Moderate RI Research Articles

Renal insufficiency increases the risk of left ventricular remodeling

Abstract Background Renal insufficiency (RI) is a common disease and associated with heart failure (HF). Left ventricular remodeling (LVR) is a vital process in the progression of HF. However, few studies investigate the relationship between RI and LVR. Methods We included 4,973 consecutive patients undergoing coronary angiography (CAG) from January 2007 to December 2018 at Guangdong Provincial People's Hospital (NCT04407936). RI was defined as estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73m2. LVR was defined as: 1) left ventricular ejection fraction (LVEF) decreased by ≥ 10% from baseline, or 2) a follow-up measurement of LVEF < 40%. Univariate and multivariate logistical regressions were used to assess the association between RI and LVR. Results Of the 4,973 patients (61.8 ± 10.5 years, female 30.8%) included in the study. The patients who developed LVR have lower eGFR (73.7 ± 24.2 vs. 78.4 ± 24.2 ml/min/1.73m2, p<0.001). Among the 3,568 (60.6%) patients with RI, 526 (14.7%) had LVR. After adjusting for confounding, multivariate logistic regression showed that RI was associated with a significantly higher risk of LVR (mild RI: OR: 1.23, 95%CI 1.00-1.51, P=0.050; moderate RI: OR: 1.48, 95%CI 1.15-1.92, P = 0.003; severe RI: OR: 1.50, 95%CI 0.91-2.40, P = 0.096). In addition, LVR patients had higher all-cause mortality compared to non-LVR patients (18.1% vs. 9.3%). Conclusions Worse renal function increases the risk of decrease in left ventricular systolic function, and severe renal function insufficiency increases the risk of decreased left ventricular systolic function as high as 80% in patients following coronary angiography.Central Illustration

Physiologically Based Pharmacokinetic Modelling to Predict Imatinib Exposures in Cancer Patients with Renal Dysfunction: A Case Study.

Imatinib is mainly metabolised by CYP3A4 and CYP2C8 and is extensively bound to α-acid glycoprotein (AAG). A physiologically based pharmacokinetic (PBPK) model for imatinib describing the CYP3A4-mediated autoinhibition during multiple dosing in gastrointestinal stromal tumor patients with normal renal function was previously reported. After performing additional verification, the PBPK model was applied to predict the exposure of imatinib after multiple dosing in cancer patients with varying degrees of renal impairment. In agreement with the clinical data, there was a positive correlation between AAG levels and imatinib exposure. A notable finding was that for recovery of the observed data in cancer patients with moderate RI (CrCL 20 to 39 mL/min), reductions of hepatic CYP3A4 and CYP2C8 abundances, which reflect the effects of RI, had to be included in the simulations. This was not the case for mild RI (CrCL 40 to 50 mL/min). The results support the finding of the clinical study, which demonstrated that both AAG levels and the degree of renal impairment are key components that contribute to the interpatient variability associated with imatinib exposure. As indicated in the 2020 FDA draft RI guidance, PBPK modelling could be used to support an expanded inclusion of patients with RI in clinical studies.

Imipenem/cilastatin/relebactam efficacy, safety and probability of target attainment in adults with hospital-acquired or ventilator-associated bacterial pneumonia among patients with baseline renal impairment, normal renal function, and augmented renal clearance.

To assess the relationship between renal function and efficacy/safety of imipenem/cilastatin/relebactam for the treatment of hospital-acquired/ventilator-associated pneumonia (HABP/VABP) from RESTORE-IMI 2 and determine the PTA. Adults with HABP/VABP were randomized 1:1 to IV imipenem/cilastatin/relebactam 1.25 g or piperacillin/tazobactam 4.5 g every 6 h for 7-14 days. Initial doses were selected by CLCR and adjusted thereafter, as appropriate. Outcomes included Day 28 all-cause mortality (ACM), clinical response, microbiological response and adverse events. Population pharmacokinetic modelling and Monte Carlo simulations assessed PTA. The modified ITT population comprised those with normal renal function (n = 188), augmented renal clearance (ARC; n = 88), mild renal impairment (RI; n = 124), moderate RI (n = 109) and severe RI (n = 22). ACM rates were comparable between treatment arms among all baseline renal function categories. Clinical response rates were comparable between treatment arms for participants with RI and normal renal function but were higher (91.7% versus 44.4%) for imipenem/cilastatin/relebactam-treated versus piperacillin/tazobactam-treated participants with CLCR ≥250 mL/min (n = 21). Microbiologic response rates were comparable between treatment arms for participants with RI but higher among those treated with imipenem/cilastatin/relebactam in participants with CLCR ≥90 mL/min (86.6% versus 67.2%). Adverse events were comparable between treatment arms across renal function categories. Joint PTA was >98% for key pathogen MICs for susceptible pathogens (MIC ≤2 mg/L). Prescribing information-defined dose adjustments in participants with baseline RI and full dosing of imipenem/cilastatin/relebactam 1.25 g every 6 h for participants with normal renal function or augmented renal clearance achieved sufficiently high drug exposures and favourable safety and efficacy profiles.

Long-term clinical outcomes in older patients with acute venous thromboembolism who have renal impairment

IntroductionRenal impairment (RI) may induce an inflammatory/procoagulant state as well as platelet dysfunction. Little is known on the prevalence of RI and long-term prognosis of older patients with venous thromboembolism (VTE) who have concomitant RI. MethodsIn a prospective multicenter cohort, we analyzed 912 patients aged ≥65 years with acute VTE. Using the CKD-EPI formula, we defined three categories of baseline renal function: estimated glomerular filtration rate ≥60 ml/min/1.73m2 (no RI), 30–59 ml/min/1.73m2 (moderate RI), and <30 ml/min/1.73m2 (severe RI). The outcomes were VTE recurrence, major bleeding, and overall mortality. We examined the association between renal function and clinical outcomes using competing risk regression models, adjusting for relevant confounders and periods of anticoagulation. ResultsWe followed 912 patients over a median duration of 29.6 months. Overall, 313 (34%) patients had moderate and 51 (6%) severe RI. One hundred and seven patients (12%) had VTE recurrence, 125 (14%) had major bleeding, and 186 (20%) died during follow-up. After adjustment, severe RI was associated with a 2-fold increased risk of major bleeding (sub-hazard ratio [SHR] 2.1, 95% CI 1.1–4.0) compared to no RI, but not with VTE recurrence (SHR 0.6, 95% CI 0.2–1.8) or overall mortality (hazard ratio 1.0, 95% CI 0.6–1.9). Moderate RI was not significantly associated with adverse clinical outcomes. ConclusionsRI was common among older patients with acute VTE. Severe RI was associated with a 2-fold increased long-term risk of major bleeding, without a risk increase in terms of VTE recurrence and overall mortality. Older patients with moderate RI did not carry worse prognosis.

OCEAN (OP-103): Melflufen Plus Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM) - Renal Impairment (RI) Analysis

OCEAN (OP-103): Melflufen Plus Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM) - Renal Impairment (RI) Analysis

MM-013 Phase 2, Multicenter Study of Pomalidomide (POM) Plus Low-Dose Dexamethasone (LoDEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI): Pharmacokinetics (PK) Analysis

MM-013 Phase 2, Multicenter Study of Pomalidomide (POM) Plus Low-Dose Dexamethasone (LoDEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI): Pharmacokinetics (PK) Analysis

Aiding and Opposing Re-circulating Mixed Convection Flows in a Square Vented Enclosure

A numerical study is performed to investigate mixed convective flow in a vertically vented square enclosure with heating or cooling one of the vertical walls and the other three walls are insulated. This study is conducted to analyse and clarify the intricate interaction between the buoyancy-induced flow and the pressure-driven external flow in a vertical upward laminar air jet for both assisting and opposing buoyancy situations. The approach of spectral-element that is introduced as a finite-element method with high-order Lagrange polynomials as interpolating functions, is applied to discretise unsteady Navier-Stokes, continuity and energy equations, and for calculating the velocity and temperature fields. The numerical solutions are obtained for air having a Prandtl number of (Pr = 0.7) and for buoyancy parameters which cover the whole mixed convection region, ranging from pure forced convection with a Reynolds number ranging between (10 ⩽Re ⩽350) to pure free convection with a Richardson number ranging between (0 ⩽Ri ⩽30), with a single dimensionless enclosure size. The results reveal that the flow and thermal patterns can be significantly influenced by both aiding and opposing buoyancies. Also, the mean heat transfer rates increase with increasing either the buoyancy force Richardson number or the forced flow Reynolds number in assisting flows. However, in opposing flows, it is found that the mean heat transfer rates decrease with increasing the buoyancy effects for small to moderate (Ri ⩽2) but, they begin rising for higher Richardson number when the free convection starts domination the flow.

Analysis of hematologic adverse events (HeAEs) in trifluridine/tipiracil (FTD/TPI)-treated patients (pts) with or without renal/hepatic impairment (RI/HI): Pooled safety analyses from TAGS and RECOURSE.

145 Background: FTD/TPI has shown clinical benefit and consistent safety in pretreated pts with metastatic colorectal cancer (mCRC) and metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) in the phase 3 RECOURSE and TAGS trials, respectively. HeAEs were the most frequent AEs with FTD/TPI treatment. Methods: Pts in this analysis received ≥1 FTD/TPI dose in the TAGS and RECOURSE trials. Subgroups included pts with normal renal function (nRF; CrCl ≥90 mL/min), mild RI (CrCl 60–89 mL/min), moderate (mod) RI (CrCl 30–59 mL/min), normal hepatic function (nHF) and mild HI (total bilirubin &lt;1.5 X ULN, or AST &gt;ULN). Results: FTD/TPI was administered to 868 pts in the overall pooled population (OPP; n=335, TAGS [mGC/GEJC]; n=533, RECOURSE [mCRC]); 52%, 36%, and 11% had nRF, mild and moderate RI, and 66% and 33% had nHF and mild HI, respectively. Frequencies of any-cause grade (gr) ≥3 HeAEs were similar across subgroups and the OPP, except for gr ≥3 anemia and gr ≥3 leukopenia, which were higher with mod RI (table). In the OPP, most gr 3/4 neutropenia events occurred within the first 2 cycles (median time to onset [mTTO], 49 d). Median time to resolution (mTTR) was 8 d. Gr 3/4 neutropenia TTO and TTR in most subgroups were consistent with the OPP, except with mod RI (mTTO, 29 d). HeAE management and correlative efficacy analyses will be presented. Conclusions: In this pooled analysis of pts with mCRC and mGC/GEJC, HeAEs with FTD/TPI in pts with mild to mod RI and mild HI were manageable and not largely different from those in the OPP. Clinical trial information: NCT02500043 and NCT01607957. [Table: see text]

316. Is there a correlation between Cobb angle and pulmonary function tests in severe scoliosis patients with respiratory impairment and treated by posterior vertebral column resection?

BACKGROUND CONTEXT Surgical treatment of spinal deformity based on the severity of curves and with a view to improve physical performance and respiratory function. However, there was still controversial in the correlation of deformity correction rate and pulmonary function tests (PFTs) change in AIS, and no more study focused on patients with >90° scoliotic curves. PURPOSE To evaluate the relationships of Cobb angle and PFTs change in severe scoliosis with RI and underwent posterior vertebral column resection (PVCR). STUDY DESIGN/SETTING A retrospective study. PATIENT SAMPLE This study enrolled severe scoliosis (Cobb angle>90°) with moderate or severe RI underwent PVCR in one center from 2004 to 2016. Exclude criteria including neuromuscular or syndromic scoliosis. OUTCOME MEASURES PFTs values, forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were used as both absolute values and percent-predicted values. Radiographic measurements of deformities included Cobb magnitude of major curve and deformity morphological classification. METHODS PFTs and radiographic data had been calculated preop and at 2yrs after PVCR. Patients were grouped according scoliosis angle (90°-130° vs >130°), age (pediatric vs adult), with >90° kyphosis or not, preop RI levels (FVC% 41-60%/moderate RI, 0-40%/severe RI). Pearson's correlation coefficients (r) and two-sample t test were used. RESULTS A total of 62 cases (29 male/33 female, mean age 18.9Yr) was enrolled. Preoperatively, the average scoliotic angle was 118.5, with apex T4-10(54, 87.1%) and T11-L1(8, 12.9%). Respiratory impairments were restrictive (FVC=1.409L, FVC%=40.85%; FEV1=1.283L, FEV1%=44.12%), and 28(45.2%) had FVC% 60 had less improvement of PFTs than angle CONCLUSIONS Severe scoliosis may reveal severe respiratory dysfunction, but preoperative PFTs values did not related to Cobb angle. Age of deformity onset, illegible etiological factors, and lung infection may play an important role for PFTs impairment. After PVCR, most of patients had significant PFTs improvement, and correlated with Cobb angle change in patients with preop moderate respiratory impairment. Much lower of preoperative FVC%, more increase PFTs at 2 years postoperative. But, residual angle 60° or less did not ultimately influence PFTs change. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

1027-P: A Phase 1, Open-Label, Single-Dose Study to Evaluate Pharmacokinetics of MEDI0382 in Patients with Renal Impairment

MEDI0382, an oxyntomodulin-like peptide with targeted GLP-1 and glucagon receptor activity, is in development for T2DM. This open-label, parallel-group study (NCT03235375) evaluated PK of SC MEDI0382 (100 µg; single dose) in subjects (N = 37) grouped by renal function: Group 1, ESRD or severe renal impairment (RI; CrCl &amp;lt; 20 mL/min); Group 2, severe RI (CrCl ≥ 20 mL/min to &amp;lt; 30 mL/min); Group 3, healthy controls (CrCl ≥ 90 mL/min); Group 4a, moderate RI (CrCl ≥ 30 mL/min to &amp;lt; 45 mL/min); and Group 4b, moderate RI (CrCl ≥ 45 mL/min to &amp;lt; 60 mL/min). Coprimary endpoints were geometric mean ratio AUC48h and Cmax of MEDI0382 (Table 1). MEDI0382 had similar PK profiles across all groups (Table 2). This suggests that PK of MEDI0382 is unaffected by renal function, allowing dosing in subjects with RI in future trials. Disclosure G.K. Klein: None. M. Petrone: Employee; Self; MedImmune. Y. Yang: Employee; Self; MedImmune. T. Hoang: Employee; Self; MedImmune. S. DiCostanza: Employee; Self; AstraZeneca. L. Hansen: Employee; Self; AstraZeneca, MedImmune. Stock/Shareholder; Self; Bristol-Myers Squibb Company, Novo Nordisk A/S. A. Flor: Employee; Self; AstraZeneca.

Impact of renal impairment on outcomes after autologous stem cell transplantation in multiple myeloma: a multi-center, retrospective cohort study

BackgroundRenal impairment (RI) is a negative prognostic factor in Multiple Myeloma (MM) and affected patients are often excluded from autologous stem cell transplantation (ASCT). However, it remains unclear whether historically inferior outcome data still hold true.MethodsFrom a total of 475 eligible MM patients who had undergone ASCT between 1998 and 2016, 374 were included in this multi-centric retrospective cohort study. Renal function was determined both at the time of MM diagnosis and ASCT by estimated glomerular filtration rate (eGFR according to the MDRD formula, RI defined as eGFR < 60 ml/min/1.73m2). Patients were categorized into 3 groups: A) no RI diagnosis and ASCT, B) RI at diagnosis with normalization before ASCT and C) RI both at the time of diagnosis and ASCT. Log-rank testing was used for overall and progression-free survival (OS, PFS) analysis.ConclusionWhile severe RI at MM diagnosis confers a risk of shorter OS, MM progression after ASCT is not affected by any stage of renal failure. It can be concluded that ASCT can be safely carried out in MM patients with mild to moderate RI and should be pro-actively considered in those with severe RI.ResultsWhen comparing all groups, no difference in OS and PFS was found (p = 0.319 and p = 0.904). After further stratification according to the degree of RI at the time of diagnosis, an OS disadvantage was detected for patients with an eGFR < 45 ml/min/m2. PFS was not affected by any RI stage.

DNS of turbulent mixed convection over a vertical backward-facing step for lead-bismuth eutectic

Studies of turbulent mixed convection over a vertical backward-facing step for liquid metals are indispensable to research the buoyancy effects in flow separation and reattachment scenarios that occurs in innovative nuclear and solar power facilities. Direct numerical simulations of turbulent buoyancy-aided flow at two moderate Richardson numbers (Ri = 0.1, 0.2) and buoyancy-opposed flow at Ri = −0.04 for lead–bismuth eutectic (LBE, Prandtl number Pr = 0.025) are performed. The forced convection and air mixed convection (Pr = 0.7, Ri = 0.1) are also simulated for comparison. In all the cases Reynolds number is 4805 and the expansion ratio is 1.5. Mean statistics like velocity components, temperature and heat fluxes are given. Second-order quantities such as Reynolds stresses, temperature fluctuations, and turbulent heat fluxes are also discussed. The results show that buoyancy has substantially altered the flow field for LBE flow compared to air flow at moderate Ri. For buoyancy-aided LBE flow, the recirculation zone is reduced in size and the reattachment length is shortened. With Ri increasing, the second vortex gradually prevails over the main vortex and finally pushes it detach from the wall, leading to positive skin-friction coefficient. Buoyancy weakens the turbulent quantities such as Reynolds stresses, temperature fluctuations and turbulent heat fluxes. Both skin-friction coefficient and Nusselt number increase due to the reduced reversed flow resulting from buoyancy acceleration near the wall. However, it is opposite for the case of buoyancy-opposed flow. The skin-friction coefficient and Nusselt number decrease due to the increased reversed flow though the turbulence is enhanced in buoyancy-opposed flow. These high-resolved data could promote the understanding of this scenario and improve turbulent modelling for flow separation and reattachment of low Prandtl fluids.

Serum free light chain levels and renal function at diagnosis in patients with multiple myeloma

BackgroundRenal impairment (RI) is common in multiple myeloma (MM) and is associated with poor survival. This study reports the associations between renal function and disease characteristics including serum free light chain (FLC) level at diagnosis in patients with MM.MethodsUsing data from the Medical Research Council Myeloma IX trial, a multicentre, randomized, open-label, phase III and factorial-design trial, we assessed the relationships between renal function, demographic, and disease characteristics, including serum FLC levels, in 1595 newly diagnosed MM patients. Multivariable linear regression was utilised to identify factors that were associated with renal function at diagnosis. A receiver operating characteristic curve (ROC) was used to identify the optimal threshold for serum FLC level at diagnosis to predict severe RI.Results52.8% of patients had an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 (no RI), 37.3% an eGFR 30–59 ml/min/1.73 m2 (mild to moderate RI), and 9.8% an eGFR < 30 ml/min/1.73 m2 (severe RI). In a multivariable analysis, factors independently and negatively associated with eGFR at diagnosis were: higher serum FLC level, female gender, and older age. Elevated serum FLC level at diagnosis, irrespective of the paraprotein type, was strongly associated with severe RI. Receiver operating characteristic curve analysis showed a serum FLC level of > 800 mg/L as the optimal cut-off associated with severe RI (area under curve 0.86, 95% confidence interval 0.77–0.84).ConclusionThere was a strong relationship between higher serum FLC levels at diagnosis and the severity of RI that was irrespective of the paraprotein type. We report an increased risk of severe RI in patients presenting with serum FLC levels above 800 mg/L at diagnosis.

Assessment of Adverse Renal Effects in Patients with Type 2 Diabetes Mellitus (T2DM) Receiving Ertugliflozin

Ertugliflozin (ERTU) is a SGLT2 inhibitor for the treatment of T2DM. Adverse renal effects were assessed in adults with T2DM receiving ERTU relative to placebo (PBO) or active comparators in pooled analyses of 7 randomized, double-blind, Phase 3 trials. Patients (N=4859) received ERTU 5 mg (n=1716), ERTU 15 mg (n=1693), or non-ERTU (PBO, glimepiride or sitagliptin; n=1450) for up to 2 years. Mean age was 57.8 years, 25.8% were ≥65 years old and 51.8% were males. Mean eGFR was 85.3 mL/min/1.73 m2 and ∼12% had moderate renal impairment (RI; eGFR &amp;lt;60 mL/min/1.73 m2). The mean duration of T2DM was 7.9 years and mean baseline A1C was 8.2%. The incidence of renal-related AEs was low across the groups (ERTU 5 mg, 0.6%; ERTU 15 mg, 0.8%; non-ERTU, 0.4%); few were serious (0.1% in all groups) or led to treatment discontinuation (0.1%, 0.2% and 0.1%, respectively). Subgroup analyses demonstrated that in patients with moderate RI, renal-related AEs were more frequent in the ERTU groups relative to the non-ERTU group (ERTU 5 mg, 3.6%; ERTU 15 mg, 2.1%; non-ERTU, 1.1%). Incidence of renal-related AEs was similar across groups for patients ≥65 years old (excluding those with moderate RI at baseline) (ERTU 5 mg, 0.3%; ERTU 15 mg, 1.0%; non-ERTU, 0.8%) or those using diuretics (ERTU 5 mg, 1.2%; ERTU 15 mg, 0.8%; non-ERTU, 0.8%) or ACE/ARB (ERTU 5 mg, 0.9%; ERTU 15 mg, 0.9%; non-ERTU, 0.5%). Independent blinded adjudication for causality was performed for pre-specified renal-related AEs and renal laboratory changes from baseline. Four patients had renal events that were adjudicated as causally related to study medication (“possible” or “very likely”; 1 in the ERTU 5 mg group, 2 in the ERTU 15 mg group and 1 in the non-ERTU group). In conclusion, there was no increased risk of adverse renal effects in patients with T2DM receiving ERTU relative to PBO or active comparators, except in those with baseline moderate RI. Disclosure S.M. Patel: Employee; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; GlaxoSmithKline plc.. Stock/Shareholder; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc. M.A. Hickman: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. R. Frederich: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc., Bristol-Myers Squibb Company. B. Lauring: Employee; Self; Merck &amp; Co., Inc. S. Terra: Employee; Self; Pfizer Inc. S.L. Johnson: Employee; Self; Pfizer Inc. S. Huyck: Employee; Self; Merck &amp; Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc..

Evaluation of Osmotic Diuresis and Volume Depletion Events in Patients with Type 2 Diabetes Mellitus (T2DM) Receiving Ertugliflozin

Ertugliflozin (ERTU) is an SGLT2 inhibitor for the treatment of T2DM. Osmotic diuresis (OD), volume depletion (VD) and change in renal function were assessed in adults with T2DM. Pooled analyses were performed on data from 7 randomized, double blind, Phase 3 trials in patients receiving ERTU or non-ERTU (placebo [PBO] or active comparator) for at least 26 weeks, including a PBO pool (subset; n=1544) and a broad pool (all studies; N=4859; ERTU 5 mg: n=1716; ERTU 15 mg: n=1693; non-ERTU: n=1450). Mean age was 57.8 years, 25.8% were ≥65 years old, 51.8% were male and 27.7% were on diuretics. Mean eGFR was 85.3 mL/min/1.73 m2. Mean duration of T2DM was 7.9 years and mean baseline (BL) A1C was 8.2%. BL characteristics were similar in the PBO pool. In the broad pool, the incidence of OD events was 2.7%, 2.2%, and 1.4% with ERTU 5 mg, ERTU 15 mg, and non-ERTU, respectively; none were serious and ≤0.2% led to treatment discontinuation. The incidence of VD events was 1.9%, 1.4%, and 1.2% with ERTU 5 mg, ERTU 15 mg and non-ERTU, respectively; 0.2%, 0% and 0%, respectively, were serious and ≤0.1% led to treatment discontinuation. In patients with moderate renal impairment (RI; n=575, ∼12%), ≥65 years old, or on diuretics, ERTU led to a higher incidence of VD events than non-ERTU. In the PBO pool, the incidence of OD events was 2.9%, 2.4%, and 1.0% and the incidence of VD events was 0.8%, 1.0%, and 1.7% with ERTU 5 mg, ERTU 15 mg and PBO, respectively. There was no increase in the proportion of patients with orthostatic hypotension with ERTU treatment. ERTU was associated with small, early decreases in eGFR that returned to or towards BL during treatment. Mean decreases in eGFR were larger in patients with BL moderate RI and returned to BL after treatment discontinuation (recently published). ERTU is associated with OD, but does not generally lead to VD events or orthostatic hypotension. Consistent with this, observed decreases in eGFR were reversible during treatment or after discontinuation. Disclosure S.M. Patel: Employee; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; GlaxoSmithKline plc.. Stock/Shareholder; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc. M.A. Hickman: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. R. Frederich: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc., Bristol-Myers Squibb Company. B. Lauring: Employee; Self; Merck &amp; Co., Inc. S. Terra: Employee; Self; Pfizer Inc. S.L. Johnson: Employee; Self; Pfizer Inc. S. Huyck: Employee; Self; Merck &amp; Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc..

A clinical audit on venous thromboembolism prophylaxis of medical patients in West Medical Ward, Mayo Hospital

Objective: To reduce risk of Deep Venous Thrombosis/ Pulmonary Embolism in an acutely ill hospitalized medical patient and the consequent clinical complications. Place and duration: The study was carried out in the West Medical Unit of Mayo Hospital, Lahore from January, 2005 to May, 2005. Subjects and methods: A total of 100 cases were selected from the patients hospitalized in the ward on the basis of presence of risk factors with no contraindications to heparin prophylaxis, taking into account the age, gender, final diagnosis of the patient, the existing risk factors, the risk stratification, the exclusion criteria, whether heparin prophylaxis was given or not, if given type of heparin administered, and whether patients receiving prophylaxis were monitored or not using Platelet Count, APTT or other monitoring techniques. Results: 19 cases were under Moderate Risk of developing Venous Thromboembolism (VTE) and 81 cases were under High Risk. 7 received Heparin prophylaxis. 3 of them were at Moderate Ri sk and 4 cases at High Risk of developing VTE. Conclusion: All acutely ill medical adult patients admitted should be adequately assessed and screened for presence of Risk Factors and categorized according to the SAVE Risk Stratification. In the absence of Exclusion factors, all cases of High Risk and Moderate Risk should be started on Heparin Prophylaxis as early as possible in hospital admission. The audit should be repeated for re-evaluation after adequate time.

Phase 1/1b Pharmacokinetic (PK) and Safety Study of the Investigational Oral Proteasome Inhibitor (PI) Ixazomib in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) with Severe Renal Impairment or End-Stage Renal Disease (ESRD) Requiring Hemodialysis

Phase 1/1b Pharmacokinetic (PK) and Safety Study of the Investigational Oral Proteasome Inhibitor (PI) Ixazomib in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) with Severe Renal Impairment or End-Stage Renal Disease (ESRD) Requiring Hemodialysis

784P - Pharmacokinetic (Pk) Activity of Cabazitaxel (Cbz) in Patients (Pts) with Renal Impairment (Ri)

ABSTRACT Aim: Limited data are available on Cbz PK in pts with RI (14 with moderate RI, 1 with severe RI [Ferron, Cancer Chemother Pharmacol 2013]). This open-label, multicentre study assessed Cbz PK in pts with advanced solid tumours and normal or impaired renal function. Methods: Pts enrolled into cohorts A (normal control, creatinine clearance [CrCL] >80 ml/min/1.73 m2), B (moderate RI, CrCL 30– Results: Pts (n = 25) received a median of 3 Cbz cycles (range 1–20: cohort A, 5 [2–13]; cohort B, 3 [1–15]; cohort C, 5 [1–20]), and 24 were eligible for PK analysis (8/cohort). For moderate and severe RI vs controls, GMR estimates were: CL/BSA 0.95 (90% CI 0.80–1.13) and 0.89 (0.61–1.32); AUC/dose 1.06 (0.88–1.27) and 1.14 (0.76–1.71); FU 0.99 (0.94–1.04) and 0.97 (0.87–1.09), respectively. Estimated slope of linear regression of log parameters vs log CrCL was: CL/BSA 0.06 (90% CI -0.15–0.28); AUC/dose -0.07 (-0.30–0.16); Cbz FU 0.02 (-0.05–0.08). Cbz safety was consistent with previous reports. Conclusions: RI had no clinically meaningful effect on Cbz PK. Non-significant trends of increasing AUC and decreasing Cbz CL with greater RI were seen. PK parameter estimates for pts with moderate and severe renal impairment and controls GM estimate (90% CI) Control CrCL 90 ml/min/1.73 m2 Moderate renal impairment CrCL 40 ml/min/1.73 m2 Severe renal impairment CrCL 15 ml/min/1.73 m2 CL/BSA, l/h/m2 29.81 (24.18–36.75) 28.34 (24.44–32.86) 26.66 (20.15–35.27) AUC/dose, ng*h/ml/mg/m2 33.23 (26.65–41.44) 35.21 (30.24–40.99) 37.75 (28.29–50.39) Cbz FU, % 5.51 (5.08–5.96) 5.44 (5.13–5.76) 5.36 (4.95–5.80) Disclosure: J. Machiels: has been a member of advisory boards for Boehringer Ingelheim and Novartis and his institution has received research funding from Sanofi; S. Rottey: has attended advisory boards and received research funding from Sanofi; R. Baird: has received research funding from Sanofi; P. Clot and C. Wack: is an employee of Sanofi; L. Shen and D. Bobilev: is an employee and stock holder of Sanofi. All other authors have declared no conflicts of interest.

INT-006 Pharmacist-physician collaboration to ensure the safe dosing in renal impairment among patients admitted to an emergency ward in Finland

BackgroundRenal impairment (RI) increases the risk of adverse drug events especially in elderly patients, since kidney function declines with age. Many risks can be avoided by appropriate dosing adjustment in...

Pomalidomide plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM): MM-003 analysis of patients (pts) with moderate renal impairment (RI).

8527 Background: Pts who have exhausted lenalidomide (LEN) and bortezomib (BORT) treatment (Tx) have a poor prognosis. A significant proportion of pts have RI with increasing incidence during disease course. POM + LoDEX has demonstrated efficacy in pts with prior LEN and BORT, including those with RI. MM-003 is an open-label, multicenter, phase 3 trial comparing POM + LoDEX vs HiDEX in RRMM pts who failed LEN and BORT and progressed on their last Tx. Methods: Pts must have failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination) and must have been refractory to last prior Tx (progressive disease [PD] during Tx or within 60 days). Pts with creatinine clearance (CrCl) &lt; 45 mL/min were excluded. Randomization was 2:1 to POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged &gt; 75 y) qw; or DEX 40 mg (20 mg for pts aged &gt; 75 y) D1–4, 9–12, and 17–20 (28-D cycles). Tx continued until PD or unacceptable adverse event (AE). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and AEs. This analysis examined pts with or without moderate RI (CrCl &lt; 60 vs ≥ 60mL/min). Results: 302 pts received POM + LoDEX; 153 pts received HiDEX, 31% and 39% had moderate RI, respectively. Pts with moderate RI were more likely to be older (64% vs 36% aged &gt; 65 y) vs no RI. Median follow-up was 4 mo. Median PFS and OS were significantly longer with POM + LoDEX vs HiDEX regardless of RI (Table). Similar AE rates for POM + LoDEX as well as HiDEX Tx were seen in pts with and without moderate RI (Table). Discontinuation due to AE was 5% vs 7% (no moderate RI) and 11% vs 5% (moderate RI). Conclusions: POM + LoDEX significantly extended PFS and OS vs HiDEX in pts with or without moderate RI. Tolerability of POM + LoDEX was acceptable across subgroups, with few discontinuations due to AE. Clinical trial information: NCT01311687. [Table: see text]