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Efficacy and safety of trelagliptin in Japanese patients with type 2 diabetes with severe renal impairment or end-stage renal disease: Results from a randomized, phase 3 study.
Kaku, K, Ishida, K, Shimizu, K, Achira, M, Umeda, Y
Journal of diabetes investigation. 2020;(2):373-381
Abstract
INTRODUCTION To investigate the efficacy and safety of trelagliptin 25 mg in patients with type 2 diabetes mellitus with severe renal impairment or end-stage renal disease. MATERIALS AND METHODS This multicenter, randomized, phase 3 study comprised a 12-week double-blind phase followed by a 40-week open-label phase. Patients had type 2 diabetes mellitus with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (undergoing hemodialysis), and were receiving diet and/or exercise therapy with/without one antidiabetic drug. RESULTS Patients were randomized to trelagliptin (A/A, n = 55) or placebo (P/A, n = 52; double-blind phase). Both groups received trelagliptin in the open-label phase. The least square mean change (95% confidence interval [CI]) from baseline in hemoglobin A1c at the end of the double-blind phase was -0.71% (95% CI -0.885, -0.542) and 0.01% (95% CI -0.170, 0.183) in the A/A and P/A groups, respectively (intergroup least square means difference -0.72%, 95% CI -0.966, -0.473; P < 0.0001). Mean hemoglobin A1c decreased after trelagliptin treatment in the P/A group to similar levels observed in the A/A group and remained comparable in both groups versus baseline up to week 52. In the double-blind phase, the incidence of treatment-emergent adverse events (TEAEs) was 72.7% and 61.5% in the A/A and P/A group, respectively; most TEAEs were mild-to-moderate, except in one patient (P/A group), who experienced two severe TEAEs. The incidence of serious TEAEs was 7.3% and 3.8% in the A/A and P/A group, respectively. CONCLUSIONS Once-weekly trelagliptin 25 mg was efficacious, with no major safety concerns, and represents a meaningful treatment option in this patient population.
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The Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Subjects With Type 2 Diabetes Mellitus.
Sahasrabudhe, V, Terra, SG, Hickman, A, Saur, D, Shi, H, O'Gorman, M, Zhou, Z, Cutler, DL
Journal of clinical pharmacology. 2017;(11):1432-1443
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Ertugliflozin is a highly selective and potent inhibitor of the sodium-glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. The glycemic efficacy of sodium-glucose cotransporter 2 inhibitors such as ertugliflozin depends on glucose filtration through the kidney. This phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, pharmacodynamics, and tolerability of ertugliflozin (15 mg) in type 2 diabetes mellitus and healthy subjects with normal renal function (estimated glomerular filtration rate not normalized for body surface area ≥90 mL/min) and type 2 diabetes mellitus subjects with mild (60-89 mL/min), moderate (30-59 mL/min), or severe (<30 mL/min) renal impairment (n = 36). Blood and urine samples were collected predose and over 96 hours postdose for pharmacokinetic evaluation and measurement of urinary glucose excretion over 24 hours. Log-linear regression analyses indicated predicted mean area under the concentration-time curve values for mild, moderate, and severe renal function groups that were ≤70% higher relative to subjects with normal renal function. Generally consistent results were obtained with categorical analysis based on analysis of variance. The increase in ertugliflozin exposure in subjects with renal impairment is not expected to be clinically meaningful. Regression analysis of change from baseline in urinary glucose excretion over 24 hours vs estimated glomerular filtration rate showed a decrease in urinary glucose excretion with declining renal function. A single 15-mg dose of ertugliflozin was well tolerated in all groups.
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Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment.
Kropeit, D, Scheuenpflug, J, Erb-Zohar, K, Halabi, A, Stobernack, HP, Hulskotte, EGJ, van Schanke, A, Zimmermann, H, Rübsamen-Schaeff, H
British journal of clinical pharmacology. 2017;(9):1944-1953
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AIMS: Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment. METHODS This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min-1 1.73m-2 ), moderate (30-59 ml min-1 1.73m-2 ) and severe (<30 ml min-1 1.73m-2 ) impairment. Oral letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses. RESULTS All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCτ,ss and Css,max ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUCτ,ss 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound letermovir concentration (R2 = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R2 = 0.0662, P = 0.2249 and R2 = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R2 = 0.3548, P = 0.0021 and R2 = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose letermovir 120 mg was well tolerated across groups. CONCLUSIONS Renal impairment increased exposure to letermovir, although age was a confounding factor.
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Acetylator Status Impacts Amifampridine Phosphate (Firdapse™) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function.
Haroldsen, PE, Sisic, Z, Datt, J, Musson, DG, Ingenito, G
Clinical therapeutics. 2017;(7):1360-1370
Abstract
PURPOSE The purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse™) and its major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals with slow acetylator (SA) and rapid acetylator (RA) phenotypes. METHODS This was a Phase I, multicenter, open-label study of the PK properties and safety profile of amifampridine phosphate in individuals with normal, mild, moderate, or severely impaired renal function. Amifampridine phosphate was given as a single 10 mg (base equivalent) dose, and the plasma and urine PK properties of amifampridine and its 3-N-acetyl metabolite were determined. The safety profile was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and physical examinations. FINDINGS Amifampridine clearance was predominantly metabolic through N-acetylation, regardless of renal function in both acetylator phenotypes. In individuals with normal renal function, mean renal clearance represented approximately 3% and 18% of the total clearance of amifampridine in RA and SA, respectively. Large differences in amifampridine exposure were observed between acetylation phenotypes across renal function levels. Mean amifampridine exposure values of AUC0-∞ and Cmax were up to 8.8-fold higher in the SA group compared with the RA group across renal function levels. By comparison, mean AUC0-∞ was less affected by renal function within an acetylator group, only 2- to 3-fold higher in individuals with severe renal impairment (RI) compared with those with normal renal function. Exposure to amifampridine in the SA group with normal renal function was higher (AUC0-∞, approximately 1.8-fold; Cmax, approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC0-∞ from normal to severe RI. No new tolerability findings were observed. IMPLICATIONS A single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting Firdapse™ administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35.
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Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301.
Miller, AA, Murry, DJ, Owzar, K, Hollis, DR, Kennedy, EB, Abou-Alfa, G, Desai, A, Hwang, J, Villalona-Calero, MA, Dees, EC, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;(11):1800-5
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PURPOSE We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction. PATIENTS AND METHODS Patients were assigned to one of nine cohorts: cohort 1, bilirubin < or = upper limit of normal (ULN) and AST < or = ULN and creatinine clearance (CC) > or = 60 mL/min; cohort 2, bilirubin more than ULN but < or = 1.5x ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5x ULN to < or = 3x ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3x ULN to 10x ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8. RESULTS Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found. CONCLUSION We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.
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Antiretroviral therapy improves renal function among HIV-infected Ugandans.
Peters, PJ, Moore, DM, Mermin, J, Brooks, JT, Downing, R, Were, W, Kigozi, A, Buchacz, K, Weidle, PJ
Kidney international. 2008;(7):925-9
Abstract
Renal dysfunction is a severe complication of advanced HIV disease. We evaluated the impact of highly active antiretroviral therapy (HAART) on renal function among HIV-infected Ugandans in the Home-Based AIDS Care clinical trial. The patients presented with symptomatic HIV disease or CD4 cell count < or = 250 cells/mm(3) and creatinine clearances above 25 ml/min determined by the Cockcroft-Gault equation. Of the 508 patients at baseline, 8% had a serum creatinine over 133 micromol/l and about 20% had reduced renal function evidenced by a creatinine clearance between 25 and 50 ml/min. After 2 years of HAART, the median serum creatinine was significantly decreased by 16% while the median creatinine clearance significantly increased 21%. The median creatinine clearance of patients with renal dysfunction at baseline, increased by 53% during 2 years of treatment. In multivariable analysis, a baseline creatinine above 133 micromol/l, a weight gain of more than 5 kg over the 2 years, female gender and a WHO stage 4 classification were all associated with greater improvements in creatinine clearance on HAART. Our study shows that renal dysfunction was common with advanced HIV disease in Uganda but this improved following 2 years of HAART.
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Hypertonic saline solution for renal failure prevention in patients with decompensated heart failure.
Issa, VS, Bacal, F, Mangini, S, Carneiro, RM, Azevedo, CH, Chizzola, PR, Ferreira, SM, Bocchi, EA
Arquivos brasileiros de cardiologia. 2007;(4):251-5
Abstract
BACKGROUND Hyponatremia and congestive phenomena indicate a bad prognosis in decompensated heart failure. The occurrence of renal failure is associated to an increased death risk. OBJECTIVE To evaluate the safety and efficacy of the hypertonic saline solution in patients with decompensated heart failure for renal failure prevention. METHODS Patients with decompensated heart failure, congestion and hyponatremia participated in the study. In addition to the standard treatment, the patients received hypertonic saline solution and were submitted to clinical as well as laboratory assessment. RESULTS Nine patients were enrolled in the study. Mean age was 55 + 14.2 years, being 5 male (55.5%) and 4 (44.5%) female patients. All of them presented functional class III-IV of the New York Heart Association (NYHA), and 5 (55.5%) received dobutamine. All of them presented initial creatinine > 1.4 mg/dl. The mean tonicity of the solution was 4.39% + 0.018% (2.5% to 7.5%) and the duration of treatment was 4.9 days + 4.1 days (1-15 days). There were no severe adverse effects; none of the patients presented clinical worsening or neurologic disorders; hypokalemia occurred in 4 cases (44.5%). The comparison of the variables before and after treatment showed a decrease in urea (105 mg/dl + 74.8 mg/dl vs. 88 mg/dl + 79.4 mg/dl; p = 0.03) and increase in the urinary volume (1,183 ml/day vs. 1,778 ml/day; p = 0.03); there was no tendency to creatinine decrease (2.0 mg/dl + 0.8 mg/dl vs. 1.7 mg/dl + 1.0 mg/dl; p = 0.08). Despite the elevation in sodium levels (131 mEq/l + 2.8 mEq/l vs. 134 mEq/l + 4.9 mEq/l) and weight decrease (69.5 kg + 18.6 kg vs. 68.2 kg + 17.1 kg), there was no statistically significant difference. CONCLUSION The use of hypertonic saline solution in patients with decompensated heart failure can be a safe therapeutic method and potentially related to clinical improvement and renal failure prevention.
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Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: a multicenter randomized clinical trial.
Yoshida, EM, Marotta, PJ, Greig, PD, Kneteman, NM, Marleau, D, Cantarovich, M, Peltekian, KM, Lilly, LB, Scudamore, CH, Bain, VG, et al
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2005;(9):1064-72
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Posttransplant chronic renal failure, secondary to calcineurin inhibitor agents, is emerging as a major problem in liver transplantation. We report a randomized clinical trial comparing daclizumab, delayed low-dose tacrolimus (target trough level 4-8 ng/mL, starting day 4-6), Investigational Arm (n = 72), to standard tacrolimus induction/maintenance dosing, Standard Arm (n = 76), with mycophenolate mofetil and tapering corticosteroids in both study arms. The end-points were renal function indicated by the Modification of Diet in Renal Disease (MDRD). There was no significant difference in patient survival (86.6% Investigational Arm vs. 92.9% Standard Arm; P = 0.21) or acute rejection (23.2% vs. 27.7%, respectively; P = 0.68). Statistically significant differences in median glomerular filtration rate (GFR) were found in favor of the Investigational Arm. With the CG equation, the GFR at the end of the first week was 110.7 vs. 89.6 mL/min (P = 0.019) without significant differences thereafter. With the MDRD, statistically significant differences extended to the first posttransplant month (86.8 vs. 70.1 mL/min/1.73 m(2); P < 0.001) with and was seen at month 6 (75.4 vs. 69.5 mL/min/1.73 m(2); P = 0.038). In conclusion, delayed low-dose tacrolimus, in combination with daclizumab and mycophenolate mofetil, preserves early renal function post-liver transplantation without the cost of increased acute rejection.