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.

Cytoprotective Palifermin Allowed Melphalan Dose Escalation to 280mg/2 for Multiple Myeloma Patients with Normal Renal Function Receiving Autologous Stem Cell Transplantation (ASCT) - Final Results of a Phase 1 Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2401-2401
Author(s):  
Muneer H. Abidi ◽  
Nishant Tageja ◽  
Lawrence G. Lum ◽  
Judith Abrams ◽  
Zaid Al-Kadhimi ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Actual Body ◽  
Median Duration ◽  
Dose Escalation ◽  
Normal Renal Function ◽  
Dose Effect ◽  
Actual Body Weight ◽  
Cd34 Cells ◽  
Grade 3

Abstract Abstract 2401 Background: Melphalan (M) 200 mg/m2 is a standard conditioning regimen for myeloma patients (pts) with normal renal function (NRF) undergoing ASCT. M exhibits a steep, log-linear dose effect with a potential for dose escalation (DE) to overcome M resistance. However, severe oral mucositis (OM) at M ≥ 200 mg/m2 precludes DE due to significant morbidity. Palifermin (P) as a cytoprotective agent has demonstrated efficacy in reducing intensity and duration of OM in pts receiving intensive chemo-radiotherapy. We designed a phase I study to determine the MTD of M in pts with NRF when used with P. Study Design: We enrolled 19 pts from 07/2007 to 09/2009. Data is reported on 18 evaluable pts as 1 pt was removed due to the inability to receive all 6 doses of P. DE was done (3 pt cohorts) in 20 mg/m2 increments, depending on the dose limiting toxicities (DLT). Level (L) 1 began at M 200 mg/m2 with P 60 mcg/kg/d, given as I.V. bolus on Day -5, -4, -3 and Day +1, +2 and +3 (PBSCs infused on Day 0). M was given on D-2 up to and including 280 mg/m2 (n = 6). If no symptomatic grade ≥ 3 DLTs were noted by day +30, an additional cohort of 3 pts were entered at the next dose level. Dose escalations were to stop if ≥ 2 DLTs occurred at M dose; with that dose declared as the MTD. Grade 3/ 4 diarrhea and ≥ grade 3 cardiac toxicity was considered DLT; grade 3/4 hematological toxicity was acceptable. The grade of OM was assessed daily according to the WHO oral-toxicity scale (grade 0–4). Key Eligibility Criteria: age 18–74 years, stage 2/3, ECOG performance status < 2, CrCl > 60, total bilirubin ≤ 1.5 × IULN, ALT/AST ≤ 3 × IULN, eligible for ASCT per institutional criteria and at least 2.0 × 106 CD34+ cells/kg cryopreserved for ASCT. Calculation of M dose: M dose was calculated using the actual body weight except when the actual body weight was > 40% above the ideal body weight; in that case, adjusted body weight was used. Results: Med age 48.5 y (33-65). Med # of prior Rx: 2 (1-5). Median CD34 cells dose 4.77 × 10(6) [2.18-11.36]; median day of neutrophil recovery +10 (10-13) and median day of platelet engraftment 19.5 (0 to 29). The overall incidence of OM ≥ grade 3 was 44% (8/18) with a median duration of OM 10 days (4 -20 d). Only 1 pt in L 1 group developed grade 4 OM. Two out of 6 pts given M 280 mg/m2 did not develop any OM. Atrial fibrillation occurred in 1/6 pts treated with M 280 mg/m2. The most common adverse events included rash (18 events, no grade 3), elevation of amylase (10, 4 grade 3-asymptomatic) and lipase (5, 2 grade 3 -asymptomatic) and edema (11, no grade 3). 11 pts (61%) required IV opioid analgesics; none needed TPN/NG feeding. All 18 pts were evaluable for response at D+100 and there were no treatment-related deaths. Median duration of follow up is 17.5 months (5.6-36.5). At D+100, all 18 patients were progression free. At D+365, 13 pts are free of progression, 2 have PD, and 2 have expired while 1 pt has not reached D+ 365 yet. First expired pt on L5 relapsed at 5 months post ASCT and no further details are available on two other expired patient. Conclusions: Palifermin permits dose escalation of M up to 280 mg/m2 with acceptable toxicity. A phase 2 trial is planned to better delineate the anti-myeloma efficacy of this regimen. Disclosures: Abidi: Millennium: Speakers Bureau. Off Label Use: Bortezomib is currently not approved for maintenance therapy after Autologous stem cells transplant. Lum: Transtarget Inc: Equity Ownership.

Unfractionated heparin infusion for treatment of venous thromboembolism based on actual body weight without dose capping

2019 ◽  
Vol 25 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Julia A Shlensky ◽  
Kristina M Thurber ◽  
John G O’Meara ◽  
Narith N Ou ◽  
Jennifer L Osborn ◽  
...  
Keyword(s):  
Body Weight ◽  
Venous Thromboembolism ◽  
Actual Body ◽  
Unfractionated Heparin ◽  
Obese Group ◽  
Morbidly Obese ◽  
Actual Body Weight ◽  
Bleeding Events ◽  
Heparin Infusion ◽  
Significant Difference

Controversy exists regarding the use of dose capping of weight-based unfractionated heparin (UFH) infusions in obese and morbidly obese patients. The primary objective of this study was to compare time to first therapeutic activated partial thromboplastin time (aPTT) in hospitalized patients receiving UFH for acute venous thromboembolism (VTE) among three body mass index (BMI) cohorts: non-obese (< 30 kg/m2), obese (30–39.9 kg/m2), and morbidly obese (⩾ 40 kg/m2). In this single-center, retrospective cohort study, patients were included if they ⩾ 18 years of age, had a documented VTE, and were on an infusion of UFH for at least 24 hours. Weight-based UFH doses were calculated using actual body weight. A total of 423 patients met the inclusion criteria, with 230 (54.4%), 146 (34.5%), and 47 (11.1%) patients in the non-obese, obese, and morbidly obese cohorts, respectively. Median times to therapeutic aPTT were 16.4, 16.6, and 17.1 hours in each cohort. Within 24 hours, the cumulative incidence rates for therapeutic aPTT were 70.7% for the non-obese group, 69.9% for the obese group, and 61.7% for the morbidly obese group (obese vs non-obese: HR = 1.02, 95% CI: 0.82–1.26, p = 0.88; morbidly obese vs non-obese: HR = 0.87, 95% CI: 0.62–1.21, p = 0.41). There was no significant difference in major bleeding events between BMI groups (obese vs non-obese, p = 0.91; morbidly obese vs non-obese, p = 0.98). Based on our study, heparin dosing based on actual body weight without a dose cap is safe and effective.

Obesity Does Not Alter the Pharmacokinetics of Drotrecogin Alfa (Activated) in Severe Sepsis

2005 ◽  
Vol 39 (2) ◽  
pp. 262-267 ◽  
Author(s):  
Howard Levy ◽  
David Small ◽  
Darell E Heiselman ◽  
Richard Riker ◽  
Jay Steingrub ◽  
...  
Keyword(s):  
Body Weight ◽  
Severe Sepsis ◽  
Actual Body ◽  
Drotrecogin Alfa ◽  
Phase Iii ◽  
Actual Body Weight ◽  
Open Label ◽  
Risk Of Death ◽  
Drotrecogin Alfa Activated ◽  
Significant Difference

BACKGROUND: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial. OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing ⩽135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients. METHODS: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups. RESULTS: Patient weight range was 59–227 kg. There were 32 patients ⩽135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range [IQR] 0.37–0.54) for patients ⩽135 kg and 0.42 L/h/kg (IQR 0.33–0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4–62.0) and 56.5 ng/mL (IQR 44.9–71.1; p = 0.570). In patients ⩽135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9–20.0) compared with 16.0 minutes (IQR 12.9–19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2–18.8). CONCLUSIONS: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing ⩽135 kg and >135 kg. DrotAA should be dosed by actual body weight.

Toxicity and effectiveness of carboplatin in obese or overweight patients

2018 ◽  
Vol 25 (6) ◽  
pp. 1328-1335 ◽  
Author(s):  
Cristina Grueso Cuesta ◽  
Jaime E Poquet Jornet ◽  
Juan M Gasent Blesa ◽  
Antonio Valdivia Perez ◽  
Francisco J Carrera Hueso ◽  
...  
Keyword(s):  
Overall Survival ◽  
Body Weight ◽  
Actual Body ◽  
Response Rate ◽  
Progression Free Survival ◽  
Normal Weight ◽  
Actual Body Weight ◽  
Free Survival ◽  
Significant Difference ◽  
Dose Reductions

Objective To evaluate the efficiency and toxicity of carboplatin using actual body weight in obese/overweight patients using the Calvert formula with Cockcroft–Gault for CrCl estimation. Methods We evaluated the association of BMI in regards to efficiency and toxicity in a retrospective cohort study of patients who started treatment with carboplatin between 2012 and 2013. Cohorts included obese/overweight patients and normal-weight patients. Efficiency was measured by overall survival, progression-free survival and response rate. Toxicity was measured by the proportion of dose reductions and delays of chemotherapy cycles. We utilized a bivariate and multivariate analysis. Results Eighty-six patients were included in the study (50% obese/overweight). There was not a statistically significant difference in effectiveness and toxicity between the two groups in BMI. In the multivariate analysis, BMI not was associated with overall survival (hazard ratio: 0.95, 95% CI: 0.54–1.66, p = 0.849), progression-free survival (hazard ratio: 0.91; 95% CI: 0.54–1.54; p = 0.732), cycle delays (odds ratio (OR): 1.47, 95% CI: 0.80–2.69, p = 0.218) or carboplatin dose reductions (OR: 0.87, 95% CI: 0.35–2.15, p = 0.760). Response rate was 53.5% in both groups. Conclusions In our study, obese and overweight cancer patients did not show a statistically significant difference in terms of effectiveness and toxicity compared to normal-weight cancer patients who were treated with carboplatin using their actual body weight with the Calvert formula and Cockcroft–Gault for CrCl estimation. Therefore, it was appropriate to use the actual body weight for our patients.

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 Daptomycin Dosing Based on Ideal Body Weight versus Actual Body Weight: Comparison of Clinical Outcomes

2013 ◽  
Vol 58 (1) ◽  
pp. 88-93 ◽  
Author(s):  
Jennifer K. Ng ◽  
Lucas T Schulz ◽  
Warren E. Rose ◽  
Barry C. Fox ◽  
David R. Andes ◽  
...  
Keyword(s):  
Body Weight ◽  
Actual Body ◽  
Clinical Success ◽  
Infection Type ◽  
Ideal Body Weight ◽  
Actual Body Weight ◽  
Success Rates ◽  
Content Type ◽  
Significant Difference ◽  
Ideal Body

ABSTRACTDaptomycin use at our institution changed to ideal body weight dosing based on a published analysis of pharmacokinetic-pharmacodynamic efficacy target attainment, bacterial ecology, and a desire to reduce drug toxicity. The current study compared outcomes between actual body weight and ideal body weight dosing of daptomycin before and after this intervention. In the evaluable group, 69 patients received doses based on actual body weight and 48 patients received doses based on ideal body weight. Patients were treated for documentedEnterococcusspecies,Staphylococcus aureus, or coagulase-negativeStaphylococcusinfections, including bloodstream, intraabdominal, skin and soft tissue, urinary, and bone. There was no statistically significant difference in clinical success between the groups (88.9% for actual body weight compared to 89.1% for ideal body weight,P= 0.97). After we adjusted for gender, age, body mass index, concomitant 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors, infection type, and organism type, clinical success rates remained similar between groups (adjusted odds ratio of 0.68 in favor of actual body weight, 95% confidence interval [CI] of 0.13 to 3.55). Microbiological outcomes, length of stay, mortality, and adverse effects were also similar between groups. Further studies are warranted to confirm that ideal body weight dosing provides similar outcomes to actual body weight dosing for all patients and types of infections and organisms.

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.

Adjusted versus actual body weight dosing of 4-factor prothrombin complex concentrate in obese patients with warfarin-associated major bleeding

2018 ◽  
Vol 47 (3) ◽  
pp. 369-374 ◽  
Author(s):  
Keaton S. Smetana ◽  
Rachel Ziemba ◽  
Casey C. May ◽  
Michael J. Erdman ◽  
Edward T. Van Matre ◽  
...  
Keyword(s):  
Body Weight ◽  
Actual Body ◽  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Obese Patients ◽  
Actual Body Weight

scholarly journals Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

2018 ◽  
Vol 63 (2) ◽  
pp. e01957-18 ◽  
Author(s):  
Anne B. Leuppi-Taegtmeyer ◽  
Laurent Decosterd ◽  
Michael Osthoff ◽  
Nicolas J. Mueller ◽  
Thierry Buclin ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Normal Renal Function ◽  
Maintenance Dose ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Optimal Dosing ◽  
Colistimethate Sodium

ABSTRACT Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60 kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5 mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8 h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.)

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