scholarly journals A reappraisal of polymyxin B dosing based on population pharmacokinetic model in patient with renal insufficiency

2020 ◽  
Author(s):  
Xuben Yu ◽  
Chunhong Zhang ◽  
Jingye Pan ◽  
Ying Dai ◽  
Ziye Zhou ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Renal Function ◽  
Steady State ◽  
Renal Insufficiency ◽  
Creatinine Clearance ◽  
Polymyxin B ◽  
Adult Patients ◽  
Population Pharmacokinetic ◽  
Population Pk ◽  
Dosing Strategy

AbstractBackgroundCurrent FDA-approved label recommends polymyxin B dosing should be adjusted according to renal function, despite several studies proved poor correlation between polymyxin B PK and creatinine clearance. The study aims to assess the impact of renal function on polymyxin B metabolism and identify an alternate dosing strategy by population analysis.MethodsBlood samples from adult patients were collected at steady state during routine therapeutic drug monitoring. Nonlinear mixed effects modeling was employed to build a population PK model of polymyxin B. Monte Carlo simulations were performed to design polymyxin B dosing regimens across various renal function.ResultsPharmacokinetic analyses included 112 polymyxin B concentrations at steady state from 32 adult patients aged 37-93 received intravenous polymyxin B (100-200 mg/d). The creatinine clearance in patients was 5.91-244 mL/min. In the final population PK model, CrCL was the significant covariate on CL (typical value, 1.59 L/hr; between-subject variability, 13%). Mean (SD) individual empirical Bayesian estimates of CL was 1.75 (0.43) L/hr. A new dosing strategy combining the PK/PD targets and Monte Carlo simulation indicated that polymyxin B dose reductions improved the probability of achieving optimal exposures in simulated patients with renal insufficiency. For severe infections caused by organisms with MIC of ≥ 2 mg/L, though a high daily dose (e.g. 200mg/day) would possible for bacterial eradication, the risk of nephrotoxicity is significantly increased.ConclusionA population PK model was established to develop individualized polymyxin B dosage regimens that the dose of polymyxin B should be adjusted according to CrCL.

scholarly journals Comparing population pharmacokinetics and acute kidney injury of polymyxin B in Chinese patients with and without renal insufficiency

2020 ◽  
Author(s):  
Peile Wang ◽  
Qilen Zhang ◽  
Zhenfeng Zhu ◽  
Hui Pei ◽  
Min Feng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Renal Insufficiency ◽  
Creatinine Clearance ◽  
Normal Renal Function ◽  
Kidney Injury ◽  
Polymyxin B ◽  
Bactericidal Effect ◽  
Chinese Patients ◽  
Population Pharmacokinetic

Despite excellent bactericidal effect, dosing adjustment of polymyxin B for patients with renal insufficiency and polymyxin B-related nephrotoxicity is still a major concern to clinicians. The aim of this study was to compare the population pharmacokinetic (PK) properties of polymyxin B in Chinese patients with different renal function and to investigate the relationship between PK parameters and polymyxin B related-acute kidney injury (AKI). A total of 37 patients with normal renal function (creatinine clearance ≥ 80 mL/min) and 33 with renal insufficiency (creatinine clearance < 80 mL/min) were included. In the two-compartment population PK models, the Cl (2.19 L/h vs 1.58 L/h; P < 0.001) and Q (13.83 L/h vs 10.28 L/h; P < 0.001) values were significantly different between the two groups. The simulated AUCss,24h values for patients with normal renal function were higher than those for patients with renal insufficiency. However, the renal dosing adjustment of polymyxin B seemed not to be necessary. Besides, during the treatment, AKI occurred in 23 (32.86%) patients. The polymyxin B AUCss,24h in patients with AKI was significantly higher than that in patients without AKI (108.66 ± 70.10 mg⋅h/L vs 66.18 ± 34.79 mg⋅h/L; P = 0.001). Both the ROC curve and Logistic regression analysis showed AUCss,24h > 100 mg⋅h/L was a good predictor for the probability of nephrotoxicity.

scholarly journals Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Visanu Thamlikitkul ◽  
Yanina Dubrovskaya ◽  
Pooja Manchandani ◽  
Thundon Ngamprasertchai ◽  
Adhiratha Boonyasiri ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Steady State ◽  
Renal Insufficiency ◽  
Actual Body ◽  
Normal Renal Function ◽  
Polymyxin B ◽  
Poor Correlation ◽  
Actual Body Weight ◽  
Significant Difference

ABSTRACT Polymyxin B remains the last-line treatment option for multidrug-resistant Gram-negative bacterial infections. Current U.S. Food and Drug Administration-approved prescribing information recommends that polymyxin B dosing should be adjusted according to the patient's renal function, despite studies that have shown poor correlation between creatinine and polymyxin B clearance. The objective of the present study was to determine whether steady-state polymyxin B exposures in patients with normal renal function were different from those in patients with renal insufficiency. Nineteen adult patients who received intravenous polymyxin B (1.5 to 2.5 mg/kg [actual body weight] daily) were included. To measure polymyxin B concentrations, serial blood samples were obtained from each patient after receiving polymyxin B for at least 48 h. The primary outcome was polymyxin B exposure at steady state, as reflected by the area under the concentration-time curve (AUC) over 24 h. Five patients had normal renal function (estimated creatinine clearance [CLCR] ≥ 80 ml/min) at baseline, whereas 14 had renal insufficiency (CLCR < 80 ml/min). The mean AUC of polymyxin B ± the standard deviation in the normal renal function cohort was 63.5 ± 16.6 mg·h/liter compared to 56.0 ± 17.5 mg·h/liter in the renal insufficiency cohort (P = 0.42). Adjusting the AUC for the daily dose (in mg/kg of actual body weight) did not result in a significant difference (28.6 ± 7.0 mg·h/liter versus 29.7 ± 11.2 mg·h/liter, P = 0.80). Polymyxin B exposures in patients with normal and impaired renal function after receiving standard dosing of polymyxin B were comparable. Polymyxin B dosing adjustment in patients with renal insufficiency should be reexamined.

Dosing of troxacitabine (Troxatyl [T], SGX-145) based on renal function

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2025-2025
Author(s):  
M. J. Kelner ◽  
F. J. Giles ◽  
E. J. Feldman ◽  
G. J. Roboz ◽  
D. J. Deangelo ◽  
...  
Keyword(s):  
Renal Function ◽  
Steady State ◽  
Creatinine Clearance ◽  
Plasma Concentrations ◽  
Myelogenous Leukemia ◽  
Blood Levels ◽  
Upper Limit ◽  
Major Route ◽  
Cancer Agent ◽  
Dosing Strategy

2025 Background: Troxacitabine (Troxatyl [T], SGX-145) is a novel L-configuration nucleoside analog anti-cancer agent with unique mechanistic/cytotoxic properties. T is clinically active against acute myelogenous leukemia (AML), chronic myeloid leukemia, myelodysplastic syndromes (MDS), renal cell carcinoma, and pancreatic cancer. A multi-center Phase 2/3 clinical trial is currently underway to evaluate the safety and efficacy of continuous IV infusion T treatment in second salvage AML. The major route of elimination of troxacitabine is renal excretion as unchanged drug (∼70%) and there is minimal protein binding. These results suggest that renal function may have a significant effect on steady-state troxacitabine plasma concentrations (Css). Methods: Pharmacokinetic and toxicity data from four AML clinical trials (>200 patients) are being analyzed to (1) Identify a minimum Css for therapeutic efficacy; (2) Define an upper limit of Css for adverse risk; and (3) Develop a mechanism to prospectively modify the troxacitabine dose based on renal function, which would avoid excessive toxicity while maintaining therapeutic blood levels. Results: Initial results from 41 patients indicate that to induce remission in AML patients, troxacitabine steady-state plasma concentrations (Css) must be ≥ 80 ng/mL. However, higher Css values correlate with increased toxicity and, thereby, increase the risks of the treatment for an individual patient, although an upper limit for adverse risk has not yet been defined. For patients with normal renal function (creatinine clearance ≥ 50 but ≤ 125 mL/min), a Calvert style formula, based on a patient’s estimated creatinine clearance, has been developed to define the dose required to achieve a therapeutic Css ≥ 80 ng/mL. Both linear and non-linear nomogram models are also being developed to adjust troxacitabine dosage for patients with moderate renal impairment (30 mL/min < creatinine clearance < 50 mL/min) or for patients with high GFR (creatinine clearance > 125 mL/min). Conclusion: A firm relationship exists between renal function, troxacitabine clearance, and Css values. This result indicates that a dosing strategy based on renal function may be warranted to obtain optimal troxacitabine Css values. [Table: see text]

Effects of sulindac on renal function and prostaglandin synthesis in patients with moderate chronic renal insufficiency

1986 ◽  
Vol 70 (5) ◽  
pp. 501-505 ◽  
Author(s):  
C. D. Mistry ◽  
C. J. Lote ◽  
R. Gokal ◽  
W. J. C. Currie ◽  
M. Vandenburg ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Insufficiency ◽  
Creatinine Clearance ◽  
Chronic Renal Disease ◽  
Renal Plasma Flow ◽  
Plasma Renin ◽  
Breakdown Product ◽  
Predisposing Factor ◽  
A Minor ◽  
Therapeutic Doses

1. The renal effects of therapeutic doses of sulindac were studied in nine patients with stable renal insufficiency, mean creatinine clearance 37.0 ± 2.2 ml min−1 1.73 m−2 (range 24.7–54.6 ml min−1 1.73 m−2). 2. Nine days' treatment with sulindac produced a small, but significant, reduction in the mean creatinine clearance (37.0 ± 2.2 to 34.7 ± 2.2 ml min−1 1.73 m−2; P < 0.02) and 99mTc diethylenetriaminepenta-acetate (DTPA) clearance (35.5 ± 3.4 to 31.4 ± 3.6 ml min−1 1.73 m−2; P < 0.02) without altering body weight, effective renal plasma flow [131I]hippuran clearance), plasma renin activity (PRA), 24 h urinary volume or electrolyte excretion. 3. After discontinuation of sulindac, creatinine clearance returned to pretreatment values. 4. In five female patients, pretreatment urinary excretion of the 6-ketoprostaglandin F1α (6-keto-PGF1α), a stable breakdown product of prostacyclin (PGI2), was significantly reduced (P < 0.02) when compared with four healthy controls, whereas prostaglandin E2 (PGE2) was unchanged. Administration of sulindac did not significantly alter the excretion rate of PGE2 or 6-ketoPGF1α in this group of patients. 5. In chronic renal disease with moderate renal impairment, reduced renal prostacyclin synthesis may be an important predisposing factor to the renal toxicity associated with the use of nonsteroidal anti-inflammatory drugs (NSAID). Short term use of sulindac in therapeutic doses does not appear to influence the excretion of prostaglandins and produces only a minor reversible change in renal function; used cautiously it may have advantages over other NSAID in these patients.-

scholarly journals Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infection

2020 ◽  
Author(s):  
Nao Kawaguchi ◽  
Takayuki Katsube ◽  
Roger Echols ◽  
Toshihiro Wajima
Keyword(s):  
Urinary Tract Infection ◽  
Renal Function ◽  
Urinary Tract ◽  
Tract Infection ◽  
Bloodstream Infection ◽  
Plasma Concentrations ◽  
Complicated Urinary Tract Infection ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Population Pk

Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gramnegative bacteria including carbapenemresistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 mL/min, and it is adjusted for patients with < 60 mL/min or ≥ 120 mL/min CrCL. A population pharmacokinetic (PK) model was constructed using 3427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors including infection sites and mechanical ventilation were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT>MIC was > 90% against MICs ≤ 4 μg/mL for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients including the patients with augmented renal function, ventilation, and/or severe illness.

Low-flow Sevoflurane Compared with Low-flow Isoflurane Anesthesia in Patients with Stable Renal Insufficiency

2002 ◽  
Vol 97 (3) ◽  
pp. 578-584 ◽  
Author(s):  
Peter F. Conzen ◽  
Evan D. Kharasch ◽  
Stephan F. A. Czerner ◽  
Alan A. Artru ◽  
Florian M. Reichle ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Insufficiency ◽  
Serum Creatinine ◽  
Creatinine Clearance ◽  
Blood Urea Nitrogen ◽  
Gas Flow ◽  
Minimum Alveolar Concentration ◽  
Low Flow ◽  
Sevoflurane Anesthesia ◽  
Urine Protein

Background Sevoflurane is degraded to compound A (CpA) by carbon dioxide absorbents containing strong base. CpA is nephrotoxic in rats. Patient exposure to CpA is increased with low fresh gas flow rates, use of Baralyme, and high sevoflurane concentrations. CpA formation during low-flow and closed circuit sevoflurane anesthesia had no significant renal effects in surgical patients with normal renal function. Preexisting renal insufficiency is a risk factor for postoperative renal dysfunction. Although preexisting renal insufficiency is not affected by high-flow sevoflurane, the effect of low-flow sevoflurane in patients with renal insufficiency is unknown. Methods After obtaining institutional review board approval, 116 patients with a stable preoperative serum creatinine concentration 1.5 mg/dl or greater were assessable. Patients were randomized to receive either sevoflurane (n = 59, 0.8-2.5 vol%) or isoflurane (n = 57, 0.5-1.4 vol%) at a fresh gas flow rate of 1 l/min or less. Use of opioids was restricted to a minimum, and Baralyme was used to increase CpA exposure. Inspiratory and expiratory CpA concentrations were measured during anesthesia. Renal function (serum creatinine and blood urea nitrogen, urine protein and glucose, creatinine clearance) was measured preoperatively and 24 and 72 h after induction. Results Demographic patient data did not differ between groups. Patients received 3.1 +/- 2.4 minimum alveolar concentration-hours sevoflurane or 3.8 +/- 2.6 minimum alveolar concentration-hours isoflurane (mean +/- SD). Durations of low flow were 201.3 +/- 98.0 and 213.6 +/- 83.4 min, respectively. Maximum inspiratory CpA with sevoflurane was 18.9 +/- 7.6 ppm (mean +/- SD), resulting in an average total CpA exposure of 44.0 +/- 30.6 ppm/h. There were no statistically significant changes from baseline to 24- and 72-h values for serum creatinine or blood urea nitrogen, creatinine clearance, urine protein, and glucose, nor were there significant differences between both anesthetics. Conclusion There were no statistically significant differences in measured parameters of renal function after low-flow sevoflurane anesthesia compared with isoflurane. These results suggest that low-flow sevoflurane anesthesia is as safe as low-flow isoflurane and does not alter kidney function in patients with preexisting renal disease.

Use of Therapeutic Dose Low Molecular Weight Heparin in Patients with Renal Insufficiency: Analysis of Anti-Xa Levels and Creatinine Clearance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 884-884
Author(s):  
Wendy Lim ◽  
Manasa Sridhara ◽  
Luqi Wang ◽  
Krystyna Kinnon ◽  
James Douketis ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Renal Function ◽  
Renal Insufficiency ◽  
Creatinine Clearance ◽  
Therapeutic Dose ◽  
Low Molecular Weight Heparin ◽  
Dose Adjustment ◽  
Low Molecular Weight ◽  
Recurrent Vte ◽  
Dependent Patient

Abstract Low molecular weight heparin (LMWH) is predominantly eliminated by the kidneys. In patients with severe renal impairment, use of therapeutic dose LMWH may be associated with accumulation and a resultant bleeding risk. Tinzaparin may be less dependent on renal clearance due to its higher molecular mass and greater negative charge compared to other LMWHs. The objective of this prospective cohort study was to serially measure the anti-Xa anticoagulant effect of therapeutic dose tinzaparin over 5–7 days, used for the initial treatment of venous thromboembolism (VTE) in patients with varying degrees of renal insufficiency. We present the anti-Xa results from the first 78 patients enrolled in the study, correlated with renal function. In this study, consecutive in- and outpatients with objectively confirmed VTE requiring anticoagulation were enrolled and stratified into 4 groups based on the calculated Cockcroft-Gault creatinine clearance (CrCl): &gt; 60 mL/min, 30–60 mL/min, ≤ 30 mL/min and hemodialysis-dependent. Tinzaparin 175 IU/kg was administered subcutaneously once daily for 5–7 days or until the INR ≥ 2.0 with warfarin therapy. Trough anti-Xa levels were measured prior to the 3rd, 5th and/or 7th tinzaparin doses. Patients with anti-Xa level &gt; 0.5 IU/mL received tinzaparin dose adjustment using a standardized nomogram. Bleeding and recurrent VTE events were recorded. The relationship between anti-Xa levels and CrCl is shown in Figure 1. Based on our predefined anti-Xa threshold of 0.5 IU/mL, 5 of 78 patients (6.4%) required dose adjustment; 1 hemodialysis dependent patient, 2 patients with CrCl &lt; 30 mL/min, 1 patient each with CrCl 30–60 and &gt; 60 mL/min, respectively. None of these patients developed bleeding or recurrent VTE. Among all 78 patients, 1 hemodialysis-dependent patient developed a hematoma following a traumatic line insertion, and no patients developed recurrent VTE. In conclusion, in a cohort of 78 patients with differing degrees of renal function including patients requiring hemodialysis, use of therapeutic-dose tinzaparin for the initial treatment of VTE resulted in accumulation (defined by trough anti-Xa &gt; 0.5 IU/mL) in 6% of patients. There appears to be a weak inverse relationship between renal function and trough anti-Xa levels, but does not result in clinically significant accumulation when tinzaparin is used for up to 7 days. Further evaluation of tinzaparin in patients with severe renal insufficiency is required. Figure Figure

Population pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations for exposure‐;tumor response relationships: Motesanib in a phase II thyroid cancer (TC) trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14528-e14528
Author(s):  
J. Lu ◽  
L. Claret ◽  
L. Sutjandra ◽  
M. Kuchimanchi ◽  
D. Stepan ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Thyroid Cancer ◽  
Monte Carlo Simulations ◽  
Tumor Size ◽  
Tumor Response ◽  
Area Under The Curve ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Population Pk ◽  
The Difference

e14528 Background: Motesanib is a highly selective, oral inhibitor of VEGF receptors 1, 2, and 3; PDGFR; and Kit that is being investigated for its antitumor activity. In a phase 2 monotherapy study, a response rate of 14% (per RECIST) was observed in patients (pts) with differentiated thyroid cancer (DTC; NEJM 359:31–42, 2008) compared with 1% in pts with medullary TC (MTC; Endocr Soc Ann Meeting 2007, abstract OR39–3). We evaluated the relationship between motesanib PK and tumor response, investigated whether differences in PK between MTC and DTC pts contributed to the observed difference in response, and simulated tumor response with different dose regimens in pts with TC. Methods: Data from the phase 2 TC trial were used for PK/PD modeling. The study enrolled 93 DTC and 91 MTC pts who received motesanib 125 mg once daily (QD). Motesanib concentrations were fitted to a 2- compartment population PK model. Estimates of pts’ PK parameters were used to calculate concentration and steady-state area under the curve values for motesanib, which were used as the exposure measures in population PK/PD modeling (ie, longitudinal exposure-tumor response modeling of drug effect on tumor growth dynamics). Monte Carlo simulations were used to evaluate the potential effect of doses other than 125 mg QD (75 mg and 100 mg QD) on tumor response in TC pts. Results: Clearance in MTC pts was 40% faster than in DTC pts (74 vs 44 L/h). The fit was significantly improved (P<0.001) when exposure instead of dose was used in the model. The exposure-tumor response model that incorporated the difference in exposure described change in tumor size well in both MTC and DTC populations. Clinical trial simulations using the preliminary model based on week 24 data predicted that DTC pts would achieve 19.7%, 15.7%, and 11.3% reductions in tumor size at week 24 following doses of 125 mg QD, 100 mg QD, and 75 mg QD, respectively. The actual change in median tumor size at week 24 following 125-mg QD dosing in DTC pts included in the PK/PD analysis was 17.9%. Conclusions: The use of 125 mg QD motesanib in DTC pts was supported by PK/PD modeling and Monte Carlo simulations. Differences in PK may explain the difference in tumor response observed in MTC and DTC patient populations. [Table: see text]

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