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 ◽  
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.

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.

Integrative assessment of the effect of renal function on ribociclib treatment and dose recommendation in advanced breast cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13037-e13037
Author(s):  
Yan Ji ◽  
Vitaly Yartsev ◽  
Yingbo Wang ◽  
Michelle Quinlan ◽  
Paolo Serra ◽  
...  
Keyword(s):  
Renal Function ◽  
Steady State ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Phase 1 ◽  
Moderate Renal Impairment ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Integrative Assessment

e13037 Background: Ribociclib is an orally administered CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative advanced breast cancer (ABC). An integrative assessment was conducted to evaluate the effect of renal function on the pharmacokinetics (PK), efficacy and safety of ribociclib. Methods: To assess the effect of mild and moderate renal impairment, a subgroup analysis was performed to evaluate PK parameters of ribociclib following oral administration of 600 mg QD 3 weeks on/1 week off in two Phase 1/2 and one Phase 3 clinical trials. Steady-state PK exposures in ABC patients at the 600 mg dose was estimated by a population PK model developed based on a pooled dataset from five Phase 1 to 3 trials and were compared by renal function. Efficacy and safety were also analyzed by renal function in a Phase 2 and three Phase 3 trials in ABC patients. The effect of severe renal impairment on ribociclib PK was assessed in a Phase I study in non-cancer subjects following a single oral 400 mg dose. Results: PK analyses in cancer patients showed that both single-dose and steady-state exposure of ribociclib at the 600 mg dose in patients with mild or moderate renal impairment were comparable to patients with normal renal function. Estimated steady-state PK exposure in patients with mild or moderate renal impairment is also comparable to patients with normal renal function. The primary efficacy results of progression free survival (PFS) and the safety profiles were comparable across renal-function cohorts in ABC patients. In non-cancer subjects administered a single oral dose of 400 mg, ribociclib AUCinf and Cmax increased 2.67- and 2.30-fold in subjects with severe renal impairment, respectively, compared to subjects with normal renal function. Conclusions: PK, efficacy and safety of ribociclib are consistent across patients with normal renal function, mild or moderate renal impairment. Hence, no dose adjustment is required in mild or moderate renal impaired patients. Severe renal impaired patients are recommended to have a reduced dose based on PK data in non-cancer subjects.

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 Pomalidomide + Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma and Renal Impairment: Analysis of Patients from the Phase 3b Stratus Trial (MM-010)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4755-4755 ◽  
Author(s):  
Katja Weisel ◽  
Meletios A. Dimopoulos ◽  
Michele Cavo ◽  
Enrique M. Ocio ◽  
Antonio Palumbo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Adverse Events ◽  
Renal Impairment ◽  
Low Dose ◽  
Dose Intensity ◽  
High Dose ◽  
Employment Equity ◽  
Safety And Efficacy ◽  
Equity Ownership

Abstract Background: Treatment (Tx) with novel agents, including lenalidomide (LEN) and bortezomib (BORT), has extended survival of patients (pts) with multiple myeloma (MM); however, pts who have relapsed on or become refractory to Tx have significantly shortened overall survival (OS) and poorer outcomes (Kumar, Leukemia, 2012). Renal impairment (RI) occurs frequently, in approximately 20% to 40% of MM pts (Kastritis, Haematologica, 2007), and is a leading cause of death in this pt population (Korbet, J Am Soc Nephrol, 2006). In the phase 3 MM-003 trial, pomalidomide plus low-dose dexamethasone (POM + LoDEX) significantly extended progression-free survival (PFS) and OS vs. high-dose dexamethasone in pts in whom BORT and LEN Tx failed, including those with moderate RI (creatinine clearance [CrCl] < 60 mL/min; Weisel, Blood, 2013). STRATUS is a multicenter, single-arm, open-label, European, phase 3b trial to further evaluate safety and efficacy of POM + LoDEX in pts with refractory or relapsed and refractory MM (N = 456), including those with moderate RI. Methods: Pts must have had refractory or relapsed and refractory disease (progressive disease [PD] during or within 60 days of last line of Tx), at least 2 prior therapies, BORT and LEN failure after ≥ 2 cycles of each (alone or in combination), and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to their last line of Tx; pts with CrCl < 45 mL/min were excluded. POM was administered 4 mg D1-21/28-day cycle and LoDEX 40 mg/day (20 mg for pts aged > 75 yrs) on D1, 8, 15, and 22 until PD or unacceptable toxicity. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent based on clinical recommendations. The primary endpoint was safety, and secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, and OS. For this analysis, pts were retrospectively grouped by baseline CrCl (< 60 mL/min vs. ≥ 60 mL/min). Results: A total of 456 pts have been enrolled, of whom 452 received POM + LoDEX and 165 (36%) had moderate RI (CrCl < 60 mL/min). After a median follow-up of 6.8 mos, the most frequently reported grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) in pts with moderate RI vs. without moderate RI (CrCl ≥ 60 mL/min) were neutropenia (39% vs. 40%), anemia (33% vs. 24%), and thrombocytopenia (19% vs. 19%); the most common Gr 3-4 nonhematologic TEAEs were pneumonia (12% vs. 11%), fatigue (6% vs. 4%), and hypercalcemia (4% vs. 4%), respectively. Only 2% of pts in each respective renal subgroup discontinued POM due to Tx-related TEAEs. Gr 3-4 renal toxicities were similar in both subgroups: acute renal failure occurred in 3% of pts with moderate RI and 2% of pts without moderate RI; blood creatinine increased in 2% and 1% of pts, respectively. Overall, Gr 3-4 deep vein thrombosis (DVT), pulmonary embolism (PE), and peripheral neuropathy (PN) were infrequent independent of renal status (Table). Median relative POM dose intensity was similar between subgroups (0.95 in pts with moderate RI vs. 0.96 in pts without moderate RI). In pts with moderate RI vs. without moderate RI, ORR was 35% vs. 34%, median DOR was 5.8 mos vs. 6.5 mos, median PFS was 3.7 vs. 4.6 mos, and median OS was 9.3 vs. not reached, respectively (Table). The 1-yr OS was 33% for pts with moderate RI vs. 53% for pts without moderate RI. Conclusions: POM + LoDEX has acceptable safety and efficacy profiles comparable to those observed in the pivotal MM-003 trial. Tolerability was consistent across renal function subgroups, with few discontinuations due to adverse events. In addition, responses to POM + LoDEX were similar between pts, irrespective of renal function. POM is currently being prospectively evaluated in pts with severe RI in the MM-008 (US) and MM-013 (EU) trials. Table.With Moderate RICrCl < 60 mL/min (n = 162)Without Moderate RICrCl ≥ 60 mL/min(n = 290)Grade 3-4 TEAEs, %Neutropenia Anemia Thrombocytopenia Pneumonia39 33 19 1240 24 19 11Grade 3-4 EOI, %DVT/PE PN2 20 1Efficacy(n = 165)(n = 291)ORR (≥ PR), % (95% CI) Median DOR (95% CI), mos Median PFS (95% CI), mos Median OS (95% CI), mos35 (27.9-43.0) 5.8 (3.7-NE) 3.7 (2.9-5.2) 9.3 (6.3-11.5)34 (28.9-40.1) 6.5 (4.7-7.9) 4.6 (3.7-5.6) NR (10.9-NR) EOI, events of interest; NE, not estimable, NR, not reached. Disclosures Weisel: Celgene Corporation: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Dimopoulos:Celgene: Consultancy, Honoraria. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau. Ocio:Celgene Corporation: Honoraria, Research Funding. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Delforge:Celgene Corp: Honoraria; Janssen: Honoraria. Oriol:Celgene Corporation: Consultancy. Goldschmidt:Celgene Corp: Consultancy, Honoraria, Speakers Bureau. Miller:Celgene Corporation: Employment, Equity Ownership. Peluso:Celgene: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene : Employment, Equity Ownership. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Prevalence and Predictors of Renal Impairment Among Patients with Multiple Myeloma (MM): An Analysis of Oncology Clinic Electronic Health Records Linked to Commercial Claims in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5657-5657
Author(s):  
Geoffrey Block ◽  
Alan Fu ◽  
Sally Wade ◽  
Renee Jaramillo ◽  
Sumita Bhatta ◽  
...  
Keyword(s):  
Risk Factors ◽  
Renal Function ◽  
Renal Impairment ◽  
Cox Model ◽  
Employment Equity ◽  
Health Records ◽  
Stage 4 ◽  
Equity Ownership ◽  
Increase In Risk

Abstract Background Although incurable, MM is responsive to treatment, and the prognosis of MM patients has improved dramatically over the past two decades. This has led to increased recognition of the importance of effective long-term management of the classic clinicopathological features of MM. Renal impairment (RI) is a defining hallmark of active myeloma. While it is known that RI is associated with poor survival and can complicate drug dosing and limit treatment options, patterns of renal function and risk factors of RI in MM are poorly characterized. This study seeks to characterize the natural history and risk factors of RI in MM using a unique real-world dataset that links patient-level electronic health records (EHR) to healthcare insurance claims. Methods The Oncology Services Comprehensive Electronic Records (OSCER) database contains EHR data from community and hospital-affiliated oncology clinics in the U.S. The MarketScan (MS) database contains healthcare claims information from large employers, managed care organizations, Medicare, and Medicaid programs. This study used a subset of MM patients with overlapping data from OSCER and MS, allowing the analysis of EHR-based serum creatinine and claims-based comorbidity data in the same patient. Patients ≥ 18 with a MM diagnosis between 2011 and February 28, 2016 in an OSCER clinic; had at least 6 months of continuous MS benefits coverage; no MM diagnosis in MS in the 3 months prior to OSCER MM diagnosis; and no evidence of another malignancy prior to MM diagnosis were included in the study. Index date was the date of OSCER MM diagnosis and patients were followed up until February 28, 2017. Baseline (BL) patient characteristics and potential risk factors of RI, including demographics, BMI, ECOG, ISS stage, and comorbidities (e.g., hypertension, diabetes, hypercalcemia, etc.) were assessed in the 6 months prior to index. Intravenous bisphosphonate (IV BP) use was assessed during follow-up. Renal function was assessed using the MDRD eGFR method or CKD stage diagnosis codes, with RI defined in this study as eGFR < 60 or stage 3+ CKD. BL eGFR was assessed using the serum creatinine measurement closest to the index in the interval 1 month before and 1 month after index. The prevalence of RI in the year following diagnosis was calculated based on the average number of at-risk patients during this period. Change in renal function for up to 4 years post-diagnosis was assessed by BL renal function and was characterized based on the worst recorded estimate of renal function during this period. A multivariate Cox model was used to assess the impact of BL risk factors and IV BP use during follow-up on progression to RI in patients without RI at BL (eGFR ≥ 60 and CKD diagnosis). Follow-up IV BP use (dose count) was treated as a time-dependent variable. Results The median number of eGFR values recorded per patient during follow-up was 18 (range: 7-36). Among newly diagnosed MM patients (n = 625), 69% (95% CI: 65-73%) experienced ≥ 1 episodes of eGFR < 60 ml/min or stage 3+ CKD diagnosis (RI) within 1 year of diagnosis, with 16% (13-20%) experiencing an episode of eGFR 15-29 or stage 4 CKD and 15% (11-18%) experiencing an episode of eGFR < 15 or stage 5 CKD. Among patients without RI at diagnosis (n = 281), 37% (31-43%) subsequently experienced at least one episode of RI during follow-up (Figure 1). In addition, 26% (20-32%) of patients with BL eGFR 30-59 or stage 3 CKD experienced progression to an episode of eGFR < 30 or stage 4+ CKD, and 31% (20-42%) of patients with BL eGFR 15-29 or stage 4 CKD progressed to an episode of eGFR < 15 or stage 5 CKD. In our multivariate Cox model, use of the IV BP zoledronic acid (ZA) during follow-up; ECOG; baseline eGFR; known predisposing conditions, including autoimmune diseases, vascular conditions, and infections of the kidney were found to be associated with higher risk for experiencing an episode of RI in patients with high BL renal function (Figure 2). In our sample, 12 doses of ZA was associated with a 2.4-fold (1.2-4.8) increase in risk of RI. A baseline ECOG of 1 vs. 0 was also associated with a 2.4-fold (1.1-5.2) increase in risk of RI. Conclusions Using a unique EHR-insurance claims linked data source, we found that two-thirds of patients experienced at least one episode of renal impairment within the first year of MM diagnosis. Repeated exposure to zoledronic acid and poor performance status may increase the risk of RI in patients without renal impairment at diagnosis. Disclosures Block: Amgen, Inc.: Consultancy. Fu:Amgen: Employment, Equity Ownership. Wade:Wade Outcomes Research and Consulting: Employment, Equity Ownership. Jaramillo:Amgen, Inc.: Consultancy; SimulStat: Employment. Bhatta:Amgen, Inc.: Employment, Equity Ownership. Raskin:Amgen, Inc.: Employment, Equity Ownership. Hernandez:Amgen, Inc.: Employment, Equity Ownership.

scholarly journals Medically Ill Patients with Moderate Renal Insufficiency Have More Thrombotic and Bleeding Events Than Those with Normal Renal Function: Insights from the Magellan and Mariner Trials of Extended Thrombprophylaxis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1236-1236
Author(s):  
Jeffrey I. Weitz ◽  
Gary E. Raskob ◽  
Alex C. Spyropoulos ◽  
Alexander T Cohen ◽  
Theodore E. Spiro ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Insufficiency ◽  
Research And Development ◽  
Board Of Directors ◽  
Normal Renal Function ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Equity Ownership ◽  
Moderate Renal Insufficiency

Abstract Background: Hospitalized medically ill patients are at risk for venous thromboembolism (VTE) for at least 45 days after discharge. This observation prompted the MAGELLAN and MARINER trials, which evaluated the efficacy and safety of rivaroxaban for extended thromboprophylaxis. In MAGELLAN, rivaroxaban (10 mg once daily) started in hospital and continued for 35 days was compared with a 10±4 day course of enoxaparin (40 mg once daily) followed by placebo. In MARINER, a 45-day course of rivaroxaban (10 mg once daily for those with creatinine clearance [CrCl] ≥50ml/min and 7.5 mg once daily for those with CrCl 30-<50ml/min) started at discharge was compared with placebo. The goals of this analysis were: (i) to compare rates of VTE (total or symptomatic) and VTE related death and major or clinically relevant bleeding in patients with moderate renal insufficiency (CrCl 30-<50ml/min) and those with normal renal function (CrCL ≥50ml/min), and (ii) to determine if revised criteria for selecting patients for extended thromboprophylaxis are associated with reduced bleeding, particularly in those with moderate renal insufficiency. Methods: We evaluated key efficacy and safety outcomes in patients with moderate renal insufficiency and those with normal renal function from days 1 to 35 in the MAGELLAN study and in a MARINER-like subpopulation of MAGELLAN using the criteria defined a priori for patient exclusion used in the MARINER study. These criteria were: 1) active gastroduodenal ulcer within 3 months of randomization or currently symptomatic, 2) any bleeding within 3 months prior to randomization or during index hospitalization prior to randomization, 3) active cancer at randomization, 4) medical history of severe bronchiectasis or pulmonary cavitation, or 5) dual antiplatelet therapy at baseline. These criteria excluded approximately 20% of subjects in MAGELLAN at high risk of bleeding. Results: The rates of VTE and VTE related death in both the rivaroxaban and enoxaparin/placebo groups were approximately twofold higher in subjects with renal impairment than in those with normal renal function, but the relative risk reduction with rivaroxaban treatment (10mg) compared with enoxaparin/placebo was similar in both renal function subgroups. Rates of major and clinically relevant bleeding in the rivaroxaban group were approximately 50% higher in patients with renal impairment compared with those with normal renal function. In the MARINER like subpopulation, the relative risk reductions for efficacy outcomes were maintained in both renal subgroups, whereas the increase in major bleeding with rivaroxaban was reduced by approximately 50%. Conclusions: Medically-ill patients with renal impairment given extended thromboprophylaxis are at increased risk for both VTE and major bleeding. Use of the MARINER criteria to exclude patients at increased risk of bleeding appears to reduce the major bleeding risk without compromising the efficacy of 10mg daily of rivaroxaban. Figure Figure. Disclosures Weitz: Novartis: Honoraria; Servier: Honoraria; Janssen: Honoraria; Ionis: Consultancy, Honoraria; Daiichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria. Raskob:Janssen: Consultancy; Bayer: Consultancy; BMS: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy. Spyropoulos:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Colorado Prevention Center - ATLAS: Consultancy; Portola: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cohen:Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Medscape: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Portola: Consultancy, Speakers Bureau; AbbVie: Consultancy; ACI Clinical: Consultancy; Boston Scientific: Consultancy; CLS Behring: Consultancy; GLG: Consultancy; Guidepoint Global: Consultancy; Leo Pharma: Consultancy; McKinsey: Consultancy; Sanofi: Consultancy; Navigant: Consultancy; ONO: Consultancy; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy. Spiro:Bayer: Employment, Equity Ownership. De Sanctis:Bayer: Employment, Equity Ownership. Xu:Janssen Research and Development LLC: Employment, Equity Ownership. Suh:Janssen Research and Development LLC: Employment, Equity Ownership. Lu:Janssen Research and Development LLC: Employment. Lipardi:Janssen Research and Development LLC: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership.

scholarly journals Rivaroxaban dosing in patients with atrial fibrillation: results from the RIVER registry – is dosing according to renal function appropriate?

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
A.J Camm ◽  
S Virdone ◽  
K.A.A Fox ◽  
K.S Pieper ◽  
J Beyer-Westendorf ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Renal Function ◽  
Renal Impairment ◽  
Major Bleeding ◽  
Cardiovascular Mortality ◽  
Normal Renal Function ◽  
Severe Renal Impairment ◽  
Real Life ◽  
High Dose ◽  
The Impact

Abstract Introduction Rivaroxaban is recommended as an option for anticoagulation in patients with nonvalvular atrial fibrillation (AF) with one or more risk factors for stroke. The approved/recommended rivaroxaban dose for stroke prevention in patients with atrial fibrillation (AF) is solely based on renal function: 20 mg once daily (od) for patients with a creatinine clearance [CrCl] ≥50 ml/min and 15 mg od in patients with CrCl 15–49 mL/min). Purpose To assess the patterns of rivaroxaban prescription as per the creatinine clearances levels and to assess the impact of the rivaroxaban dosing on the rate of events at 2-year follow-up in patients with AF. Methods RIVaroxaban Evaluation in Real Life setting (RIVER) is a prospective international registry of patients with newly diagnosed non-valvular AF treated with rivaroxaban for the prevention of thromboembolic stroke and at least one investigator-determined risk factor for stroke. Adjusted hazard ratios (HRs) were obtained through Cox proportional-hazard model. Results Among 3402 patients with normal renal function (CrCl ≥50 mL/min), 82.1% were prescribed the recommended rivaroxaban dose of 20 mg (od) at baseline. Among 524 patients with moderate or severe renal impairment (CrCl 15–50 mL/min), 55.3% patients received rivaroxaban 15 mg (od), 39.9% received 20 mg (od) and 4.2% 10 mg (od). Non-recommended dosing was rare in patients younger than 70 (13.5%) but more frequent in older patients (28.8%). Non-recommended low dosing was more frequent in Asians (38.9%), compared to non-Asian patients (13.8%). Regarding clinical outcomes, adjusted hazards ratios (HR, presented with 95% confidence intervals) showed that the non-recommended low dosing (&lt;20 mg od) was associated with higher risk of non-cardiovascular mortality (HR 2.09 (1.16–3.77)) in patients with normal renal function. The non-recommended high dosing (&gt;15 mg od) was associated with lower risk of all-cause mortality (HR 0.63 (0.42–0.93)) and cardiovascular mortality (HR 0.32 (0.13–0.77)) and higher risk of major bleeding (HR 2.86 (1.49–5.50)) in patients with moderate to severe renal impairment (figure 1 and 2). Conclusion In patients with normal renal function, non-recommended low dose rivaroxaban was associated with increased cardiovascular mortality without reducing the risk of major bleeding compared to recommended dosing. In patients with CrCl &lt;50 ml/min, non-recommended high dose rivaroxaban was associated with reduced cardiovascular mortality but at the cost of increased major bleeding. These observational data largely support the reduction of rivaroxaban dosing according to renal function but educational strategies are needed to ensure that rivaroxaban is used appropriately. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by an unrestricted research grant from Bayer AG, Berlin, Germany, to TRI, London, UK, which sponsors the RIVER registry. This work is supported by KANTOR CHARITABLE FOUNDATION for the Kantor-Kakkar Global Centre for Thrombosis Science.

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