Methods Baseline patient characteristics, clinical features (comorbidities/medical history), and anticoagulant therapy were tabulated descriptively for the subgroups of age (&lt;75, ≥75 years) and creatinine clearance (&lt;30, 30 to &lt;50 [moderate impairment], 50 to &lt;80 [mild impairment], ≥80 mL/min). Anticoagulant therapy at baseline and at hospital discharge or 14 days after diagnosis (whichever was later) was recorded. Results In this observational study of 6122 patients with acute deep vein thrombosis, the proportions of patients at baseline who were ≥75 years of age (25.2%) or who had mild to moderate renal impairment (38.1%) were higher than in RCTs of non-vitamin K antagonist oral anticoagulants (NOACs) for acute VTE treatment (∼12–13% elderly and ∼26–29% with mild or moderate renal impairment) (from analyses of the RE-COVER trials; Hokusai-VTE and AMPLIFY). Older patients and those with renal impairment were more often female and were more likely to have comorbidities than the younger or normal renal function groups (Table). At the time of hospital discharge or 14 days after diagnosis, whichever was later, the majority was treated with NOACs (54%). Vitamin K antagonists were prescribed to approximately 1 in 5 patients. The use of NOACs decreased with worsening renal function, whereas the proportions treated with parenteral anticoagulation alone increased in the moderate renal impairment group compared with patients with normal renal function. Conclusion The population treated for acute VTE in routine clinical practice includes more elderly and renally impaired patients than represented in RCTs. These baseline data provide a snapshot of patient characteristics and patterns of anticoagulant therapy. Acknowledgement/Funding Funded by Boehringer Ingelheim

Risk Factors for Bleeding Events with Enoxaparin, Dabigatran and Fondaparinux in Hospitalized Patients with Varying Levels of Renal Impairment

Background: Anticoagulants with renal elimination may accumulate in patients with renal impairment and potentially increase the risk of bleeding. Limited data are available to elucidate the potential bleeding risk present in patients with moderate renal impairment defined as creatinine clearance of 30-50 mL/min. Objective: To evaluate potential risk factors for bleeding over various renal function ranges in patients on enoxaparin, fondaparinux, or dabigatran. Methods: Retrospective chart review from 2010 until 2011 identified patients who incurred a bleeding episode on therapeutic dosed enoxaparin, dabigatran, or fondaparinux stratified according to renal function and presence of pre-defined potential risk factors for bleeding. Bleeding episodes identified using UHC Safety Intelligence, a selfreporting database used to identify safety improvement opportunities. Results: A total of 27 (2.16%) bleeding episodes were identified, 20 occurring during enoxaparin pharmacotherapy and 7 during treatment with dabigatran. There were no fondaparinux bleeds identified. Patients with normal renal function, moderate renal impairment and severe renal impairment incurred 9, 12 and 6 bleeds, respectively. Conclusion: A similar number of patients incurred bleeding episodes on enoxaparin in the normal renal function group and moderate renal impairment group. Patients experiencing bleeding episodes in the enoxaparin group with moderate renal impairment were of advanced age and female. Enoxaparin bleeding episodes were noted in patients with hypertension in all renal function ranges. Patients who bled on dabigatran had some degree of renal impairment and were of advanced age. Concomitant p-glycoprotein inhibitor use was observed in patients with bleeding episodes on dabigatran in patients with renal impairment.

An Open-Label, Phase 1 Study Evaluating the Safety and Pharmacokinetics of Pralatrexate in Relapsed/Refractory Advanced Solid Tumors or Advanced Lymphoma/Myeloma Patients with Mild, Moderate, and Severe Renal Impairment

Introduction: Pralatrexate is a folate analogue indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) that is preferentially taken up in cancer cells through the reduced folate carrier. While 34% of pralatrexate is excreted unchanged in the urine following a single, 30 mg/m2 dose administered as an IV push, a population PK analysis showed that drug clearance decreased with decreasing creatinine clearance. In addition, methotrexate, also a folate analogue, does need to be dose-reduced for patients with moderate or severe renal impairment. Pralatrexate, however, has not been formally tested in patients with renal impairment, and previous studies excluded patients with severe renal impairment. This study was, therefore, conducted to determine the need for pralatrexate dosing adjustments in patients with renal impairment.Methods: This was an open label, nonrandomized, Phase 1 study to determine the PK profile of pralatrexate in patients with relapsed/refractory advanced solid tumors or advanced lymphoma/myeloma with renal impairment. Primary objective of the study was to establish dosing recommendation of pralatrexate in renally compromised patients and to determine the pharmacokinetic profile in these patients. Four cohorts (n=6 per cohort) were planned to be enrolled in this study for a total of 24 patients. Patients with normal renal function (eGFR ≥90 mL/min/1.73 m2, Cohort A), mild (eGFR= 60 to <90 mL/min/1.73 m2, Cohort B) and moderate renal function (eGFR = 30 to < 60 mL/min/1.73 m2, Cohort C) were dosed with 30 mg/m2 pralatrexate once weekly for 6-weeks in a 7-week cycle. The pralatrexate dose was empirically reduced to 20 mg/m2 in patients with severe renal impairment (eGFR = 15 to < 30 mL/min/1.73 m2, Cohort D). Plasma and urine samples were collected at pre-specified time points to determine the PK profile. Patients who continued treatment with pralatrexate were then followed for safety and tolerability.Results: A total of 29 patients (14 male and 13 female) were enrolled in the study with 6 patients in each cohort. There were slightly more male patients (n=14, 52%) than female patients (n=13, 48%) enrolled; fewer males (33%) were in the mild renal impairment group and more males (83%) were in the moderate renal impairment group. The median age was 62.0 years. The majority of patients were White (n=22, 81%); the remaining patients were Black (n=5, 19%). Because of a qualifying toxicity in Cohort C, the starting dose was reduced to 15 mg/m2 in Cohort D. The major effect of chronic renal impairment was to decrease renal clearance of the pralatrexate diastereomers, PDX-10a and PDX-10b, but systemic exposure to these diastereomers was not dramatically affected by renal impairment. Mean total exposures of PDX-10a and PDX-10b were comparable across cohorts, including Cohort D. The empiric dose reduction to 15 mg/m2 in Cohort D was able to match the average exposures for Cohort A (with normal dose of 30 mg/m2). Although Cohorts B and C had elevated mean exposures and higher inter-patient variability than Cohorts A and D, it appears to be a result of non-renal factors. In summary, total exposures of PDX-10a and PDX-10b after a single IV injection of racemic pralatrexate are not dramatically affected by renal impairment.There was no apparent difference in either the incidence or types of TEAEs between the four treatment cohorts, and, therefore, the safety of pralatrexate was not affected by differences in renal function. The most common treatment related AEs were stomatitis (n=23, 83%), nausea (n=10, 37%), anemia (n=7, 26%) and fatigue (n=6, 22%).Conclusion: The pralatrexate exposure in patients with mild or moderate renal impairment is similar to the patients with normal renal function at a dose of 30 mg/m2. For patients with severe renal impairment, a pralatrexate dose of 15 mg/m2 is recommended. DisclosuresGabrail:Sanofi: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Onyx: Honoraria, Speakers Bureau; BI: Honoraria, Speakers Bureau. Edenfield:Celgene: Research Funding. Reddy:spectrum: Employment, Equity Ownership.

Safety, Tolerability, and Pharmacokinetics of Ribavirin in Hepatitis C Virus-Infected Patients with Various Degrees of Renal Impairment

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

Pharmacokinetics of Intravenous Conivaptan in Subjects With Hepatic or Renal Impairment

Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved in the United States as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. The pharmacokinetics of intravenous conivaptan had not been studied in patients with hepatic or renal impairment. The objective of this study was to assess the pharmacokinetics and tolerability of intravenous conivaptan in subjects with mild or moderate hepatic or renal impairment compared with subjects with normal function. These studies were phase I, open-label pharmacokinetic studies conducted at two sites in the US. Men and non-pregnant women 30-70 years of age were allocated to the mild (Child-Pugh classification score of 5-6) or moderate (Child-Pugh classification score of 7-9) hepatically impaired groups (n = 8-9 per group) based on their liver function assessed at screening. For the renal study, men and non-pregnant women between 18 and 70 years of age were assigned to renal function groups (n = 8-9 per group) based on estimated glomerular filtration rate (eGFR) assessed at screening. Normal renal function was defined as an eGFR >80 ml/min, mild renal impairment as 50-80 ml/min, and moderate renal impairment as 30-49 ml/min. Subjects with normal hepatic or renal function were selected to match the race, sex, age, and body mass index of subjects enrolled in the impaired groups. Subjects were administered a 20-mg/30-min intravenous loading dose of conivaptan on day 1, followed by a 20-mg/23.5-h continuous conivaptan infusion. On day 2, immediately following the end of the day 1 infusion, a 20-mg/24-h continuous conivaptan infusion was administered. Primary pharmacokinetic parameters estimated were the area under the plasma conivaptan concentration-time curve from time 0 to infinity (AUC∞), plasma conivaptan concentrations at the end of the 20-mg loading dose (C LD), and plasma conivaptan concentrations at the end of the second day 20-mg/24-h continuous infusion (C 48). For each of C LD, C 48, and AUC∞, the mean values were similar for subjects with mild hepatic impairment and subjects with normal hepatic function. Subjects with moderate hepatic impairment had a 73 % higher C 48 and an 80 % higher AUC∞ compared with subjects with normal hepatic function. There were no clinically relevant changes in conivaptan exposure in the mild and moderate renal impairment groups compared with subjects with normal renal function. Intravenous conivaptan was generally well tolerated in subjects with mild or moderate hepatic or renal impairment. Infusion-site reaction was the most commonly reported adverse event. Overall exposure to conivaptan increased in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. Therefore, in patients with moderate hepatic impairment, conivaptan should be initiated with a loading dose of 10 mg over 30 min followed by 10 mg per day as a continuous infusion for 2-4 days, which is half the approved dose. No dose adjustment is necessary in patients with mild or moderate renal impairment and in patients with mild hepatic impairment.

Efficacy and Pharmacokinetics of Adefovir Dipivoxil Liquid Suspension in Patients With Chronic Hepatitis B and Renal Impairment

The study evaluated whether a liquid suspension of adefovir dipivoxil (ADV) is effective and safe when dose adjusted based on varying degrees of renal impairment in patients with chronic hepatitis B. Patients had stable mild, moderate, or severe renal impairment or end-stage renal disease. Twenty-eight patients were enrolled: 10 (mild), 12 (moderate), and 6 severe renal impairment or end-stage renal disease with hemodialysis. Statistical testing demonstrated that daily dosages of ADV liquid suspension at 10 mg and 5 mg in the mild and moderate renal impairment groups, respectively, were clinically similar to ADV 10-mg tablets. However, the antiviral effect observed with the 5-mg/d dose was clearly numerically less than that observed with the 10-mg/d dose. Steady-state adefovir plasma exposures after administration of the ADV liquid suspension were generally within the ranges observed in patients with normal renal function. Treatment with ADV liquid suspension for up to 48 weeks was generally well tolerated. The daily dose-adjustment approach was not clearly safer or more efficacious than the dosing-interval adjustment. Therefore, the results do not support daily ADV dosing using a liquid suspension over the current strategy of adjustment of the ADV dosing interval in patients with impaired renal function.

Effect of renal impairment on the pharmacokinetics of exenatide

What is already known about this subjectNonclinical studies have shown that exenatide is primarily cleared by the renal system.It was not known to what degree the clinical pharmacokinetics and tolerability would be affected by increasing renal impairment (RI).What this study adds Patients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide.However, exenatide is not recommended in patients with severe RI or end-stage renal disease.AimsTo evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI).MethodsExenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft–Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL.ResultsMean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.).ConclusionsSince tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD.

Effect of Drospirenone on Serum Potassium and Drospirenone Pharmacokinetics in Women With Normal or Impaired Renal Function

This open-label study investigated whether drospirenone, a novel progestin with antimineralocorticoid properties, increases the risk for hyperkalemia in subjects with renal impairment. Women with normal renal function and mild or moderate renal impairment were given drospirenone 3 mg/d for 14 days. Mean serum potassium concentrations did not significantly change during steady-state drospirenone treatment. No difference in drospirenone effects on serum potassium concentrations in subjects with renal insufficiency versus subjects with normal renal function was found. Steady-state pharmacokinetics was similar in subjects with normal renal function and mild renal impairment, whereas, due to results from 1 subject, drospirenone exposure was slightly higher in the moderate renal impairment group. Given the reported tolerability of drospirenone, this small increase in serum drospirenone is not expected to be clinically significant. In conclusion, this study demonstrated that drospirenone has no significant effect on serum potassium levels in patients with mild to moderate renal insufficiency.