scholarly journals Effect of Impaired Renal Function on the Pharmacokinetics of Tomopenem (RO4908463/CS-023), a Novel Carbapenem

2008 ◽  
Vol 52 (7) ◽  
pp. 2360-2366 ◽  
Author(s):  
Navita L. Mallalieu ◽  
Siân Lennon ◽  
Mei Liu ◽  
Christopher Kirkpatrick ◽  
Richard Robson ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Impaired Renal Function ◽  
Open Label ◽  
Mean Values ◽  
Constant Rate ◽  
Inactive Metabolite ◽  
Total Body ◽  
The Impact

ABSTRACT The objective of this study was to assess the impact of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite in humans. Thirty-two subjects were enrolled in an open-label, two-center study. Subjects were evenly assigned to one of four groups, based on creatinine clearance ranges of ≥80, 50 to 79, 30 to 49, and <30 ml/min. The drug was given as a single 1,500-mg constant-rate intravenous infusion over 60 min. There were no safety concerns with increasing renal dysfunction. Renal impairment had a significant impact on exposure of both tomopenem and its metabolite. Mean (± standard deviation) areas under the curve for tomopenem increased with decreasing renal function, from 191 ± 35.2 to 1,037 ± 238 μg·h/ml. The maximum concentration of drug in plasma (C max) increased with a maximum difference of 44% between the severe and normal groups. In contrast, the corresponding increase in C max of the metabolite was much higher, at 174%. Total body clearance was linearly correlated with creatinine clearance (R 2 = 0.97; P < 0.0001). Renal clearance for tomopenem decreased with increasing severity of disease, with mean values decreasing from 4.63 ± 0.89 to 0.59 ± 0.19 liters/h. The results of this study indicated a strong correlation between the creatinine clearance and total clearance of tomopenem. While renal impairment appeared to have a significant effect on the pharmacokinetics of tomopenem, an even greater effect was seen on the elimination of the inactive metabolite.

Melphalan 200 Mg/m2 in Patients with Renal Impairment Is Associated with Increased Short Term Toxicity but Improved Response and Longer Treatment-Free Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1998-1998 ◽  
Author(s):  
Karen Sweiss ◽  
Katie Culos ◽  
Seema Patel ◽  
Annie L. Oh ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Normal Renal Function ◽  
Disease Risk ◽  
Short Term ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Number Of Patients ◽  
The Impact

Abstract Renal impairment (RI) is a common complication of multiple myeloma (MM) and is reported in up to 40 percent of patients. There is limited data on the outcomes of melphalan 200 mg/m2 (MEL200) and autologous stem cell transplantation (ASCT) in patients with serum creatinine > 2 g/dL since they have been excluded from most studies. Therefore we retrospectively evaluated the impact of RI on outcome of patients with MM treated with MEL200 and ASCT at our institution. One hundred and forty nine consecutive patients who received MEL200 and ASCT between 2000 and 2011 were included in the analysis. Forty-six patients had a CrCl< 60 ml/min and 103 had a CrCl ≥ 60 ml/min. Baseline characteristics were similar between the two groups including measures of disease risk and treatment history. Median creatinine clearance was 50 ml/min (20-59) in the RI cohort and 83 ml/min (60-128) in the normal renal function cohort. Patients with a CrCl < 60 ml/min experienced a longer median time to neutrophil (10 vs. 9 days, p=0.008) and platelet (12 vs. 10 days p<0.001) engraftment despite a similarmean dose of infused CD34+ cells between the two groups. The median duration of hospitalization was significantly longer in patients with RI (16 (11-47) versus 14 (12-36) days, p=0.02). More patients in the CrCl < 60 ml/min group experienced diarrhea, required the use of anti-motility agents, required total parenteral nutrition administration, and developed infection, as compared to the CrCl >60 ml/min group. Response was measured using the International Myeloma Working Group criteria and was assessed immediately prior to transplant and again between 90 to 180 days after transplant. Although there was an increase in the number of patients achieving CR in both groups, this was found to be significant only in the CrCl<60 group (p=0.02). In addition, the overall response rate increased in the CrCl<60ml/min group. No difference in overall survival was seen between the two groups. Median treatment free survival was 37 months in the RI group and 17 months in normal renal function group (p=0.0025). A multivariate cox regression analysis revealed that creatinine clearance <60 ml/min (HR 3.5, p=0.0004) and prior proteasome inhibitor therapy (HR 2.441, p=0.025) were factors that predicted longer treatment free survival. Number of prior therapies (HR 0.7, p=0.03) predicted for a shorter treatment free survival. This represents one of the largest analyses of outcomes of MEL200 in MM patients with RI. We report that although short-term toxicity is increased in the RI group, long-term outcomes may be superior to those patients without renal impairment. We propose that this may be due to greater melphalan exposure in patients with RI. Based on these findings, we would consider MEL200 safe and effective in select patients with creatinine clearance between 30 and 60 ml/min. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pharmacokinetics of Zanamivir following Intravenous Administration to Subjects with and without Renal Impairment

2013 ◽  
Vol 57 (7) ◽  
pp. 2967-2971 ◽  
Author(s):  
Stephen Weller ◽  
Lori S. Jones ◽  
Yu Lou ◽  
Amanda Peppercorn ◽  
Judith Ng-Cashin
Keyword(s):  
Renal Function ◽  
Regression Analysis ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Clinical Laboratory ◽  
Severe Renal Impairment ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Time Curve ◽  
Clinical Safety

ABSTRACTIntravenous zanamivir is in clinical development for the treatment of influenza in hospitalized patients, many of whom have renal impairment. This open-label study evaluated zanamivir pharmacokinetics and clinical safety following a single 100-mg intravenous infusion dose in subjects with impaired renal function compared with normal renal function. Male and female subjects between 18 and 79 years of age were recruited, four subjects to each renal function group (normal function and mild, moderate, and severe impairment). Serial blood samples were collected up to 24 h after dose administration (48 h for the severe renal impairment group) to estimate zanamivir serum pharmacokinetic parameters. Urine was collected over the same 24-h (or 48-h) period for estimation of renal clearance (CLR). Zanamivir pharmacokinetics were assessed by regression analysis of systemic clearance (CL) and CLRas a function of creatinine clearance (CLCR). Safety evaluations included adverse-event monitoring, vital signs, electrocardiogram, and clinical laboratory assessments. Zanamivir clearance (total and renal) significantly decreased with decreasing renal function, with corresponding increases in area under the concentration-time curve and elimination half-life. Renal impairment had no apparent effects on peak concentration or volume of distribution. Regression analysis indicated that zanamivir clearance was highly correlated (r2= 0.89) with creatinine clearance: CL ≅ 7.08 + 0.826 · CLCR. There were no patterns or trends in adverse events, and no new safety concerns were identified following administration of intravenous zanamivir. Results from this study support the inclusion of subjects with renal impairment, with appropriate dose adjustment, in studies to evaluate intravenous zanamivir in the treatment of influenza.

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

2013 ◽  
Vol 57 (12) ◽  
pp. 6097-6105 ◽  
Author(s):  
B. J. Brennan ◽  
K. Wang ◽  
S. Blotner ◽  
M. O. Magnusson ◽  
J. J. Wilkins ◽  
...  
Keyword(s):  
Renal Function ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Impaired Renal Function ◽  
Severe Renal Impairment ◽  
Moderate Renal Impairment ◽  
Open Label ◽  
Time Curve

ABSTRACTRibavirin (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 AUC0–12was 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.

A Phase I Open-Label Trial To Determine the Pharmacokinetics of Glucarpidase in Subjects with Normal and Impaired Renal Function.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4450-4450
Author(s):  
Marc A. Phillips ◽  
Tim R. Auton ◽  
Suzanne B. Ward ◽  
William B. Smith ◽  
Guhan Balan
Keyword(s):  
Renal Function ◽  
Adverse Events ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Normal Renal Function ◽  
Impaired Renal Function ◽  
Prolonged Exposure ◽  
The Body ◽  
Calculated Creatinine Clearance ◽  
The Mean

Abstract Methotrexate (MTX) is used in high doses in the treatment of cancers such as NHLs, leukemias and osteosarcoma. In some patients it produces renal damage which delays its elimination from the body. Prolonged exposure to high concentrations of MTX results in serious toxic effects. Glucarpidase (Voraxaze™, formerly carboxypeptidase G2) contains a recombinant enzyme which rapidly and predictably breaks down MTX in the blood within 15 minutes of administration. Multiple studies to date have evaluated glucarpidase as an intervention for patients at risk or experiencing toxicities related to MTX overexposure. Continuing studies seek to evaluate the use of glucarpidase in a planned way to circumvent toxicity and prevent prolonged hospitalization. The current study examined the pharmacokinetics of glucarpidase in subjects who had both normal and severely impaired renal function, similar to that of the intended patient population. Methods: Twelve male and female subjects participated in this study; 8 with normal renal function (calculated creatinine clearance >80 mL/min) and 4 with severely impaired renal function (calculated creatinine clearance <30 mL/min). Each subject received a single intravenous dose of glucarpidase 50 units/kg (equivalent to 114.5 μg/kg), infused over 5 min. Serum glucarpidase profiles were evaluated for all subjects using 7 mL blood samples collected at the following time points: pre-dose (prior to start of glucarpidase IV dose), end of 5-minute infusion, and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 48, 72, and 96 hours following the start of the infusion. The study protocol was approved by the Crescent City Institutional Review Board IRB (New Orleans, LA) and all subjects gave their written informed consent prior to inclusion in the study. Results: The mean (SD) Cmax for glucarpidase in renally impaired subjects was 2.9 μg/mL (0.83), the mean half-life was 10.0 (2.1) h and mean AUC0-∞ was 24.5(9.4) μg.h/mL. Similar values were found in subjects with normal renal function (mean Cmax 3.1 μg/mL, mean t1/2 9.0 h and mean AUC0-∞ 23.4 μg.h/mL). No adverse events were recorded in the study. Conclusions: The results indicated little effect of renal impairment on the serum pharmacokinetics of glucarpidase. Evaluations of adverse events, clinical laboratory assessments, vital signs, ECGs, and physical examinations indicated that a single 50 unit/kg dose of glucarpidase was safe and well-tolerated when administered to subjects with normal renal function and subjects with severe renal impairment. PK parameters found in this study may be relevant to cancer patients treated with 50 units/kg glucarpidase, including those with MTX-induced renal toxicity.

Pharmacokinetics of Plerixafor (AMD3100) in Volunteers with Renal Impairment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2878-2878 ◽  
Author(s):  
Ronald MacFarland ◽  
Reginal B. Ewesuedo ◽  
Karin Badel ◽  
Gary Calandra
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Clinical Studies ◽  
Impaired Renal Function ◽  
Severe Renal Impairment ◽  
Pharmacokinetic Parameters ◽  
Hematopoietic Stem ◽  
Control Subjects

Abstract Introduction: Plerixafor (AMD3100) is a first-in-class, small molecule inhibitor of the CXCR4 chemokine receptor that blocks binding of its cognate ligand, SDF-1α. In clinical studies conducted in non-Hodgkin’s lymphoma and multiple myeloma patients, plerixafor when used with G-CSF was shown to be safe and effective in mobilizing CD34+ cells for autologous hematopoietic stem cell transplantation. Non-clinical studies conducted using radiolabeled plerixafor have shown 60-70% recovery of total radioactivity in urine within 24 hours after subcutaneous (SQ) administration. Based on this observation, we hypothesized that plerixafor clearance from plasma is likely to be reduced in patients with impaired renal function, which is commonly observed in multiple myeloma patients. The purpose of this study was to determine the pharmacokinetic parameters of plerixafor in subjects with renal impairment. Methods: This open-label study examined the pharmacokinetics of a single 240 mcg/kg SQ dose of plerixafor in subjects with varying degrees of renal impairment. Otherwise healthy subjects of normal weight and liver function, not requiring kidney dialysis, were classified into 4 groups of varying renal function, based on 24 hour creatinine clearance collected within 2 weeks prior to plerixafor administration. Approximately 6 subjects are to be enrolled into each group. Serial blood and urine samples were collected over a 24 hour period for analysis of plerixafor concentration using a validated LC-MS method. Plerixafor pharmacokinetics were characterized using noncompartmental methods. Results: Data were available from 18 subjects (aged 36–74 years) at the time this abstract was prepared. Pharmacokinetic parameters from available subjects are summarized in Table 1. Plerixafor clearance was dependent upon renal function. A statistically significant correlation between decreasing renal function, as determined by creatinine clearance, and reduced plerixafor clearance was observed, p < 0.001. Median clearance values were reduced from 3.96 L/hr in control subjects to 1.65 L/hr in subjects with severe renal impairment. A corresponding increase in half-life was observed from 4.7 hours in control subjects to 12.5 hours in subjects with severe renal impairment. No significant change in Cmax was observed across the groups, with time to Cmax observed at the 0.5 or 1 hour sampling time points in all subjects. Conclusions: These preliminary findings indicate a correlation between decreasing renal function and reduced plerixafor clearance from plasma. While peak exposures to plerixafor were apparently independent of renal function, total drug exposure over time was dependent on renal function. Preliminary review of the available results suggests that dose reduction of plerixafor may be warranted in patients with moderately to severely impaired renal function. Pharmacokinetic Parameters1 Cohort CrCl (mL/min) Cmax(ng/mL) AUC0-24h(ng*hr/mL) t1/2(hr) CLCR(L/hr) 1values shown are median (range) Control (n=6) 136 (107-455) 895 (812-1260) 5089 (3886-6218) 4.7 (4.3-5.7) 3.96 (3.65-5.63) Mild (n=2) 73 (71-74) 738 (705-770) 5563 (4580-6545) 7.1 (6.0-8.2) 3.09 (2.51-3.66) Moderate (n=6) 41 (31-51) 964 (559-1270) 7096 (4661-8388) 11.1 (8.8-15.0) 2.03 (1.67-4.74) Severe (n=4) 11 (9-14) 781 (609-1140) 7840 (5807-8010) 12.5 (12.1-22.0) 1.65 (1.59-1.80)

scholarly journals Does gender influence the impact of impaired renal function on prognosis after ST-segment elevated myocardial infarction?

2013 ◽  
Vol 20 (5) ◽  
pp. 526-532 ◽  
Author(s):  
Joon Seok Choi ◽  
Min Jee Kim ◽  
Yong Un Kang ◽  
Chang Seong Kim ◽  
Eun Hui Bae ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Renal Function ◽  
Impaired Renal Function ◽  
Gender Influence ◽  
St Segment ◽  
The Impact

Dosage Regimen Adjustments in Renal Impairment

1973 ◽  
Vol 7 (9) ◽  
pp. 382-387 ◽  
Author(s):  
Donald L. Giusti ◽  
William L. Hayton
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Dosage Regimen ◽  
Drug Dosage ◽  
Loading Dose ◽  
Dosage Regimens ◽  
Drug Dosage Regimen ◽  
Pharmacokinetic Approach

A pharmacokinetic approach based on creatinine clearance has been outlined which permits drug dosage regimen adjustments in patients with renal impairment. The parameters needed for calculating a loading dose and a maintenance regimen are the fraction of a dose excreted unchanged in the urine, the creatinine clearance of the patient, and the half-life of the drug in patients with normal renal function. In varying degrees of renal failure, predicted dosage regimens agree closely with dosage regimens predicted by other methods for a number of drugs.

scholarly journals Associations between radiographic characteristics and change in renal function following partial nephrectomy using 24-hour creatinine clearance

2013 ◽  
Vol 5 (1) ◽  
pp. 45
Author(s):  
Rodney H. Breau ◽  
Aaron T.D. Clark ◽  
Chris Morash ◽  
Dean Fergusson ◽  
Ilias Cagiannos
Keyword(s):  
Renal Function ◽  
Creatinine Clearance ◽  
Partial Nephrectomy ◽  
Tumour Size ◽  
Multivariable Analysis ◽  
Function Change ◽  
Tumour Location ◽  
Function Preservation ◽  
The Mean ◽  
The Impact

Background: Radiographic characteristics may be associated withthe degree of renal function preservation following partial nephrectomy.The purpose of this study was to determine the impact ofpreoperative radiographic variables on change in renal functionusing 24-hour urine creatinine clearance (uCrCl).Methods: Patients with partial nephrectomy performed fromNovember 2003 to 2008 were enrolled in the study. Serum creatinineand 24-hour urine was collected preoperatively and at3, 6 and 12 months postoperatively. Computed tomography ormagnetic resonance imaging was used to determine tumour size,tumour location and renal volume.Results: Of the 36 patients, median age was 62 (range 30-78) and21 (58%) were male. The mean tumour diameter was 2.8±1.4 cm.Twenty-two (61%) tumours were located at the renal pole and11 (31%) were endophytic. Overall, mean preoperative uCrClwas 88.8±34.2 mL/min and mean postoperative uCrCl was82.8±33.6 mL/min (6.8%; p < 0.01). On multivariable analysis,no single characteristic was associated with a clinically prohibitivedecrease in renal function (-9.4% if endophitic, p = 0.06; -0.57%per cm diameter, p = 0.73; and -6.9% if located at the renal pole,p = 0.15). The total renal volume was also not significantly associatedwith renal function change (-1.1% per 100 cc, p = 0.86).Interpretation: Preoperative radiographic characteristics seem tobe associated with small changes in renal function following partialnephrectomy. These data support renal functional benefits of partialnephrectomy regardless of tumour size and location.

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