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

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02151-13 ◽

2014 ◽

Vol 58 (4) ◽

pp. 2249-2255 ◽

Cited By ~ 48

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.

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.773 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S318-S318 ◽

Cited By ~ 1

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01128-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 7

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.)

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00608-13 ◽

2013 ◽

Vol 57 (12) ◽

pp. 6097-6105 ◽

Cited By ~ 14

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

Blood ◽

10.1182/blood-2018-99-111926 ◽

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.

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

Blood ◽

10.1182/blood.v110.11.2878.2878 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2878-2878 ◽

Cited By ~ 1

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)

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1514 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1514-1519 ◽

Cited By ~ 64

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.

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MM-008 trial: Pharmacokinetics (PK) and tolerability of pomalidomide plus low-dose dexamethasone (POM plus LoDEX) in relapsed/refractory multiple myeloma (RRMM) patients with renal impairment (RI).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8585 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8585-8585

Author(s):

Jeffrey Matous ◽

David Samuel DiCapua Siegel ◽

Hien Kim Duong ◽

Claudia Kasserra ◽

Lars Sternas ◽

...

Keyword(s):

Renal Function ◽

Renal Impairment ◽

Dose Escalation ◽

Drug Exposure ◽

Severe Renal Impairment ◽

Phase 1 ◽

Parent Drug ◽

Clinical Activity ◽

Open Label ◽

Grade 3

8585^ Background: POM + LoDEX has shown significant clinical activity in RRMM pts including those refractory to lenalidomide and bortezomib. Renal impairment is a common comorbidity for MM pts, occurring in > 40%. POM is extensively metabolized with less than 5% renally eliminated as parent drug. Thus, renal function may not substantively affect parent drug exposure. Previous POM trials excluded pts with severe renal impairment. MM-008 is a phase 1, multicenter, open-label study designed to assess the PK and safety of POM + LoDEX in RRMM pts and normal or impaired renal function. Methods: RRMM pts (≥ 1 prior therapy [Tx]) with creatinine clearance (CrCl) ≥ 60 ml/min (cohort A) or severe renal impairment (CrCl < 30 ml/min [cohort B]) not requiring dialysis were included. Cohort A received POM 4 mg and cohort B received POM 2 mg or 4 mg D1-21/28-day cycle following a standard 3 + 3 dose-escalation design. Both cohorts received DEX 40 mg (20 mg for pts aged > 75 y) D1, 8, 15, and 22. Cohort C will assess pts with severe renal impairment (CrCl < 30 ml/min) requiring dialysis (up to 14 pts planned). Pts were not permitted to enroll in more than 1 cohort. G-CSF was not permitted in cycle 1. Tx continued until progressive disease or unacceptable toxicity. Results: As of Feb 5, 2013, 11 pts have been treated (8 pts in cohort A; 3 pts in cohort B at 2 mg). Age ranged from 46-71 y (cohort A) and 57-64 (cohort B). 5 pts were aged > 65 y in cohort A (aged 66, 69 [n = 3], and 71 y); none in cohort B. 7 pts in cohort A have received > 1 cycle of Tx; 5 pts have received ≥ 3 cycles. One pt in cohort B has received > 3 cycles. All 3 pts in cohort B have completed 1 full cycle of Tx with no dose-limiting toxicities reported. Dose escalation is planned. The most common grade 3/4 adverse events (AEs) in cohort A were neutropenia (n = 3) and pneumonia (n = 2). No grade 3/4 AEs have been observed for pts in cohort B to date. POM dose reduction due to AE occurred in 2 pts (both in cohort A), all pts remain on study. PK and updated AE data will be presented at the meeting. Conclusions: MM-008 is an ongoing trial evaluating PK and safety in pts with renal impairment. Early tolerability data are encouraging. Clinical trial information: NCT01575925.

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Single-Dose Pharmacokinetics and Safety of Meropenem-Vaborbactam in Subjects with Chronic Renal Impairment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02103-17 ◽

2018 ◽

Vol 62 (3) ◽

Cited By ~ 17

Author(s):

Christopher M. Rubino ◽

Sujata M. Bhavnani ◽

Jeffery S. Loutit ◽

Brooke Lohse ◽

Michael N. Dudley ◽

...

Keyword(s):

Renal Function ◽

Single Dose ◽

Renal Impairment ◽

Plasma Clearance ◽

Phase 1 ◽

Fold Increase ◽

Pharmacokinetic Parameters ◽

Open Label ◽

Single Dose Study ◽

Chronic Renal Impairment

ABSTRACTVaborbactam is a member of a new class of β-lactamase inhibitors with inhibitory activity against serine carbapenemases (e.g.,Klebsiella pneumoniaecarbapenemase) that has been developed in combination with meropenem. The pharmacokinetics of the combination was evaluated in 41 subjects with chronic renal impairment in a phase 1, open-label, single-dose study. Subjects were assigned to one of five groups based on renal function: normal (creatinine clearance of ≥90 ml/min), mild (estimated glomerular filtration rate [eGFR] of 60 to 89 ml/min/1.73 m2), moderate (eGFR of 30 to <60), or severe (eGFR of <30) impairment plus end-stage renal disease (ESRD) patients on hemodialysis. Subjects received a single intravenous dose of 1 g of meropenem plus 1 g of vaborbactam by 3-h infusion. The ESRD group received two doses (on and off dialysis) separated by a washout. Pharmacokinetic parameters were estimated by standard noncompartmental methods. For both meropenem and vaborbactam, the area under the concentration-time curve was larger and the elimination half-life was longer with decreasing renal function. Meropenem and vaborbactam total plasma clearance (CLt) rates were similar and decreased with decreasing renal function. Slopes of the linear relationship between eGFR and CLt were similar, indicating a similar proportional reduction in CLt with decreasing renal function. Hemodialysis significantly increased drug clearance of meropenem (mean of 2.21-fold increase in CLt,P< 0.001) and vaborbactam (mean of 5.11-fold increase,P= 0.0235) relative to drug administration off dialysis, consistent with dose recovery rates of 38.3% and 52.9% for meropenem and vaborbactam, respectively, in dialysate. Plasma clearance of meropenem and vaborbactam is reduced with renal impairment, requiring dose adjustment. Hemodialysis removes both drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT02020434.)

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01249-07 ◽

2008 ◽

Vol 52 (7) ◽

pp. 2360-2366 ◽

Cited By ~ 6

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.

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