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

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02330-12 ◽

2013 ◽

Vol 57 (7) ◽

pp. 2967-2971 ◽

Cited By ~ 8

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.

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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 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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439. Iclaprim Use for Acute Bacterial Skin and Skin Structure Infection (ABSSSI) is Not Associated with Hyperkalemia: Phase 3 REVIVE Studies

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.512 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S218-S218

Author(s):

David B Huang ◽

Stephanie S Noviello ◽

Thomas Lodise ◽

James McKinnell ◽

Jamie P Dwyer

Keyword(s):

Renal Impairment ◽

Severe Renal Impairment ◽

Angiotensin Receptor Blockers ◽

Study Drug ◽

Angiotensin Converting Enzyme Inhibitors ◽

Distal Portion ◽

Phase 3 ◽

Two Phase ◽

Double Blind ◽

Converting Enzyme Inhibitors

Abstract Background Trimethoprim inhibits sodium channels in the distal portion of the renal tubule, thereby impairing renal potassium excretion. Trimethoprim has been associated with a greater risk of hyperkalemia compared with other antibiotics (amoxicillin, nitrofurantoin, cefalexin, ciprofloxacin). An analysis of Phase 3 studies was conducted to determine whether iclaprim, under development for ABSSSI and also a selective bacterial dihydrofolate reductase inhibitor like trimethoprim, is associated with hyperkalemia, relative to vancomycin, an antibiotic not associated with hyperkalemia. Methods A post-hoc safety analysis was conducted on pooled results of two Phase 3, double-blind, randomized (1:1), active-controlled trials (REVIVE-1/-2) in patients with ABSSSI. These trials compared iclaprim 80 mg fixed doses with vancomycin 15 mg/kg; both administered intravenously every 12 hours for 5–14 days. Hyperkalemia was defined as serum potassium (K) ≥5.5 mmol/L, if normal at baseline, while on study drug. Hyperkalemia was compared between treatment groups and stratified subgroup comparisons were performed. Results Demographics and baseline disease characteristics were similar between the pooled iclaprim and vancomycin groups (table). Hyperkalemia occurred during treatment in 1.5% (9/592) and 2.5% (15/599) of patients treated with iclaprim and vancomycin, respectively. Of the patients with hyperkalemia, one patient in each treatment group had moderate to severe renal impairment (creatinine clearance [CrCl] 15–59 mL/minute). Among patients with moderate to severe renal impairment on any RAS, KSD or K supplements, hyperkalemia occurred in 1/16 and 0/16 patients in the iclaprim and vancomycin groups, respectively, and in 2/83 and 0/46 patients with mild to no renal impairment. No patients with hyperkalemia experienced adverse events of palpitations, chest pain, myalgia, muscular weakness or fatigue. Conclusion No differences in hyperkalemia were seen between the iclaprim and vancomycin groups in the Phase 3 REVIVE studies. In general, few cases of hyperkalemia occurred among patients with renal impairment treated with concomitant angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers treated with iclaprim. Disclosures All authors: No reported disclosures.

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A 2-Part Phase I Study in Patients with Solid or Hematologic Malignancies: Dose Proportionality of Subcutaneous (SC) Azacitidine (AZA) and Pharmacokinetics of SC AZA in Patients with Severe Renal Impairment,

Blood ◽

10.1182/blood.v118.21.3480.3480 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3480-3480

Author(s):

Eric Laille ◽

Alain C. Mita ◽

Sanjay Goel ◽

Nashat Y. Gabrail ◽

Joseph Schwarz ◽

...

Keyword(s):

Renal Function ◽

Renal Impairment ◽

Normal Renal Function ◽

Severe Renal Impairment ◽

Hematologic Malignancies ◽

Dose Proportionality ◽

Employment Equity ◽

Post Dose ◽

Equity Ownership ◽

To Receive

Abstract Abstract 3480 Background: The recommended starting dose for all patients receiving SC AZA is 75 mg/m2 daily for 7 days in 28-day cycles. If no response is observed, the dose may be increased to 100 mg/m2. Conversely, if cytopenias do not adequately resolve between dosing cycles, AZA dose may be reduced. Similarly, because AZA and its metabolites are primarily excreted by the kidneys, patients with renal impairment may require monitoring for elevations of BUN or serum creatinine (cr), in which case the next AZA treatment cycle should be delayed until values return to baseline and the next AZA dose should be reduced by 50% (Vidaza® prescribing information, 2011). Currently, the pharmacokinetics (PK) of SC AZA in reduced (<75 mg/m2) or increased (100 mg/m2) doses, and AZA exposure at the recommended dose in patients with renal impairment, are unknown. Objectives: To assess the dose proportionality of AZA PK after single SC doses ranging from 25 to 100 mg/m2, and to determine the effect of renal impairment on AZA PK after single and multiple (5 days) SC doses of 75 mg/m2. Also, the safety and tolerability of AZA in patients with severe renal impairment were determined. Methods: This 2-part multicenter, randomized, open-label study included patients with solid or hematologic malignancies. Part 1 was a 4-treatment, parallel-group evaluation of the dose proportionality of SC AZA in patients with normal renal function (cr clearance [CLcr] >80 mL/min/1.73 m2, Cockcroft-Gault equation adjusted for body surface area). Patients were randomized to receive a single dose of 25-, 50-, 75-, or 100-mg/m2 SC AZA. Blood and urine samples were collected before dosing and at various time points up to 8 hours post-dose. The 75 mg/m2 dosing group in Part 1 received an additional 4 days of AZA treatment and blood and urine were collected from these patients on the same schedule on Day 5. For Part 2, patients with severe renal impairment (CLcr <30 mL/min/1.73 m2) received SC AZA 75 mg/m2 for 5 consecutive days. PK parameters were determined using non-compartmental methods. Patients could continue to receive treatment with AZA (75 mg/m2/d SC x 7d q 28 days) in an extension phase for up to 6 cycles (patients were followed for safety only). Results: At the time of this analysis, 21 patients were enrolled and were included in safety evaluations, with PK data available for 18 patients. At baseline, median ages of patients with normal renal function (n=17) or severe renal impairment (n=4) were 61 years (range: 38–76) and 71 years (range: 54–90), respectively. Of patients with normal renal function, 12 (70%) had solid tumors, 4 had MDS (RAEB-t [n=2], RA, RARS), and 1 had multiple myeloma. Of patients with severe renal impairment, 2 (50%) had solid tumors, 1 had CMML, and 1 had MDS (RA). In Part 1, 14 patients were randomized to either 25 mg/m2 (n=4), 50 mg/m2 (n=4), 75 mg/m2 (n=3), or 100 mg/m2 (n=3). Mean [±SD] AUC0-∞ in the 25-, 50-, 75-, and 100 mg/m2 dose groups were 490 [146], 895 [300], 1270 [480], and 1410 [212] ng*hr/mL, respectively. Preliminary results show AZA is dose proportional across the 25–100 mg/m2dose range (Figure 1). In Part 2, on Days 1 and 5 of 5 consecutive days of SC AZA administration, AZA was rapidly absorbed by patients with severe renal impairment, reaching Cmax within 0.75 hours post-dose. AZA concentration decreased thereafter in a pseudobiphasic manner (Figure 2). Similar profiles were observed in patients with normal renal function who received the same dose. Mean [±SD] AUC0-∞ values after a 75 mg/m2 SC AZA dose on Day 1 were 1270 [480] ng*hr/mL in patients with normal renal function and 1630 [913] ng*hr/mL in patients with severely impaired renal function. On Day 5, mean AUC0-∞ values were 901 [92] and 1280 [728] ng*hr/mL, respectively. Similar observations were noted for Cmax. No accumulation of AZA was noted on Day 5 in either group. High inter-patient variability was noted in both groups (% coefficient of variation up to ∼82%). Patients with or without renal impairment did not show unusual or unexpected adverse events. Conclusions: AZA is dose-proportional over the 25–100 mg/m2 dosing range. PK parameters from patients with severe renal impairment treated with multiple doses of AZA 75 mg/m2 SC were comparable to those obtained from patients with normal renal function. Treatment with AZA 75 mg/m2 SC over multiple days was safe and well tolerated in this small group of patients with normal renal function or severe renal impairment. Disclosures: Laille: Celgene Corporation: Employment, Equity Ownership. Goel:Celgene: Research Funding. Schwarz:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

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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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Considerations in the Selection of Renal Dosage Adjustments for Patients with Serious Infections and Lessons Learned from the Development of Ceftazidime-Avibactam

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02105-19 ◽

2020 ◽

Vol 64 (4) ◽

Author(s):

Jianguo Li ◽

Mark Lovern ◽

Todd Riccobene ◽

Timothy J. Carrothers ◽

Paul Newell ◽

...

Keyword(s):

Renal Function ◽

Renal Impairment ◽

Severe Renal Impairment ◽

Complicated Urinary Tract Infection ◽

Development Program ◽

Lessons Learned ◽

Total Daily Dose ◽

Population Pharmacokinetic ◽

Phase 3 ◽

Two Phase

ABSTRACT An extensive clinical development program (comprising two phase 2 and five phase 3 trials) has demonstrated the efficacy and safety of ceftazidime-avibactam in the treatment of adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). During the phase 3 clinical program, updated population pharmacokinetic (PK) modeling and Monte Carlo simulations using clinical PK data supported modified ceftazidime-avibactam dosage adjustments for patients with moderate or severe renal impairment (comprising a 50% increase in total daily dose compared with the original dosage adjustments) to reduce the risk of subtherapeutic drug exposures in the event of rapidly improving renal function. The modified dosage adjustments were included in the ceftazidime-avibactam labeling information at the time of initial approval and were subsequently evaluated in the final phase 3 trial (in patients with HAP, including VAP), providing supportive data for the approved U.S. and European ceftazidime-avibactam dosage regimens across renal function categories. This review describes the analyses supporting the ceftazidime-avibactam dosage adjustments for renal impairment and discusses the wider implications and benefits of using modeling and simulation to support dosage regimen optimization based on emerging clinical evidence.

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Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-020-04207-9 ◽

2021 ◽

Author(s):

Naveed Shaik ◽

Robert R. LaBadie ◽

Brian Hee ◽

Geoffrey Chan

Keyword(s):

Plasma Concentration ◽

Renal Impairment ◽

Peak Plasma ◽

Severe Renal Impairment ◽

Peak Plasma Concentration ◽

Safety Data ◽

Normal Group ◽

Open Label ◽

Post Dose ◽

The Impact

Abstract Purpose Glasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed. Methods Open-label, parallel-group study (NCT03596567). Participants of good general health were selected and categorized, based on their estimated glomerular filtration rate, into normal (≥ 90 mL/min), moderate (≥ 30 to < 60 mL/min), or severe (< 30 mL/min) renal impairment groups. Blood samples were collected up to 120 h post-dose. PK exposure parameters were calculated using non-compartmental analysis. Results All 18 participants completed the study. Respectively, ratios of adjusted geometric means (90% confidence interval) for glasdegib area under the curve from time 0 to infinity and peak plasma concentration versus normal participants were 205% (142–295%) and 137% (97–193%) in the moderate group, and 202% (146–281%) and 120% (77–188%) in the severe group. Glasdegib median time to peak plasma concentration was 2.0 h in both impairment groups and 1.5 h in the normal group. Mean oral clearance was decreased by approximately 50% in both renal impairment groups compared with the normal group. The plasma-free fraction of glasdegib was not altered by renal impairment. Five all-causality adverse events were reported in three participants; two were considered treatment-related. Conclusion The similar changes in exposure observed for participants with renal impairment, coupled with the known safety data from clinical experience, suggest that a lower starting dose of glasdegib may not be required for moderate or severe renal impairment. Trial registration: ClinicalTrials.gov: NCT03596567 (started May 17, 2018).

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