scholarly journals Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment

2016 ◽  
Vol 60 (9) ◽  
pp. 5135-5140 ◽  
Author(s):  
Joseph M. Custodio ◽  
Marshall Fordyce ◽  
William Garner ◽  
Mona Vimal ◽  
Kah Hiing J. Ling ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Filtration Rate ◽  
Estimated Glomerular Filtration Rate ◽  
Severe Renal Impairment ◽  
Infinite Time ◽  
Time Curve ◽  
Active Moiety ◽  
Blood And Urine Samples ◽  
Tenofovir Alafenamide ◽  
Oral Prodrug

ABSTRACTTenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIV-uninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, ≥90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (Cmax) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUCinf) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFVCmaxand AUCinfwere 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens.

scholarly journals Effect of severe renal impairment on the pharmacokinetics of brigatinib

2021 ◽  
Author(s):  
Neeraj Gupta ◽  
Michael J. Hanley ◽  
David Kerstein ◽  
Meera Tugnait ◽  
Narayana Narasimhan ◽  
...  
Keyword(s):  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Renal Impairment ◽  
Protein Binding ◽  
Healthy Volunteers ◽  
Glomerular Filtration ◽  
Normal Renal Function ◽  
Filtration Rate ◽  
Estimated Glomerular Filtration Rate ◽  
Severe Renal Impairment

SummaryBackground Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non–small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.

scholarly journals Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis

Haematologica ◽  
2021 ◽  
Author(s):  
Marcelo Capra ◽  
Thomas Martin ◽  
Philippe Moreau ◽  
Ross Baker ◽  
Ludek Pour ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Renal Impairment ◽  
Glomerular Filtration ◽  
Subgroup Analysis ◽  
Filtration Rate ◽  
Estimated Glomerular Filtration Rate ◽  
Phase 3 ◽  
New Therapies

Renal impairment (RI) is common in patients with multiple myeloma (MM) and new therapies that can improve renal function are needed. The Phase 3 IKEMA study (NCT03275285) investigated isatuximab (Isa) with carfilzomib and dexamethasone (Kd) vs Kd in relapsed MM. This subgroup analysis examined results from patients with RI, defined as estimated glomerular filtration rate

scholarly journals Finding the Dose for Ceftolozane-Tazobactam in Critically Ill Children with and without Acute Kidney Injury

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 887
Author(s):  
Laura Butragueño-Laiseca ◽  
Iñaki F. Troconiz ◽  
Santiago Grau ◽  
Nuria Campillo ◽  
Xandra García ◽  
...  
Keyword(s):  
Renal Replacement Therapy ◽  
Renal Impairment ◽  
Replacement Therapy ◽  
Critically Ill ◽  
Severe Renal Impairment ◽  
Kidney Injury ◽  
Volume Of Distribution ◽  
Critically Ill Children ◽  
Multi Drug Resistance ◽  
Time Curve

Background: Ceftolozane-tazobactam is a new antibiotic against multidrug-resistant pathogens such as Pseudomonas aeruginosas. Ceftolozane-tazobactam dosage is still uncertain in children, especially in those with renal impairment or undergoing continuous renal replacement therapy (CRRT). Methods: Evaluation of different ceftolozane-tazobactam dosing regimens in three critically ill children. Ceftolozane pharmacokinetics (PK) were characterized by obtaining the patient’s specific parameters by Bayesian estimation based on a population PK model. The clearance (CL) in patient C undergoing CRRT was estimated using the prefilter, postfilter, and ultrafiltrate concentrations simultaneously. Variables such as blood, dialysate, replacement, and ultrafiltrate flow rates, and hematocrit were integrated in the model. All PK analyses were performed using NONMEM v.7.4. Results: Patient A (8 months of age, 8.7 kg) with normal renal function received 40 mg/kg every 6 h: renal clearance (CLR) was 0.88 L/h; volume of distribution (Vd) Vd1 = 3.45 L, Vd2 = 0.942 L; terminal halflife (t1/2,β) = 3.51 h, dosing interval area under the drug concentration vs. time curve at steady-state (AUCτ,SS) 397.73 mg × h × L−1. Patient B (19 months of age, 11 kg) with eGFR of 22 mL/min/1.73 m2 received 36 mg/kg every 8 h: CLR = 0.27 L/h; Vd1 = 1.13 L; Vd2 = 1.36; t1/2,β = 6.62 h; AUCSS 1481.48 mg × h × L−1. Patient C (9 months of age, 5.8 kg), with severe renal impairment undergoing CRRT received 30 mg/kg every 8 h: renal replacement therapy clearance (CLRRT) 0.39 L/h; Vd1 = 0.74 L; Vd2= 1.17; t 1/2,β = 3.51 h; AUCτ,SS 448.72 mg × h × L−1. No adverse effects attributable to antibiotic treatment were observed. Conclusions: Our results suggest that a dose of 35 mg/kg every 8 h can be appropriate in critically ill septic children with multi-drug resistance Pseudomonas aeruginosa infections. A lower dose of 10 mg/kg every 8 h could be considered for children with severe AKI. For patients with CRRT and a high effluent rate, a dose of 30 mg/kg every 8 h can be considered.

Pomalidomide Plus Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment: Results From a Phase II Trial

2018 ◽  
Vol 36 (20) ◽  
pp. 2035-2043 ◽  
Author(s):  
Meletios Dimopoulos ◽  
Katja Weisel ◽  
Niels W.C.J. van de Donk ◽  
Karthik Ramasamy ◽  
Barbara Gamberi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Glomerular Filtration Rate ◽  
Adverse Events ◽  
Renal Impairment ◽  
Glomerular Filtration ◽  
Phase Ii ◽  
Filtration Rate ◽  
Low Dose ◽  
Estimated Glomerular Filtration Rate ◽  
Phase Ii Trial

Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to < 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate, < 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed.

scholarly journals Kidney Dysfunction among COVID-19 Patients in the United Arab Emirates

2021 ◽  
Vol 36 (1) ◽  
pp. e221-e221
Author(s):  
brahim Y. Hachim ◽  
Mahmood Y. Hachim ◽  
Kashif Bin Naeem ◽  
Haifa Hannawi ◽  
Issa Al Salmi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Renal Function ◽  
Renal Impairment ◽  
United Arab Emirates ◽  
Estimated Glomerular Filtration Rate ◽  
Severe Renal Impairment ◽  
Hematological Indices ◽  
Laboratory Markers ◽  
Function Impairment ◽  
Univariate Statistics

Objectives: We sought to determine the estimated glomerular filtration rate (eGFR) among patients with COVID-19 and to examine its correlation with different demographic, clinical, and laboratory characteristics. Methods: This study examined patients diagnosed with COVID-19 and enrolled at Al Kuwait Hospital, Dubai, UAE. eGFR was calculated using the Modification of Diet in Renal Disease equation, 186 × (SCr mg/dL)-1.154 × (age)-0203 × 0.742 [if female] × 1.212 [if black], and compared for 250 COVID-19 cases and 153 non-COVID-19 controls. Analysis were performed using univariate statistics. Results: The overall mean age of the cohort was 47.2±14.0 years, and 54.6% (n = 220) were males. The results showed that 45.3% of COVID-19 patients had mild-severe renal impairment, as reflected in the eGFR. When compared to patients with normal eGFR, those with severe renal impairment were older (62.5 vs. 40.2 years; p < 0.001), more likely to be male (100% vs. 71.1%; p = 0.016), and have comorbidities (90.9% vs. 40.0%; p < 0.001) including diabetes mellitus (72.7% vs. 21.5%; p < 0.001) and hypertension (72.7% vs. 25.2%; p = 0.003). They were also more likely to be associated with those that had severe (36.4% vs. 25.9%; p < 0.001) and critical (63.6% vs. 16.3%; p < 0.001) COVID-19 infection as well as intensive care unit admission (72.7% vs. 16.3%; p < 0.001). Correlational analysis showed a significant association between renal function indicators and different laboratory markers, including hematological indices and different liver enzymes. Conclusions: This is the first study to examine the renal function among COVID-19 cases in the Middle East. Nearly half of COVID-19 patients had moderate to severe renal impairment. Diabetes mellitus and hypertension were the most common underlying comorbidities associated with moderate-severe renal function impairment among COVID-19 patients.

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