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2.  Complement Activation in Patients with Focal Segmental Glomerulosclerosis 
PLoS ONE  2015;10(9):e0136558.
Background
Recent pre-clinical studies have shown that complement activation contributes to glomerular and tubular injury in experimental FSGS. Although complement proteins are detected in the glomeruli of some patients with FSGS, it is not known whether this is due to complement activation or whether the proteins are simply trapped in sclerotic glomeruli. We measured complement activation fragments in the plasma and urine of patients with primary FSGS to determine whether complement activation is part of the disease process.
Study Design
Plasma and urine samples from patients with biopsy-proven FSGS who participated in the FSGS Clinical Trial were analyzed.
Setting and Participants
We identified 19 patients for whom samples were available from weeks 0, 26, 52 and 78. The results for these FSGS patients were compared to results in samples from 10 healthy controls, 10 patients with chronic kidney disease (CKD), 20 patients with vasculitis, and 23 patients with lupus nephritis.
Outcomes
Longitudinal control of proteinuria and estimated glomerular filtration rate (eGFR).
Measurements
Levels of the complement fragments Ba, Bb, C4a, and sC5b-9 in plasma and urine.
Results
Plasma and urine Ba, C4a, sC5b-9 were significantly higher in FSGS patients at the time of diagnosis than in the control groups. Plasma Ba levels inversely correlated with the eGFR at the time of diagnosis and at the end of the study. Plasma and urine Ba levels at the end of the study positively correlated with the level of proteinuria, the primary outcome of the study.
Limitations
Limited number of patients with samples from all time-points.
Conclusions
The complement system is activated in patients with primary FSGS, and elevated levels of plasma Ba correlate with more severe disease. Measurement of complement fragments may identify a subset of patients in whom the complement system is activated. Further investigations are needed to confirm our findings and to determine the prognostic significance of complement activation in patients with FSGS.
doi:10.1371/journal.pone.0136558
PMCID: PMC4559462  PMID: 26335102
3.  A pilot study of leukocyte expression patterns for drug metabolizing enzyme and transporter transcripts in autoimmune glomerulonephritis 
Objective
Leukocyte mRNA expression patterns of drug metabolizing enzyme genes and transporter genes that are relevant for the disposition of cyclophosphamide and mycophenolate were studied. The relationships between expression and patient-level data and pharmacokinetics were evaluated.
Methods
The study included patients with glomerulonephritis secondary to lupus nephritis (SLE, n = 36), small vessel vasculitis (SVV, n = 35), healthy controls (HC, n = 10), and disease controls (VC, n = 5; LC, n = 5). Transcript assays targeted metabolizing enzymes (UGT1A7,UGT1A9, UGT2B7, CYP3A4, CYP2C9, CYP2B6) and transporters (ABCB1, ABCC2,ABCG2, SLCO1A2). Genotyping for specific variants was conducted. Group transcript fold-changes were evaluated. Patient level data was evaluated for transcript fold-change and disease, treatment, gender, race, and genotype.
Results
Significant differences were noted in expression of UGT1A7, ABCB1, and ABCC2; for UGT1A7, SVV (0.17 ± 0.42; p < 0.05) and SLE (0.03 ± 0.1; p < 0.05) groups had lower expression than HC (0.79 ± 2.02). For ABCB1, SLE had a lower expression (0.33 ± 0.21; p < 0.05) than HCs (1 ± 0.82). For ABCG2, SVV group had a lower expression (0.17 ± 0.14; p < 0.05) than HCs (1 ± 1.82). Differences in expression of ABCC2 approached statistical significance with VC patients (2.02 ± 1.13) exhibiting higher expression than SVV patients (1.06 ± 1.11; p = 0.05). The relationships between transcript expression and patient-level data demonstrated; ABCC2 expression was different by race (1.26 ± 1.82 Caucasian versus 1.37 ± 0.86 non-Caucasian; p = 0.049) and CYP2B6 expression was different by treatment (2.07 ± 2.94 cyclophosphamide versus 0.45 ± 0.5 mycophenolate; p = 0.01).
Conclusions
The current study showed differential expression of drug metabolizing enzyme and transporter transcripts and contributes to the literature on transcript expression of drug transporters in leukocytes. The implications of altered local metabolism and transport in leukocytes may be important in autoimmune diseases and transplant patients where treatment is targeted to leukocytes.
doi:10.5414/CP201972
PMCID: PMC4123858  PMID: 24548980
glomerulonephritis; drug metabolizing enzymes; transporters; uridine glucuronosyltransferases (UGTs); cytochrome P450 2B9; ABCB1; ABCC2; ABCG2
4.  Automating and estimating glomerular filtration rate for dosing medications and staging chronic kidney disease 
Objective
The purpose of this paper is to serve as a review for primary care providers on the bedside methods for estimating glomerular filtration rate (GFR) for dosing and chronic kidney disease (CKD) staging and to discuss how automated health information technologies (HIT) can enhance clinical documentation of staging and reduce medication errors in patients with CKD.
Methods
A nonsystematic search of PubMed (through March 2013) was conducted to determine the optimal approach to estimate GFR for dosing and CKD staging and to identify examples of how automated HITs can improve health outcomes in patients with CKD. Papers known to the authors were included, as were scientific statements. Articles were chosen based on the judgment of the authors.
Results
Drug-dosing decisions should be based on the method used in the published studies and package labeling that have been determined to be safe, which is most often the Cockcroft–Gault formula unadjusted for body weight. Although Modification of Diet in Renal Disease is more commonly used in practice for staging, the CKD–Epidemiology Collaboration (CKD–EPI) equation is the most accurate formula for estimating the CKD staging, especially at higher GFR values. Automated HITs offer a solution to the complexity of determining which equation to use for a given clinical scenario. HITs can educate providers on which formula to use and how to apply the formula in a given clinical situation, ultimately improving appropriate medication and medical management in CKD patients.
Conclusion
Appropriate estimation of GFR is key to optimal health outcomes. HITs assist clinicians in both choosing the most appropriate GFR estimation formula and in applying the results of the GFR estimation in practice. Key limitations of the recommendations in this paper are the available evidence. Further studies are needed to better understand the best method for estimating GFR.
doi:10.2147/IJGM.S61795
PMCID: PMC4014374  PMID: 24833913
laboratory automation; glomerular filtration rate; medications; dose adjustment
5.  A pilot study of leukocyte expression patterns for drug metabolizing enzyme and transporter transcripts in autoimmune glomerulonephritis  
Objective: Leukocyte mRNA expression patterns of drug metabolizing enzyme genes and transporter genes that are relevant for the disposition of cyclophosphamide and mycophenolate were studied. The relationships between expression and patient-level data and pharmacokinetics were evaluated. Methods: The study included patients with glomerulonephritis secondary to lupus nephritis (SLE, n = 36), small vessel vasculitis (SVV, n = 35), healthy controls (HC, n = 10), and disease controls (VC, n = 5; LC, n = 5). Transcript assays targeted metabolizing enzymes (UGT1A7, UGT1A9, UGT2B7, CYP3A4, CYP2C9, CYP2B6) and transporters (ABCB1, ABCC2, ABCG2, SLCO1A2). Genotyping for specific variants was conducted. Group transcript fold-changes were evaluated. Patient level data was evaluated for transcript fold-change and disease, treatment, gender, race, and genotype. Results: Significant differences were noted in expression of UGT1A7, ABCB1, and ABCC2; for UGT1A7, SVV (0.17 ± 0.42; p < 0.05) and SLE (0.03 ± 0.1; p < 0.05) groups had lower expression than HC (0.79 ± 2.02). For ABCB1, SLE had a lower expression (0.33 ± 0.21; p < 0.05) than HCs (1 ± 0.82). For ABCG2, SVV group had a lower expression (0.17 ± 0.14; p < 0.05) than HCs (1 ± 1.82). Differences in expression of ABCC2 approached statistical significance with VC patients (2.02 ± 1.13) exhibiting higher expression than SVV patients (1.06 ± 1.11; p = 0.05). The relationships between transcript expression and patient-level data demonstrated; ABCC2 expression was different by race (1.26 ± 1.82 Caucasian versus 1.37 ± 0.86 non-Caucasian; p = 0.049) and CYP2B6 expression was different by treatment (2.07 ± 2.94 cyclophosphamide versus 0.45 ± 0.5 mycophenolate; p = 0.01). Conclusions: The current study showed differential expression of drug metabolizing enzyme and transporter transcripts and contributes to the literature on transcript expression of drug transporters in leukocytes. The implications of altered local metabolism and transport in leukocytes may be important in autoimmune diseases and transplant patients where treatment is targeted to leukocytes.
doi:10.5414/CP201972
PMCID: PMC4123858  PMID: 24548980
glomerulonephritis; drug metabolizing enzymes; transporters; uridine glucuronosyltransferases (UGTs); cytochrome P450 2B9; ABCB1; ABCC2; ABCG2
6.  Cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics in patients with glomerulonephritis secondary to lupus and small vessel vasculitis 
AIMS
Cyclophosphamide, the precursor to the active 4-hydroxycyclophosphamide, is used in active glomerulonephritis despite limited pharmacokinetics data. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were evaluated. The influence of laboratory and pharmacogenomic covariates on pharmacokinetics was evaluated as a secondary aim.
METHODS
Glomerulonephritis patients (n = 23) participated in a pharmacokinetic evaluation. Blood was serially collected and assayed for cyclophosphamide and 4-hydroxycyclophosphamide by LC/MS methods. Kidney function, serum albumin and polymorphisms in drug metabolism or transport genes were evaluated. Analyses included non-compartmental pharmacokinetics and parametric and non-parametric statistics.
RESULTS
The mean area under the plasma concentration–time curve (AUC(0,∞)) data were 110 100 ± 42 900 ng ml−1 h and 5388 ± 2841 ng ml−1 h for cyclophosphamide and 4-hydroxycyclophosphamide, respectively. The mean metabolic ratio was 0.06 ± 0.04. A statistically significant relationship was found between increased serum albumin and increased half-life (0.584, P = 0.007, 95% CI 0.176, 0.820) and a borderline relationship with AUC(0,∞) (0.402, P = 0.079, 95% CI –0.064, 0.724) for 4-hydroxycyclophosphamide. Covariate relationships that trended toward significance for cyclophosphamide included decreased serum albumin and increased elimination rate constant (–0.427, P = 0.061, 95% CI 0.738, 0.034), increased urinary protein excretion and increased AUC(0,∞) (–0.392, P = 0.064, 95% CI –0.699 to 0.037), decreased Cmax (0.367, P = 0.085, 95% CI –0.067, 0.684) and decreased plasma clearance (–0.392, P = 0.064, 95% CI –0.699, 0.037). CYP2B6*9 variants vs. wildtype were found to have decreased elimination rate constant (P = 0.0005, 95% CI 0.033, 0.103), increased Vd (P = 0.0271, 95% CI −57.5, −4.2) and decreased Cmax (P = 0.0176, 95% CI 0.696, 6179) for cyclophosphamide. ABCB1 C3435T variants had a borderline decrease in cyclophosphamide elimination rate constant (P = 0.0858; 95% CI –0.005, 0.102).
CONCLUSIONS
Pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in patients with lupus nephritis and small vessel vasculitis are similar. Clinical and pharmacogenetic covariates alter disposition of cyclophosphamide and 4-hydroxycyclophosphamide. Clinical findings of worsened glomerulonephritis lead to increased exposure to cyclophosphamide vs. the active 4-hydroxycyclophosphamide, which could have relevance in terms of clinical efficacy. The CYP2B6*9 and ABCB1 C3435T polymorphisms alter the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in glomerulonephritis.
doi:10.1111/j.1365-2125.2012.04223.x
PMCID: PMC3477346  PMID: 22380717
4-hydroxycylophosphamide; cyclophosphamide; glomerulonephritis; lupus nephritis; pharmacogenomics; pharmacokinetics
7.  Effects of uridine diphosphate glucuronosyltransferase 2B7 and 1A7 pharmacogenomics and patient clinical parameters on steady-state mycophenolic acid pharmacokinetics in glomerulonephritis 
Purpose
The role of pharmacogenomics, clinical and demographic parameters in pharmacokinetic predictions was evaluated in patients receiving mycophenolic acid (MPA).
Methods
A cohort study design of patients with glomerulonephritis secondary to lupus nephritis and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was employed. Forty-six patients with lupus nephritis and ANCA vasculitis who were receiving MPA were recruited from the nephrology clinic. The study assessed the relative single and combined roles of genomic, clinical, and demographic characteristics on pharmacokinetic parameters using general linear models. The study focused on polymorphisms in UGT1A7, UGT2B7, and ABCB1/MDR1; all of which have limited data available concerning MPA pharmacokinetics. All patients had pharmacokinetic assessments for MPA and glucuronide metabolites (MPAG, AcMPAG). Genotyping was performed for known variants of UGTs (UGT1A9, UGT1A7, UGT2B7), and multidrug resistance protein (ABCB1/MDR1), involved in MPA disposition. Analyses included univariate and multivariate linear modeling.
Results
In univariate analyses, UGT2B7 heterozygosity (coefficient 0.3508; R2=0.0873) and UGT1A7 heterozygosity (coefficient 0.3778; R2=0.0966) predicted increased apparent oral clearance of MPA. UGT1A7 heterozygosity (coefficient −0.4647; R2 0.0897) predicted lower MPA trough concentrations. In multivariate assessments, higher urinary protein excretion, lower serum creatinine, and increased weight predicted greater apparent oral clearance of MPA (p< 0.0001). White race and higher serum creatinine predicted higher MPA trough concentrations (p<0.0001). Higher exposure to MPA was predicted by decreased urinary protein excretion and increased serum creatinine.
Conclusions
Clinical and demographic parameters were 2–4 times more important in MPA disposition than genotypes and explained 30–40% of the pharmacokinetic parameters.
doi:10.1007/s00228-010-0846-x
PMCID: PMC3739695  PMID: 20567810
Mycophenolic acid; UGT2B7; UGT1A7; ABCB1; MDR1; Glomerulonephritis
8.  Use of Enantiomeric Bupropion and Hydroxybupropion to Assess CYP2B6 Activity in Glomerular Kidney Diseases 
Journal of clinical pharmacology  2010;50(6):714-720.
doi:10.1177/0091270009353031
PMCID: PMC3614080  PMID: 20103693
glomerulonephritis; bupropion; hydroxybupropion; single-dose pharmacokinetics; CYP2B6; lupus nephritis; ANCA vasculitis
9.  Population Pharmacokinetics of Mycophenolic Acid and Metabolites in Patients with Glomerulonephritis 
Therapeutic drug monitoring  2010;32(5):594-605.
Mycophenolic acid (MPA) is an inosine monophosphate dehydrogenase inhibitor used for glomerulonephritis treatment. The objective of the current study was to develop a population pharmacokinetic model for MPA and metabolites in glomerulonephritis in order to enable appropriate design of MPA regimens in these patients with alterations in kidney structure and function.
Thirty-nine patients with glomerulonephritis and receiving mycophenolate mofetil were recruited to participate in a 24-hour pharmacokinetic (PK) study. Blood was collected at times 0, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours and urine was collected over the intervals of 0-6, 6-12, and 12-24 hours. Plasma and urine samples were assayed for MPA and MPAG by high-performance liquid chromatography (HPLC), and for AcMPAG by liquid chromatography / mass spectrometry (LC/MS). Population PK analysis and covariate model building were evaluated using Non-linear Mixed Effect Modeling software (NONMEM, version 6.2.0, ICON Development Solutions, Ellicott City, MD).
The final model for MPA and it's metabolites consisted of 9 discrete compartments; 1)depot gastrointestinal, 2)central MPA, 3)peripheral MPA, 4)gallbladder, 5)MPA urine, 6)MPAG central, 7)MPAG urine, 8)AcMPAG central, and 9)AcMPAG urine compartment. The MPA population mean estimates for apparent non-renal clearance (ClNR/F) and apparent central volume of distribution were 14.3 L/hr and 21.1 L, respectively. The mean population estimate for apparent renal clearance (ClR/F) was dependent on estimated creatinine clearances (eClcr); 0.0975 L/hr for eClcr ≤80 mL/min and 0.157 L/hr for eClcr > 80 mL/min. Covariate analyses identified: eClcr on CLNR,MPA/F (P<0.001), eClcr (with a cut-off value at 80 ml/min) on CLR,MPA/F (P<0.025), serum albumin on CLNR,MPA/F (P<0.01), eClcr on CLR,MPAG/F (P<0.001) and eClcr on CLR,AcMPAG/F (P<0.001). Evaluation of the final model by visual predictive check showed that most of the observed values were within the 95th percent prediction interval generated from 100 simulations of the final model.
The current population PK model demonstrated eClcr and serum albumin influenced the renal and nonrenal components of Cl/F, suggesting patients with glomerulonephritis would have highly altered MPA exposures.
doi:10.1097/FTD.0b013e3181ee52e2
PMCID: PMC2944917  PMID: 20736896
mycophenolic acid; mycophenolic acid glucuronide; pharmacokinetics; glomerulonephritis
10.  Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design 
BMC Nephrology  2011;12:8.
Background
The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing.
Methods/Design
The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT.
Discussion
This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases
Trial Registration
ClinicalTrials.gov, NCT00814255
doi:10.1186/1471-2369-12-8
PMCID: PMC3045306  PMID: 21310077
11.  Validation and application of a liquid chromatography-tandem mass spectrometric method for quantification of the drug transport probe fexofenadine in human plasma using 96-well filter plates 
A rapid method to determine fexofenadine concentrations in human plasma using protein precipitation in 96-well plates and liquid chromatography-tandem mass spectrometry was validated. Plasma proteins were precipitated with acetonitrile containing the internal standard fexofenadine-d6, mixed briefly, and then filtered into a collection plate. The resulting filtrate was diluted and injected onto a Phenomenex Gemini C18 (50 × 2.0 mm, 5 micron) analytical column. The mobile phase consisted of 0.1% formic acid, 5 mM ammonium acetate in deionized water and methanol (35:65, v/v). The flow rate was 0.2 ml/min and the total run time was 2 min. Detection of the analytes was achieved using positive ion electrospray ionization and high resolution multiple reaction monitoring mode (H-SRM). The linear standard curve ranged from 1 to 500 ng/ml and the precision and accuracy (intra- and inter-run) were within 4.3% and 8.0%, respectively. The method has been applied successfully to determine fexofenadine concentrations in human plasma samples obtained from subjects administered a single oral dose of fexofenadine. The method is rapid, sensitive, selective and directly applicable to human pharmacokinetic studies involving fexofenadine.
doi:10.1016/j.jchromb.2009.12.022
PMCID: PMC2818817  PMID: 20045385
Fexofenadine; fexofenadine-d6; protein precipitation; LC-MS; human plasma
12.  Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group 
Background
Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end stage kidney disease. Antifibrotic agents, such as tumor necrosis factor α (TNF-α) antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data.
Study Design
Phase I clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to TNF-α.
Setting and Participants
Ten patients (4 male and 6 female), age 16.8±9.0 yr, and estimated GFR 105±50 mL/min/1.73 m2, were studied as out-patients
Intervention
Adalimumab, 24 mg/m2 every 14 days for 16 weeks (total 9 doses)
Outcomes
Pharmacokinetic assessment, tolerability, and safety
Measurements
Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state
Results
Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P<0.001) and clearance was increased by 160% (P<0.01) in patients with resistant FSGS compared to healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria declined by ≥50% in 4 of 10 treated patients.
Limitations
Insufficient power to assess safety or efficacy of adalimumab therapy for patients with resistant FSGS
Conclusions
Pharmacokinetic assessment demonstrated increased clearance of adalimumab in patients with resistant primary FSGS and validated the need for evaluating the disposition of novel therapies in this disease to define appropriate dosing regimens. The study provides a rationale to evaluate efficacy of adalimumab as an antifibrotic agent for resistant FSGS in Phase II/III clinical trials.
doi:10.1053/j.ajkd.2009.08.019
PMCID: PMC2804955  PMID: 19932542
FSGS; pharmacokinetics; nephrotic syndrome; adalimumab; tumor necrosis factor-α; antifibrotic
13.  CYP2C9 Genotype and Pharmacodynamic Responses to Losartan in Patients with Primary and Secondary Kidney Diseases 
Losartan is used for anti-proteinuric as well as blood pressure effects in chronic kidney disease (CKD). It is metabolized by cytochrome P450 2C9 to active E-3174. Single nucleotide polymorphisms in CYP2C9 that reduce catalytic activity could reduce clinical benefits. The study aims were to determine whether CYP2C9 variant alleles (*2 and *3) altered urinary protein excretion, glomerular filtration rate, and blood pressure in Caucasians prescribed losartan. Differences between baseline and six-month follow-up outcomes were compared by CYP2C9 genotypes in 59 patients using unpaired T-test or Mann Whitney U test. Primary renal disease patients had a trend toward less favorable antiproteinuric response (−31.7±156 vs −125±323%; p=0.123) when carrying variant alleles. Patients with secondary renal diseases had less favorable diastolic blood pressure (9.8±16.0 mm Hg vs −3.2±10.6 mm Hg; p=0.043) and systolic blood pressure (16.2±27.1 mm Hg vs −5.5±17.5 mm Hg; p=0.044) with CYP2C9 variants. Preliminary results suggest a possible influence of CYP2C9 genotype on proteinuria and blood pressure in Caucasian CKD patients treated with losartan.
doi:10.1007/s00228-009-0707-7
PMCID: PMC2901912  PMID: 19669737
Cytochrome P450 2C9; losartan; chronic kidney disease; proteinuria; blood pressure
14.  Pharmacokinetics of Mycophenolic Acid in Patients with Lupus Nephritis 
Pharmacotherapy  2009;29(1):7-16.
Lupus nephritis is associated with urinary protein excretion, hypoalbuminemia, and renal function declines, which may impact the pharmacokinetics (PK) of mycophenolic acid (MPA).
The primary study objective was to evaluate and describe the PK of MPA and its glucuronide (MPAG) in lupus nephritis. Secondary objectives were to determine the single and/or multiple effects of clinical parameters (urinary protein excretion, serum albumin, and creatinine clearance) and demographic variables (age, race, and gender) on total and unbound MPA and MPAG PK.
Plasma and urine were collected for 24-hours and assayed by HPLC with UV detection. Noncompartmental PK analysis was performed using WinNonlin v4.1. Statistics included descriptive analyses, urivariate and multiple regression tests, and T-test or nonparametric equivalent.
Time to maximal concentration (0.5 to 8 hrs) was variable. Unbound MPA was 2.6±1.9% and oral clearance (Cl/F 343 ± 200 mL/min) was ~ 2-fold higher than previously reported. Multiple regression showed MPA Cl/F was predicted by creatinine clearance (Clcr) and serum albumin (MPA lnCl/F = 5.358 + 0.0092 (Clcr) − 0.078 (ranked albumin), R2 51.1%, p = 0.0195). UP:Cr ≥ 1 g/d had lower trough and area under the curve (AUC 0-12) and higher Cl/F versus UP:Cr < 1 g/d. Serum albumin < 4 g/dL had higher MPA Cl unbound and MPAG Clr 0-12 versus serum albumin ≥ 4g/dL. Recycling AUC (AUC6-12) and equally gender and age predicted renal clearance of MPAG.
Clcr and serum albumin were identified as primary contributors to MPA exposure and should be considered when evaluating dosages. The results of future studies should clarify the interactions of other variables on drug exposure and treatment responses. Clinicians need to be mindful of clinical changes that occur throughout the course of lupus nephritis in order to maintain efficacy and reduce toxicity from MPA therapy.
doi:10.1592/phco.29.1.7
PMCID: PMC2901907  PMID: 19113793
lupus nephritis; mycophenolic acid; pharmacokinetics; individualized therapy
15.  Pre-Dialysis Chronic Kidney Disease: Evaluation of Quality of Life in Clinic Patients Receiving Comprehensive Anemia Care 
Background
Anemia is common in chronic kidney disease (CKD), and suboptimal management of anemia can lead to serious health complications and poor quality of life.
Objectives
1) To describe health-related and overall quality of life among patients entering a clinic focused on anemia management; 2) to compare their baseline quality of life with other relevant populations; 3) to explore predictors of quality of life prior to anemia management; and 4) to explore changes in quality of life over 1 year for patients managed in the clinic.
Methods
The Kidney Disease Quality of Life questionnaire – short form (KDQOL™-SF) was used to measure kidney disease specific and overall quality of life in a cohort of pre-dialysis CKD patients (n=79) enrolled in the clinic from January 2003 to September 2004. Baseline measures were compared to previously published measurements. The influence of demographic and clinical characteristics on baseline quality of life was explored. Changes in quality of life were evaluated over time.
Results
Patients with CKD entering the clinic had lower overall quality of life compared with estimates from the general US population (physical composite 35.7 vs. 48.4 and mental composite 46.0 vs. 50.2, respectively). Clinic patients had better kidney disease specific scores than patients with end stage kidney disease. General quality of life scores were similar regardless of kidney disease severity, with the exception of physical functioning which was lowest for patients with end-stage disease. Hemoglobin was the only factor predictive of quality of life. Over time, quality of life improved among patients managed in the CKD clinic, with statistically significant improvements in sleep (change of 6.2 ± 15.2; p < 0.05) and social function (change of 11.6 ± 27.7; p < 0.05).
Conclusions
Patients with anemia of chronic kidney disease reported reduced quality of life compared to populations without kidney disease, but better quality of life compared to populations with end stage kidney disease on dialysis. Quality of life generally improved among patients managed in the multidisciplinary anemia clinic.
doi:10.1016/j.sapharm.2008.06.004
PMCID: PMC2722114  PMID: 19524862
Quality of life; chronic kidney disease; anemia; SF-36; KDQOL; multidisciplinary
16.  Influence of Clinical and Demographic Variables on Mycophenolic Acid Pharmacokinetics in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis 
The Annals of pharmacotherapy  2009;43(6):1020-1027.
Background
Mycophenolic acid (MPA) is used off-label to treat many forms of glomerulonephritis.
Objective
To evaluate the pharmacokinetics of MPA and its glucuronide (MPAG) in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis patients with renal manifestations and to determine the effects of clinical (urinary protein excretion, serum albumin, creatinine clearance) and demographic (age, race, sex) variables on MPA and MPAG pharmacokinetics.
Methods
Twenty-three patients taking MPA at steady-state were evaluated. Plasma and urine samples were collected over 24 hours. Analyses included noncompartmental pharmacokinetics and statistics including Mann-Whitney U test and univariate/multiple regression.
Results
MPA clearance (Cl/F 288 ± 154 mL/min) was approximately 2-fold higher than previously reported from transplant patients and predicted by weight and race (ranked MPA Cl/F = −11.766 + 0.2035 [wt] + 4.9578 [race]; R2 41.8%; p = 0.005). Creatinine clearance (CrCl) less than 60 mL/min resulted in higher MPA exposure, total area under the curve (AUC)0-12, and AUC6-12, as well as unbound AUC0-12. The metabolic ratio (MPAGAUC/MPAAUC) of 8.67 ± 5.57 was lower than that previously reported in renal transplant recipients.
Conclusions
Diminished kidney function (eg, CrCl <60 mL/min) demonstrated enhanced MPA and MPAG exposure in patients with ANCA vasculitis. However, unlike renal transplant recipients, patients with ANCA vasculitis had enhanced Cl/F and diminished metabolic ratio, suggesting the need to comprehensively evaluate the role of disease-specific factors on MPA pharmacokinetics.
doi:10.1345/aph.1L699
PMCID: PMC2778272  PMID: 19491317
antineutrophil cytoplasmic antibody–associated vasculitis; individualized therapy; mycophenolic acid; pharmacokinetics
17.  Determinants of Ceftazidime Clearance by Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodialysis 
Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m2 acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m2 polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m2 polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CIdiffusion) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17% ± 7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (P < 0.0001) were observed between CIdiffusion of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.
PMCID: PMC89925  PMID: 10817721

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