Effect of renal function and dialysis modality on daprodustat and predominant metabolite exposure

Abstract Background Current therapies for anemia of chronic kidney disease (CKD) include administration of supplemental iron (intravenous and/or oral), blood transfusions and replacement of erythropoietin through the administration of recombinant human erythropoietin (rhEPO) and rhEPO analogs, each with limitations. Daprodustat is an orally active, small molecule hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently in Phase 3 clinical studies. As it is well appreciated that the kidney represents a major route of elimination of many drugs, and daprodustat will be administered to patients with advanced CKD as well as patients with end-stage kidney disease, it is important to characterize the pharmacokinetic profile in these patient populations to safely dose this potential new medicine. Methods The primary objective of these studies, conducted under two separate protocols and with identical assessments and procedures, was to characterize the steady-state pharmacokinetics of daprodustat and the six predominant metabolites (i.e. metabolites present in the highest concentration in circulation) in subjects with normal renal function, anemic non-dialysis (ND)-dependent CKD subjects (CKD Stage 3/4) and anemic subjects on either hemodialysis (HD) or peritoneal dialysis (PD). All enrolled subjects were administered daprodustat 5 mg once daily for 14 days (all except HD subjects) or 15 days (for HD subjects). Blood, urine and peritoneal dialysate were collected at various times for measurement of daprodustat, predominant metabolite, erythropoietin and hepcidin levels. Results The pharmacokinetic properties of steady-state daprodustat peak plasma concentration (Cmax), area under the plasma daprodustat concentration-time curve (AUC) and the time of Cmax (tmax) were comparable between all cohorts in this study. In addition, there was no clinically relevant difference in these properties in the HD subjects between a dialysis and ND day. For CKD Stage 3/4, HD (dialysis day) and PD subjects, the AUC of all daprodustat metabolites assessed was higher, while the Cmax was slightly higher than that in subjects with normal renal function. Over the course of the 14 or 15 days of daprodustat administration, hemoglobin levels were seen to be relatively stable in the subjects with normal renal function, CKD Stage 3/4 and PD subjects, while HD subjects had a decrease of 1.9 gm/dL. All renally impaired subjects appeared to have similar erythropoietin responses to daprodustat, with approximately a 3-fold increase in these levels. In subjects with minimal to no change in hemoglobin levels, hepcidin levels remained relatively stable. Daprodustat, administered 5 mg once daily for 14–15 days, was generally well tolerated with a safety profile consistent with this patient population. Conclusion These studies demonstrated no clinically meaningful change in the pharmacokinetic properties of daprodustat when administered to subjects with various degrees of renal impairment, while for CKD Stage 3/4, HD (dialysis day) and PD subjects, the Cmax and AUC of all daprodustat metabolites assessed were higher than in subjects with normal renal function. Administration of daprodustat in this study appeared to be generally safe and well tolerated.

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Renal function trajectories in hepatitis C infection: differences between renal healthy and chronic kidney disease individuals

Scientific Reports ◽

10.1038/s41598-021-96782-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cheng-Kai Hsu ◽

Tai-Shuan Lai ◽

Yih-Ting Chen ◽

Yi-Ju Tseng ◽

Chin-Chan Lee ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Renal Function ◽

Hepatitis C ◽

Kidney Disease ◽

Normal Renal Function ◽

Elderly Women ◽

Hcv Infection ◽

Diabetic Patients ◽

Subgroup Analyses ◽

Egfr Decline

AbstractAssociations between hepatitis C virus (HCV) and chronic kidney disease (CKD) have been reported; however, differences of renal progression between general and CKD population remain to be elucidated in prospective studies. A total of 1179 participants, who have tested for anti-HCV antibody, were enrolled and prospectively followed for 3 years. The risks associated with HCV infection, in terms of incidence of CKD, annual estimated glomerular filtration rate (eGFR) changes and 50% decline of eGFR at 3-year from baseline, were compared between normal renal function subjects and CKD patients. Overall, 111 of 233 (47.6%) CKD patients and 167 of 946 (17.7%) non-CKD subjects had HCV infection. The crude incidence rates of CKD were 226.9 per 1000 person-years and 14.8 per 1000 person-years in in HCV and non-HCV infected patients, respectively. The adjusted hazard ratio of HCV infection for incident CKD was 7.9 (95% CI 5–12.7). The HCV-infected normal renal function subjects were independently associated with increased risks of eGFR decline in the 1-year, 2-year and 3-year, respectively. The risk associations remained significant in 50% decline of eGFR at 3 years models and in different subgroup analyses. The increases of risks of eGFR decline were also notorious among overall HCV-infected CKD patients. However, the risk associations were less prominent in subgroup analyses (elderly, women and diabetic patients). The findings highlighted the importance of viral diagnosis with not only prognostic but also public health implications for preserving kidney function.

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P0949EFFECT OF DIETARY PHOSPHORUS RESTRICTION ON FIBROBLAST GROWTH FACTOR,KLOTHO AND BODY COMPOSITION IN CHRONIC KIDNEY DISEASE PATIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0949 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Trisha Sachan ◽

Anita Saxena ◽

Amit Gupta

Keyword(s):

Chronic Kidney Disease ◽

Body Composition ◽

Renal Function ◽

Kidney Disease ◽

Urinary Protein ◽

Dietary Phosphorus ◽

Ckd Stage ◽

Significant Difference ◽

The Mean ◽

Fgf 23

Abstract Background and Aims Changes in dietary phosphorus regulate serum FGF-23, parathyroid hormone, 1,25(OH)(2)D and Klotho concentrations . Cardiovascular disease (CVD) is the principal killer of patients with chronic kidney disease and hyperphosphetemia is a potent risk factor it. Of many causative factors for CVD in CKD, dietary interventions involving restriction of dietary phosphorous intake can help reduce onset of CVD at early stages of CKD with other corrective measures. Muscle wasting is a consequence of uremic syndrome which alters body composition. The aim of the study was to study effect of dietary phosphorous restriction on FGF-23, iPTH, Klotho, 1,25(OH)(2)D and body composition in chronic kidney disease patients. Method This is a longitudinal study with 12 months intervention, approved by Ethics Committee of the institute. A total 132 subjects were recruited (66 healthy controls, 66 CKD patient. of 66 patients 33 were in CKD stage 1 and 33 in stage 2. GFR was calculated with the help of MDRD formula. Biochemical parameters of subjects were evaluated at baseline, 6 and 12 months along with the anthropometric measurements (body weight, height, mid upper arm circumference (MUAC), and skin folds). Three days dietary recall was taken to evaluate energy, protein and phosphorous intake. CKD patients whose dietary phosphorous intake was more than 1000 mg/day, were given intense dietary counseling and prescribed dietary modifications by restricting dietary phosphorous between 800-1000 mg/day. Results The mean age of controls and patients was 37.01±9.62 and 38.27±12.06 and eGFR of 136.94±11.77 and 83.69±17.37 respectively. One way ANOVA showed significant difference among controls and the study groups in hemoglobin (p<0.001), s albumin (p<0.001), FGF-23 (p<0.001), klotho (p<0.001), urinary protein (p<0.001) and Nephron Index (p<0.001).The mean energy intake (p = 0.001) and dietary phosphorous intake (p<0.001) of the CKD patients decreased significantly with the decline in the renal function along with the anthropometric measures i.e. BMI (p = 0.041),WHR (p = 0.015) and all four skin folds (p<0.001). On applying Pearson’s correlation, eGFR correlated negatively with urinary protein (-0.739, 0.000), FGF-23 (-0.679, 0.000) and serum phosphorous (-0.697, 0.000) and positively with klotho (0.872, 0.000). FGF-23 correlated negatively with klotho (-0.742, 0.000). Dietary phosphorous was found to be positively correlated with urinary protein (0.496, 0.000), serum phosphorous (0.680, 0.000) and FGF-23 (0.573, 0.000) and negatively with Klotho (-0.602, 0.000). Nephron index revealed a positive correlation with eGFR (0.529, 0.000). Urinary protein correlated negatively with klotho (-0.810, 0.000). A multiple linear regression was run to predict eGFR from anthropometric variables such as BMI, WHR, MUAC, skin folds thickness and handgrip strength. All anthropometric variables predicted decline in eGFR (p<0.05, R2 =0.223). At 6 and 12 months; repeated ANOVAs analysis showed a statistically significant difference in serum creatinine (p=0.000), serum phosphorous (p=0.000), FGF-23(p=0.000) and klotho (p=0.000). Conclusion Elevated levels of FGF-23 and decreased Klotho levels, with the moderate decline in renal function improved with the restricted phosphorous diet at 6 and 12 months emphasizing the importance of phosphorus restriction at an early stage.

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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0234 ◽

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.

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Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00766-12 ◽

2012 ◽

Vol 56 (10) ◽

pp. 5076-5081 ◽

Cited By ~ 39

Author(s):

Keith A. Rodvold ◽

Mark H. Gotfried ◽

J. Gordon Still ◽

Kay Clark ◽

Prabhavathi Fernandes

Keyword(s):

Steady State ◽

High Performance ◽

Healthy Adult ◽

Plasma Concentrations ◽

Epithelial Lining ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Once Daily ◽

Drug Concentrations ◽

The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

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

Canadian Journal of Diabetes ◽

10.1016/j.jcjd.2012.07.327 ◽

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

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Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00008-07 ◽

2007 ◽

Vol 51 (8) ◽

pp. 2982-2984 ◽

Cited By ~ 4

Author(s):

Mary B. Wire ◽

Charles H. Ballow ◽

Julie Borland ◽

Mark J. Shelton ◽

Yu Lou ◽

...

Keyword(s):

Steady State ◽

Healthy Subjects ◽

Open Label ◽

Time Curve ◽

Once Daily ◽

Open Label Study ◽

Label Study ◽

Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

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Risk of Stroke, Bleeding, and Death in Patients with Nonvalvular Atrial Fibrillation and Chronic Kidney Disease

Cardiology ◽

10.1159/000504877 ◽

2020 ◽

Vol 145 (3) ◽

pp. 178-186

Author(s):

Yoav Arnson ◽

Moshe Hoshen ◽

Adi Berliner-Sendrey ◽

Orna Reges ◽

Ran Balicer ◽

...

Keyword(s):

Atrial Fibrillation ◽

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Impaired Renal Function ◽

Bleeding Risk ◽

Intracranial Bleeding ◽

Increased Risk ◽

Ckd Stage ◽

Stroke Death

Introduction: Atrial fibrillation (AF) and chronic kidney disease (CKD) are both associated with increased risk of stroke, and CKD carries a higher bleeding risk. Oral anticoagulation (OAC) treatment is used to reduce the risk of stroke in patients with nonvalvular AF (NVAF); however, the risk versus benefit of OAC for advanced CKD is continuously debated. We aim to assess the management and outcomes of NVAF patients with impaired renal function within a population-based cohort. Methods: We conducted a retrospective observational cohort study using ICD-9 healthcare coding. Patients with incident NVAF between 2004 and 2015 were identified stratified by CKD stage. We compared treatment strategies and estimated risks of stroke, death, or any major bleeding based on CKD stages and OAC treatment. Results: We identified 85,116 patients with incident NVAF. Patients with impaired renal function were older and had more comorbidities. OAC was most common among stage 2 CKD patients (49%) and least in stages 4–5 CKD patients (27.6%). Higher CKD stages were associated with worse outcomes. Stroke rates increased from 1.04 events per 100 person-years (PY) in stage 1 CKD to 3.72 in stages 4–5 CKD. Mortality increased from 3.42 to 32.95 events/100 PY, and bleeding rates increased from 0.89 to 4.91 events/100 PY. OAC was associated with reduced stroke and intracranial bleeding risk regardless of CKD stage, and with a reduced mortality risk in stages 1–3 CKD. Conclusion: Among NVAF patients, advanced renal failure is associated with higher risk of stroke, death, and bleeding. OAC was associated with reduced stroke and intracranial bleeding risk, and with improved survival in stages 1–3 CKD.

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Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis

Scientific Reports ◽

10.1038/s41598-019-53628-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Satoshi Nakano ◽

Shuhei Osaka ◽

Yusuke Sabu ◽

Kei Minowa ◽

Saeko Hirai ◽

...

Keyword(s):

Plasma Concentration ◽

Intrahepatic Cholestasis ◽

Clinical Symptoms ◽

Peak Plasma ◽

Oral Treatment ◽

Peak Plasma Concentration ◽

Open Label ◽

Time Curve ◽

Single Dose Study ◽

Progressive Familial Intrahepatic Cholestasis

AbstractProgressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0–3.0;P = 0.003) and 2.4-fold (95% CI, 1.7–3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.

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Oral Administration System Based on Meloxicam Nanocrystals: Decreased Dose Due to High Bioavailability Attenuates Risk of Gastrointestinal Side Effects

Pharmaceutics ◽

10.3390/pharmaceutics12040313 ◽

2020 ◽

Vol 12 (4) ◽

pp. 313 ◽

Cited By ~ 3

Author(s):

Noriaki Nagai ◽

Fumihiko Ogata ◽

Hiroko Otake ◽

Naohito Kawasaki

Keyword(s):

Therapeutic Effect ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Time Curve ◽

Oral Formulations ◽

Gastrointestinal Lesions ◽

Bead Mill ◽

Gastrointestinal Side Effects ◽

High Bioavailability ◽

High Absorption

Meloxicam (MLX) is widely applied as a therapy for rheumatoid arthritis (RA); however, it takes far too long to reach its peak plasma concentration for a quick onset effect, and gastrointestinal toxicity has been observed in RA patients taking it. To solve these problems, we designed MLX solid nanoparticles (MLX-NPs) by the bead mill method and used them to prepare new oral formulations. The particle size of the MLX-NPs was approximately 20-180 nm, and they remained in the nano-size range for 1 month. The tmax of MLX-NPs was shorter than that of traditional MLX dispersions (MLX-TDs), and the intestinal penetration of MLX-NPs was significantly higher in comparison with MLX-TDs (P < 0.05). Caveolae-dependent endocytosis (CavME), clathrin-dependent endocytosis (CME), and micropinocytosis (MP) were found to be related to the high intestinal penetration of MLX-NPs. The area under the plasma MLX concentration-time curve (AUC) for MLX-NPs was 5-fold higher than that for MLX-TDs (P < 0.05), and the AUC in rats administered 0.05 mg/kg MLX-NPs were similar to rats administered the therapeutic dose of 0.2 mg/kg MLX-TDs. In addition, the anti-inflammatory effect of the MLX-NPs was also significantly higher than that of MLX-TDs at the corresponding dose (P < 0.05), and the therapeutic effect of 0.2 mg/kg MLX-TDs and 0.05 mg/kg MLX-NPs in adjuvant-induced arthritis (AA) rats showed no difference. Furthermore, the gastrointestinal lesions in AA rats treated repetitively with 0.05 mg/kg MLX-NPs were fewer than in rats receiving 0.2 mg/kg MLX-TDs (P < 0.05). In conclusion, we demonstrate that MLX solid nanoparticles allow a quick onset of therapeutic effect and that three endocytosis pathways, CavME, CME, and MP, are related to the high absorption of solid nanoparticles. In addition, we found that MLX solid nanoparticles make it possible to reduce the amount of orally administered drugs, and treatment with low doses of MLX-NPs allows RA therapy without intestinal ulcerogenic responses to MLX. These findings are useful for designing therapies for RA patients.

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Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01337-16 ◽

2016 ◽

Vol 61 (1) ◽

Cited By ~ 26

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.

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