scholarly journals Effect of Renal Impairment on the Pharmacokinetics and Safety of Rivipansel in Subjects with Renal Impairment and in Healthy Subjects

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1083-1083
Author(s):  
Brinda Tammara ◽  
Kelly Ryan ◽  
Anna Plotka ◽  
Frank E. Shafer ◽  
Hua Wei ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Healthy Subjects ◽  
Severe Renal Impairment ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Mild Renal Impairment ◽  
Plasma And Urine Samples

Abstract Background: Rivipansel is a pan-selectin inhibitor in phase 3 development for treatment of sickle cell disease vaso-occlusive crises. Previous studies have shown almost complete elimination of unchanged drug in urine following an intravenous (IV) infusion. The objective of this study was to evaluate the effect of varying degrees of renal impairment on the pharmacokinetics (PK), safety, and tolerability of rivipansel. Methods: A single 840-mg dose of open-label rivipansel was administered IV over 20 minutes to 7 subjects with mild, 7 with moderate, and 7 with severe renal impairment, and to 7 healthy subjects with normal renal function. Classification of renal impairment groups was based on the Cockroft-Gault estimated glomerular filtration rate (CGeGFR): 60-89 mL/min (mild), 30-59 mL/min (moderate), and <30 mL/min (severe). Normal renal function was CGeGFR ≥90 mL/min. Plasma and urine samples were collected for 96 hours postdose and analyzed by validated LC-MS/MS methods. Pharmacokinetic parameters were estimated using noncompartmental modeling. ANOVA was used to assess the effect of renal impairment on PK parameters. Results: All 28 subjects completed the study. A summary of PK parameters is presented in Table 1. Overall rivipansel exposure was greater in subjects with mild, moderate, and severe renal impairment, with values 1.4×, 2.3×, and 5.5× that of subjects with normal renal function, respectively. Renal clearance decreased with decreasing renal function. Total clearance was lower by 31%, 56%, and 82% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function group. Five treatment-emergent adverse events (TEAEs) were reported in 3 subjects in the mild renal impairment group, and 3 TEAEs were reported in 2 subjects in the severe renal impairment group. None of the TEAEs reported was considered to be treatment-related. Conclusions: Greater rivipansel exposure and decreased clearance were observed in subjects with renal impairment compared with subjects with normal renal function. A single 840-mg IV dose of rivipansel was well tolerated in all groups. Disclosures Tammara: Pfizer Inc.: Employment. Ryan:Pfizer Inc.: Employment. Plotka:Pfizer Inc.: Employment. Shafer:Pfizer Inc.: Employment. Wei:Pfizer Inc.: Employment. Readett:Pfizer Inc.: Employment. Fang:Pfizer Inc.: Employment. Korth-Bradley:Pfizer Inc.: Employment.

scholarly journals Pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with renal dysfunction.

1996 ◽  
Vol 40 (6) ◽  
pp. 1514-1519 ◽  
Author(s):  
A E Heald ◽  
P H Hsyu ◽  
G J Yuen ◽  
P Robinson ◽  
P Mydlow ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Moderate Renal Impairment ◽  
Pharmacokinetic Parameters ◽  
Geometric Means ◽  
Immunodeficiency Virus

The purpose of this study was to determine the safety and pharmacokinetics of lamivudine (3TC), a nucleoside analog that has shown potent in vitro and recent in vivo activity against human immunodeficiency virus. Sixteen human immunodeficiency virus-infected patients, six with normal renal function (creatinine clearance [CLCR], > or = 60 ml/min), four with moderate renal impairment (CLCR, 10 to 40 ml/min), and six with severe renal impairment (CLCR, < 10 ml/min), were enrolled in the study. After an overnight fast, patients were administered 300 mg of 3TC orally. Blood was obtained before 3TC administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, and 48 h afterward. Timed urine collections were performed for patients able to produce urine. Serum and urine were assayed for 3TC by reverse-phase high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. The peak concentration of 3TC increased with decreasing renal function; geometric means were 2,524, 3,538, and 5,684 ng/ml for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. The terminal half-life also increased with decreasing renal function; geometric means were 11.5, 14.1, and 20.7 h for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. Both oral and renal clearances were linearly correlated with CLCR. A 300-mg dose of 3TC was well tolerated by all three patient groups. The pharmacokinetics of 3TC is profoundly affected by impaired renal function. Dosage adjustment, by either dose reduction or lengthening of the dosing interval, is warranted.

scholarly journals Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment

2007 ◽  
Vol 51 (12) ◽  
pp. 4231-4235 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Suzanne Swan ◽  
William B. Smith ◽  
Thomas C. Marbury ◽  
Gloria Dubuc-Patrick ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Normal Function ◽  
Plasma Exposure ◽  
Mild Renal Impairment ◽  
Severe Impairment ◽  
Stage Renal Disease ◽  
End Stage

ABSTRACT This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CLCR), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CLR), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CLR and CLCR. In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of ∼45%, representing a ∼23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.

scholarly journals 1324. Target Attainment of Exebacase, a First-In-Class Antibacterial Lysin, to Determine Optimal Doses for Adult Patients with Staphylococcus aureus (S. aureus) Bloodstream Infections (Bacteremia) Including Endocarditis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S673-S673
Author(s):  
Parviz Ghahramani ◽  
Tatiana Khariton ◽  
Joannellyn Chiu ◽  
Cara Cassino
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Healthy Subjects ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Bloodstream Infections ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Target Attainment

Abstract Background Exebacase, a novel, antibacterial direct lytic agent for the treatment of S. aureus bacterimia and endocarditis, studied in Phase 1 and 2 trials, demonstrated potential to improve clinical outcomes when used in addition to conventional antibiotics. Objectives were to develop population PK (PPK) model and perform target attainment (TA) simulations to determine optimal clinical doses. Methods PPK model was developed with data from 72 patients receiving Exebacase, in addition to the standard of care, as single 2-hr infusion of 0.25 mg/kg (0.12 mg/kg for patients with creatinine clearance (CrCL) &lt; 60 mL/min). PPK model was used for TA simulations of various IV regimens. Results 3-compartment model best fit the data, parameters were well estimated (CL=4.2 L/hr (RSE=5.5%), Vc=4.5 L (RSE=8.2%)). Total volume of distribution (Vd) was 20.2 L. Values were lower than estimated previously in healthy subjects, CL=7.1 L/hr and Vd=27.7 L. CrCL was the only clinically meaningful covariate. Patients with moderate and severe renal impairment are expected to have 1.3 to 2-fold higher AUC0-24 or Cmax than patients with normal renal function. Age was statistically significant on peripheral clearance but was not clinically meaningful (≤4% effect on exposure). TA simulations were stratified by renal function across a range of fixed as well as weight-based doses (all simulated as 2-hr infusion). In patients with normal renal function or mild impairment, 18 mg dose result in Cmax and AUC0-24 of 1254 ng/mL and 3026 ng*hr/mL, respectively. In patients with moderate or severe renal impairment, 12 mg dose result in Cmax and AUC0-24 of 1107 ng/mL and 3099 ng*hr/mL, respectively. In ESRD patients including hemodialysis, 8 mg dose result in Cmax and AUC0-24 of 910 ng/mL and 3109 ng*hr/mL, respectively. These exposures place &gt;99% subjects above efficacious thresholds of AUC/MIC &gt;0.2 established in animals. Conclusion PPK model described exebacase PK in patients adequately. CL and Vd were estimated to be 40% and 17% lower, respectively, than healthy subjects. CrCL was the only clinically meaningful covariate requiring dose adjustment. TA assessments identified doses that achieve minimum efficacy target (AUC/MIC≥0.2) in &gt;99% of patients with S. aureus. Based on these simulations, fixed dosing schedule was recommended. Disclosures Parviz Ghahramani, PhD, PharmD, MSc, MBA, Consultant to ConatFect (Consultant) Tatiana Khariton, PhD, Consultant to ConatFect (Consultant) Joannellyn Chiu, PhD, Consultant to ConatFect (Consultant) Cara Cassino, MD, ContraFect Corporation (Employee)ContraFect Corporation (Employee)

scholarly journals Impact of Renal Function on the Pharmacokinetics and Safety of Ceftolozane-Tazobactam

2014 ◽  
Vol 58 (4) ◽  
pp. 2249-2255 ◽  
Author(s):  
Myra Wooley ◽  
Benjamin Miller ◽  
Gopal Krishna ◽  
Ellie Hershberger ◽  
Gurudatt Chandorkar
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Moderate Renal Impairment ◽  
Open Label ◽  
Two Phase ◽  
Time Curve ◽  
Mild Renal Impairment ◽  
Before And After ◽  
Stage Renal Disease

ABSTRACTCeftolozane-tazobactam is a novel antipseudomonal cephalosporin with a β-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, open-label studies, a single dose of ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of ceftolozane-tazobactam (500/250 mg each), pre- and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC0-∞) for ceftolozane and tazobactam increased 1.4- and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC0-∞increased 2.5- and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC0-∞for ceftolozane and tazobactam increased 4.4- and 3.8-fold, respectively. In ESRD subjects, ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC0-∞before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups.

scholarly journals 705. Pharmacokinetics (PK) and Safety of Lefamulin (LEF) After Single Intravenous Dose Administration in Subjects With Impaired Renal Function and in Those Requiring Hemodialysis

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S318-S318 ◽  
Author(s):  
Wolfgang Wicha ◽  
Thomas C Marbury ◽  
James A Dowell ◽  
Lori Lykens ◽  
Cathie Leister ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Study Drug ◽  
Normal Subjects ◽  
Pharmacokinetic Parameters ◽  
Drug Discontinuation ◽  
Open Label ◽  
Two Phase ◽  
Post Dose

Abstract Background Renal comorbidities are common in patients hospitalized with community-acquired bacterial pneumonia (CABP). LEF, a novel pleuromutilin antibiotic (IV/oral), was generally well tolerated and noninferior to moxifloxacin in two phase 3 studies of adults with CABP. We investigated the PK and safety of LEF and its main metabolite, BC-8041, in subjects with severe renal impairment and those requiring hemodialysis (HD). Methods In this open-label study, subjects were allocated to 1 of 3 groups based on renal function level. Severe subjects (estimated glomerular filtration rate <30 mL/minute/1.73 m2, not on HD, Severe) were matched (gender, age, and weight) to subjects with normal renal function (estimated creatinine clearance ≥90 mL/minute, Normal). Subjects in the Normal and Severe groups received a single 1-hour 150 mg LEF infusion. Subjects in the HD group started HD within 1 hour after LEF infusion (“On-dialysis”) and on a nondialysis day (“Off-dialysis”). Blood and urine samples were collected predose and over a 36-hour period postdose for PK analysis; LEF and BC-8041 were assayed in plasma and urine with validated methods. Safety assessments included treatment-emergent adverse events (TEAEs), labs, vital signs, and electrocardiograms. Results 23 subjects enrolled in and completed the study (n = 7, Normal; n = 8, Severe; n = 8, HD). LEF and BC-8041 pharmacokinetic parameters (table) were comparable between the Normal and Severe groups and between the On-dialysis and Off-dialysis treatment periods for the HD group. The majority of LEF and BC-8041 were excreted nonrenally in Normal and Severe subjects and were not measurably filtered into dialysate. TEAEs were reported in 2 (28.6%) subjects in the Normal group, 4 (50%) in the Severe group, and 4 (50%) in the HD group. None of the TEAEs were serious or led to study drug discontinuation. Within 4 h post-dose, the maximum mean change from baseline in the QTcF interval was 8.9, 6.6, 15.9, and 17.6 msec in the normal, severe, on-dialysis, and off-dialysis groups, respectively. Conclusion No dosage adjustment is required for LEF when treating subjects with severe renal impairment, and LEF can be administered without regard to HD timing. LEF was generally well tolerated in all subjects regardless of renal function status. Disclosures All authors: No reported disclosures.

scholarly journals 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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3966-3966
Author(s):  
Kevin R. Kelly ◽  
Nashat Y. Gabrail ◽  
William J Edenfield ◽  
A Craig Lockhart ◽  
Anthony J. Olszanski ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Solid Tumors ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Moderate Renal Impairment ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Study

Abstract 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. Disclosures Gabrail: Sanofi: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Onyx: Honoraria, Speakers Bureau; BI: Honoraria, Speakers Bureau. Edenfield:Celgene: Research Funding. Reddy:spectrum: Employment, Equity Ownership.

scholarly journals A Phase 1 Study To Assess the Pharmacokinetics of Intravenous Plazomicin in Adult Subjects with Varying Degrees of Renal Function

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Allison S. Komirenko ◽  
Valerie Riddle ◽  
Jacqueline A. Gibbons ◽  
Scott Van Wart ◽  
Julie D. Seroogy
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Open Label ◽  
Time Curve ◽  
Open Label Study ◽  
Severe Impairment ◽  
Tract Infections

ABSTRACTPlazomicin is an FDA-approved aminoglycoside for the treatment of complicated urinary tract infections. In this open-label study, 24 adults with normal renal function or mild, moderate, or severe renal impairment (n= 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion. Total clearance declined with renal impairment, resulting in 1.98-fold and 4.42-fold higher plazomicin exposures, as measured by the area under the concentration-time curve from 0 h to infinity, in subjects with moderate and severe impairment, respectively, than in subjects with normal renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT01462136.)

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.

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