scholarly journals Meropenem–Vaborbactam Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses as Support for Dose Selection in Patients with Normal Renal Function and Varying Degrees of Renal Impairment

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S530-S531 ◽  
Author(s):  
Sujata M Bhavnani ◽  
Michael Trang ◽  
David C Griffith ◽  
Olga Lomovskaya ◽  
Jeffrey P Hammel ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Target Attainment ◽  
Dose Selection

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) < 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 >99% subjects above efficacious thresholds of AUC/MIC >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 >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)

P0234LOW URINARY CITRATE LEVELS ARE NOT SPECIFIC OF AUTOSOMAL POLYCYSTIC KIDNEY DISEASE (ADPKD) AND ARE PRESENT WHEN RENAL FUNCTION IS IMPAIRED IN ALL NEPHROPATIES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Francisco-Jose Borrego-Utiel ◽  
Enoc Merino Garcia ◽  
Isidoro Herrera ◽  
Clara Moriana Dominguez ◽  
Victoria Camacho Reina ◽  
...  
Keyword(s):  
Renal Function ◽  
Uric Acid ◽  
Kidney Disease ◽  
Renal Impairment ◽  
Polycystic Kidney Disease ◽  
Normal Renal Function ◽  
Serum Bicarbonate ◽  
Polycystic Kidney ◽  
Glomerular Diseases ◽  
Urinary Citrate

Abstract Background and Aims In polycystic kidney disease (PKD) it is frequently found a reduction in urinary citrate that is related with degree of renal impairment but it is unknown if this alteration is specific or if it is also present in other nephropathies. Recently it has been suggested that urinary citrate could be a marker of covert metabolic acidosis and reflects acid retention in chronic kidney disease (CKD). Our aim was to compare urinary citrate in PKD with other renal diseases and to show its relation with serum bicarbonate and excretion of uric acid and calcium. Method We determined citrate, calcium and uric acid in 24-hour urine in patients with PKD and with other nephropathies with varied degree of renal impairment followed in a outpatient clinic of nephrology. Results We included 291 patients, 119 with glomerular diseases, 116 with PKD, 21 with other nephropathies, and 35 patients with normal renal function. Urinary citrate was higher in women (Females 309±251 mg/gCr vs. males 181±145 mg/gCr, p<0.001) and in patients with normal renal function (normal 380±210 mg/gCr; PKD 203±166 mg/gCr; glomerular 279±282 mg/gCr; p<0,001). PKD patients showed similar values of urinary citrate to patients with glomerular diseases and with other nephropathies. We observed a progressive reduction in urinary citrate parallel to degree of renal impairment, in a comparable way among patients with PKD and glomerular diseases. We did not observe a relationship between urinary citrate and serum bicarbonate levels. Calcium and uric acid elimination in ADPKD patients was similar to other nephropathies and lower to patients with normal renal function. However, serum uric acid was significantly higher in glomerular patients than other nephropathies after adjust with glomerular filtration rate and sex. Conclusion Hypocitraturia is not specific of PKD but it is also present in all nephropathies. Urinary citrate are related to degree of renal impairment and it is not related with serum bicarbonate. We think that it could be interesting to study urinary citrate as a marker of renal function and its role as prognostic factor of renal deterioration.

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.

Insulin Degludec has Similar Pharmacokinetic Properties in Subjects with Renal Impairment and Subjects with Normal Renal Function

2012 ◽  
Vol 36 (5) ◽  
pp. S36
Author(s):  
István Kiss ◽  
Gerhard Arold ◽  
Susanne G. Bøttcher ◽  
Carsten Roepstorff ◽  
Jovana Kapor ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Insulin Degludec ◽  
Pharmacokinetic Properties

scholarly journals Dose of Gentamicin in Patients with Normal Renal Function and Renal Impairment

BMJ ◽  
1968 ◽  
Vol 2 (5596) ◽  
pp. 19-22 ◽  
Author(s):  
J. C. Gingell ◽  
P. M. Waterworth
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Normal Renal Function

scholarly journals 1392. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses to Support Inhaled ME1100 Dose Selection

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S427-S428
Author(s):  
Sujata M Bhavnani ◽  
Jeffrey P Hammel ◽  
Elizabeth A Lakota ◽  
Brian D VanScoy ◽  
Yu Nagira ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Phase 1 ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Total Drug ◽  
Target Attainment ◽  
Research Support ◽  
Dose Selection

Abstract Background ME1100 (arbekacin inhalational solution) is an inhaled aminoglycoside being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). PK-PD target attainment analyses were undertaken to evaluate ME1100 regimens for patients with HABP/VABP arising from Klebsiella pneumoniae (KP), Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA), including those with renal impairment. Methods Data used included a population pharmacokinetic (PPK) model developed using Phase 1 and post-marketing PK data, nonclinical PK-PD targets from one compartment in vitro and/or in vivo infection models, and MIC data. Using parameter estimates from the PPK model (four-compartment model with first-order elimination), total-drug epithelial lining fluid concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr; mL/minute/1.73 m2) and by CLcr group. Twice daily (BID) ME1100 regimens ranging from 300 to 900 mg were assessed in simulated patients with CLcr &gt;80 to ≤120 mL/minute/1.73 m2. Percent probabilities of PK-PD target attainment by MIC were determined based on total-drug ELF AUC:MIC ratio targets associated with 1- and 2-log10 CFU reductions from baseline for KP, PA and SA using Day 1 AUC. Regimens in simulated patients with renal impairment that best matched the BID regimen in the normal CLcr group with high percent probabilities of PK-PD target attainment and a low percent probability of Cmin &gt; 2 mg/L were identified. Results ME1100 600 mg BID in simulated patients with CLcr &gt;80 to ≤120 mL/minute/1.73 m2, with 600 mg once daily, 450 mg BID and 600 mg BID in simulated patients with CLcr of 0 to ≤30, &gt;30 to ≤50 and &gt;50 to ≤80 mL/minute/1.73 m2, respectively, achieved high percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at relevant MIC values for KP, PA and SA, and relatively lower Cmin values. In simulated patients with varying CLcr who received these regimens, high percent probabilities of PK-PD target attainment were achieved for KP, PA and SA at the upper margins of the MIC distributions (Figures 1–3). Conclusion The data provide support for ME1100 dose selection for patients with HABP/VAPB. Disclosures S. M. Bhavnani, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. J. P. Hammel, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. E. A. Lakota, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. B. D. VanScoy, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. Y. Nagira, Meiji Seika Pharma Co. Ltd.: Employee, Salary. C. M. Rubino, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support. N. Sato, Meiji Seika Pharma Co. Ltd.: Employee, Salary. T. Koresawa, Meiji Seika Pharma Co. Ltd.: Employee, Salary. K. Kondo, Meiji Seika Pharma Co. Ltd.: Employee, Salary. P. G. Ambrose, Meiji Seika Pharma Co. Ltd.: Research Contractor, Research support.

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