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1.  Pharmacokinetics and Tolerability of Intravenous Sildenafil in Two Subjects with Child-Turcotte-Pugh Class C Cirrhosis and Renal Dysfunction 
Digestive diseases and sciences  2015;60(11):3491-3494.
Phosphodiesterase-5 (PDE-5) inhibitors have been used successfully in patients with cirrhosis to treat porto-pulmonary hypertension. Additionally, in cirrhosis, PDE-5 inhibitors can potentially improve portal hypertension and renal hemodynamics. No pharmacokinetics and tolerability studies of intravenous (IV) sildenafil have been conducted in Child-Turcotte-Pugh (CTP) class C cirrhosis and renal dysfunction. We report two subjects with CTP class C cirrhosis and estimated glomerular filtration rate of 25.8 and 22.4 ml/min/1.73m2 treated with a single-dose, IV bolus injection of 2.5 mg sildenafil. Both subjects had diuretic-refractory ascites with model for end-stage liver disease scores of 25 and 35. Both subjects tolerated IV Sildenafil without side effects. The observed maximum concentrations of plasma sildenafil were 35 and 20.6 ng/ml, with modeled pharmacokinetic estimates for clearance (11.9 and 14.9 L/hr), volumes of distribution (72.8 and 77.3 L) and half-life (4.2 and 3.6 hrs). N-desmethyl sildenafil concentrations ranged from 3 to 40% of the parent concentrations. Our results showed that in CTP class C cirrhosis and renal dysfunction, IV bolus injection of 2.5 mg sildenafil is safe and tolerable.
PMCID: PMC4623880  PMID: 26143343
2.  A Pilot Study to Evaluate Renal Hemodynamics in Cirrhosis by Simultaneous Glomerular Filtration Rate, Renal Plasma Flow, Renal Resistive Indices and Biomarkers Measurements 
American journal of nephrology  2014;39(6):543-552.
Renal hemodynamic measurements are complicated to perform in patients with cirrhosis; yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics.
In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic sensitive and 2 diuretic refractory ascites).
Patients with diuretic refractory ascites had the lowest mean GFR (36.5 ml/min/1.73m2) and RPF (133.6 ml/min/1.73m2) when compared to those without ascites (GFR=82.9 ml/min/1.73m2, RPF=229.9 ml/min/1.73m2) and with diuretic-sensitive ascites (GFR=82.3 ml/min/1.73m2, RPF=344.1 ml/min/1.73m2). A higher mean filtration fraction (FF= GFR/RPF=0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF≃0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and beta-2 microglobulin performed better compared to Cr in estimating RPF; beta-trace protein, beta-2 microglobulin, SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index.
The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention, and reduce mortality from kidney failure in cirrhosis.
PMCID: PMC4287415  PMID: 24943131
End-stage liver disease; glomerular filtration rate; renal plasma flow; renal resistive index; cystatin C; beta-trace protein; beta-2 microglobulin; kidney injury molecule-1 (KIM-1); Neutrophil Gelatinase-Associated Lipoprotein (NGAL)
3.  Performance of Chronic Kidney Disease Epidemiology Collaboration Creatinine-Cystatin C Equation for Estimating Kidney Function in Cirrhosis 
Hepatology (Baltimore, Md.)  2013;59(4):1532-1542.
Conventional creatinine-based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD-EPI creatinine-cystatin C equation (2012) was superior to previous creatinine- or cystatin C-based GFR equations. To evaluate the performance of the CKD-EPI creatinine-cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by non-radiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the “bias”, “precision” and “accuracy” of the new CKD-EPI creatinine-cystatin C equation to that of 24-hour urinary creatinine clearance (CrCl), Cockcroft-Gault (CG) and previously reported creatinine- and/or cystatin C-based GFR-estimating equations. Accuracy of CKD-EPI creatinine-cystatin C equation as quantified by root mean squared error of difference scores [differences between mGFR and estimated GFR (eGFR) or between mGFR and CrCl, or between mGFR and CG equation for each subject] (RMSE=23.56) was significantly better than that of CrCl (37.69, P=0.001), CG (RMSE=36.12, P=0.002) and GFR-estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P=0.024), CG (P=0.0001), 4-variable MDRD (P=0.027) and CKD-EPI creatinine 2009 (P=0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD-EPI creatinine-cystatin C equation differed from the mGFR by more than 30%.
The diagnostic performance of CKD-EPI creatinine-cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis.
PMCID: PMC3883887  PMID: 23744636
End-stage liver disease; liver transplantation; cystatin C; glomerular filtration rate; gender disparity
4.  Glomerular Filtration Rate Equations Overestimate Creatinine Clearance in Older Individuals Enrolled in the Baltimore Longitudinal Study on Aging (BLSA): Impact on Renal Drug Dosing 
Pharmacotherapy  2013;33(9):912-921.
To evaluate performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population.
Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005–December 31, 2010.
Two hundred sixty-nine men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr) of 1.1 ± 0.4 mg/dl, and mean measured 24-hour creatinine clearance (mClcr) of 53 ± 13 ml/minute.
Measurements and Main Results
Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease Study (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr. Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared to the FDA-approved dosages. The CG equation was the least biased estimate of mClcr. The MDRD and CKD-EPI equations were significantly positively biased compared to CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, p<0.001) and mClcr (29 ± 47% and 18 ± 40%, respectively, p<0.001). Rounding low Scr values (< 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dL resulted in CG values (44±10 mL/min) that were significantly lower than mClcr (56±12 mL/min, p<0.001) and CG (56±15 mL/min, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively.
The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus, GFR-estimating equations should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dL for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed.
PMCID: PMC3732548  PMID: 23625813
GFR; glomerular filtration rate; creatinine clearance; geriatrics; BLSA; drug safety
5.  Optimum Ribavirin Exposure Overcomes Racial Disparity in Efficacy of Peginterferon and Ribavirin Treatment for Hepatitis C Genotype 1 
Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90 % of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24.
Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule.
Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P < 0.05) and week 72 (SVR) (36.6 % vs 54.8 %; P < 0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P < 0.05). Ribavirin exposures ≥ 4,065 and ≥ 4,480 ng/ml/day in the first week (AUC0–7) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC0–7 level than CA (P < 0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84 %) and SVR (AA: 52 vs. CA: 60 %) rates in patients who met the ribavirin AUC0–7 thresholds. Ribavirin AUC0–7 predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC0–7 levels increased response rates primarily in AA with the less favorable non-C/C genotypes.
Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1.
PMCID: PMC3718255  PMID: 23090351
6.  Population Pharmacokinetics and Pharmacodynamics of Ribavirin in Patients with Chronic Hepatitis C Genotype 1 Infection 
The AAPS Journal  2012;14(3):571-580.
We report a population pharmacokinetic (PK) and pharmacodynamic (PD) model of orally administered ribavirin in patients with chronic hepatitis C virus (HCV) infection enrolled in a multicenter clinical trial, including the estimation of covariate effects on ribavirin PK parameters and sustained viral response (SVR). Ribavirin concentrations obtained from 144 patients, consisting of n = 71 African American (AA) and n = 73 Caucasian Americans (CA), during 24 weeks of therapy were best described by a two-compartment model with first-order absorption and elimination parameterized in terms of apparent oral clearance (CL/F), apparent central volume (Vc/F), apparent peripheral volume (Vp/F), and apparent intercompartmental clearance (Q/F). The typical population parameters were CL/F (19.0 L/h), Vc/F (1,130 L), Vp/F (4,020 L), and Q/F (38.6). The Vp/F was approximately 50% greater in AA compared to CA. Significant covariates in the SVR model included IL-28B genotype, homeostasis model assessment of insulin resistance, and ribavirin exposure during the first week (AUC0 − 7). The population PK and logistic regression models both described the observed ribavirin concentration data and SVR data well. These findings suggest that optimization of ribavirin plasma concentrations during the first week of ribavirin dosing is most critical in AA patients in order to increase the rate of SVR, especially those with the IL-28B TT genotype.
PMCID: PMC3385833  PMID: 22639111
hepatitis C; pharmacodynamics; population pharmacokinetics; ribavirin
7.  The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training 
Blood pressure  2009;18(4):171-179.
The purpose of this study was to examine the effects of aerobic exercise training (AEXT) on dipping status in pre-hypertensive and stage-1 hypertensive individuals. A secondary purpose was to evaluate whether AEXT alters oxidative stress and endothelial biomarkers correlated to dipping status.
Twenty-three subjects underwent 24-h ambulatory blood pressure monitoring at baseline and after 6 months of AEXT. AEXT consisted of training at 70% VO2max 3 days/week for 6 months. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)-cholesterol, oxidized LDL (ox-LDL), triglycerides, urinary and plasma nitric oxide end-products, superoxide dismutase and 8-iso-PGF2α were measured before and after AEXT. Statistically, ANOVA and linear regression were used.
Before and after AEXT, there were no significant differences between dippers and non-dippers in any of the biomarkers except for total cholesterol following AEXT. In a sub-analysis following AEXT, 14 subjects retained their original dipping status, five subjects changed from dippers to non-dippers and four subjects changed from non-dippers to dippers. Significant differences existed between these groups in changes in total and LDL-cholesterol, ox-LDL, 8-iso-PGF2α and % Dip.
Changes in cholesterol levels but not oxidative stress or endothelial biomarkers were related to changes in BP variables following AEXT in dippers and non-dippers.
PMCID: PMC2922419  PMID: 19544106
Aerobic exercise; ambulatory blood pressure monitoring; dipper; non-dipper; hypertension; oxidative stress
8.  Differential aerobic exercise-induced changes in plasma aldosterone between African Americans and Caucasians 
Experimental physiology  2007;92(5):871-879.
Aldosterone influences the kidney’s regulation of blood pressure (BP), but aldosterone can contribute to the pathogenesis of hypertension. Blood pressure is reduced with aerobic exercise training (AEX), but the extent to which plasma aldosterone (PA) levels change is unclear. The purpose of this study was to determine whether 6 months of AEX changed PA levels, 24 h sodium (Na+) excretion and BP in prehypertensive and hypertensive subjects and whether these changes differed according to ethnicity. The study was performed in the Kinesiology Department at the University of Maryland, College Park, and 35 (22 Caucasian; 13 African American) sedentary prehypertensive and hypertensive subjects completed 6 months of AEX. Blood samples were collected under fasting and supine conditions, and PA was measured by radioimmunoassay. In total population aerobic exercise training increased maximal oxygen consumption (24 ± 0.8 versus 28 ± 1 ml kg−1 min−1, P < 0.001) and decreased PA levels (97 ± 11 versus 72 ± 6 pg ml−1, P = 0.01), body mass index (28 ± 0.5 versus 28 ± 0.5 kg m−2, P = 0.004) and weight (85 ± 2 versus 83 ± 2 kg, P = 0.003). Aerobic exercise training decreased PA levels (from 119 ± 16 to 81 ± 7 pg ml−1, P = 0.02) in the Caucasians but there was no change in BP or Na+ excretion. African American participants had no significant changes in PA levels, BP and Na+ excretion. Plasma aldosterone levels were 47% lower at baseline (P = 0.01) and 30% lower after AEX (P = 0.04) in African American participants compared with Caucasians. Baseline (P = 0.08) and final PA levels (P = 0.17) did not differ between the two groups after accounting for baseline and final intra-abdominal fat, respectively. The reduction in PA levels with AEX appeared to be driven by the change in PA levels in Caucasian participants. Fat distribution contributed to the ethnic differences in PA levels.
PMCID: PMC2729146  PMID: 17483200
9.  Peginterferon Pharmacokinetics in African American and Caucasian American Patients with Hepatitis C Virus Genotype 1 Infection 
Background & Aims
The relationship between serum peginterferon pharmacokinetics and pharmacodynamics and the early virologic response (EVR) to peginterferon and ribavirin therapy was assessed in patients with chronic hepatitis C virus (HCV) genotype 1 infection in the Virahep-C study.
333 patients [160 African Americans (AA) and 173 Caucasian Americans (CA)] who received peginterferon alfa-2a (180 μg/wk) without a dose modification during the initial 4 weeks of therapy were analyzed. Peginterferon and 2,5-OAS serum levels were measured on days 0, 1, 2, 3, 7, 14, 28, 56, 84, and 168 of treatment. The EVR: (≥ 2 log10 decline in HCV RNA levels by week 12 of therapy) was the primary virologic endpoint.
Peginterferon pharmacokinetics after the first dose were similar in AA and CA, but AA had greater peginterferon concentrations at days 1, 3, 14 and 28 (p < 0.05). AA had higher absolute serum 2,5-OAS levels on days 0, 1, 2, 3, 7, 14, 28 and 56 (p < 0.05), but the magnitude of 2,5-OAS induction during treatment relative to day 0 were similar. AA patients exhibited a smaller decline in serum HCV RNA during the first 28 days of treatment (p < 0.001) and a lower EVR (65% vs. 83%). AA and CA with EVR had significantly higher serum peginterferon concentrations and serum 2,5-OAS induction during the first 12 weeks than patients without an EVR.
Peginterferon alfa-2a pharmacokinetic and pharmacodynamic variability is associated with EVR in both AA and CA with HCV infection, but do not explain the racial disparity in combination treatment efficacy.
PMCID: PMC2704736  PMID: 18407798
10.  Phase 1 Safety and Pharmacokinetic Study of Chimeric Murine-Human Monoclonal Antibody cαStx2 Administered Intravenously to Healthy Adult Volunteers 
Hemolytic-uremic syndrome (HUS) is a serious complication of infection by Shiga toxin-producing Escherichia coli. Shiga toxin type 2 (Stx2) is responsible for the renal toxicity that can follow intestinal infection and hemorrhagic colitis due to E. coli. A chimeric mouse-human antibody, designated cαStx2, that has neutralizing activity in a mouse model was produced and tested in healthy adult volunteers. In this phase I dose escalation study, cαStx2 was generally well tolerated. Pharmacokinetic studies indicated that clearance was stable over the dose range of 1.0 to 10 mg/kg of body weight (0.249 ± 0.023 ml/kg/h) but was higher for the 0.1-mg/kg dose (0.540 ± 0.078 ml/kg/h), suggesting saturable elimination. A similar nonlinear trend was observed for the volume of distribution, where average values ranged from 0.064 ± 0.015 liter/kg for the 1.0- to 10-mg/kg doses and 0.043 ± 0.005 for the 0.01-mg/kg dose. The relatively small volume of distribution suggests that the antibody is limited to the vascular (plasma) compartment. The mean half-life was 165 ± 66 h, with lowest values observed for the 0.1-mg/kg dose (56.2 ± 9.7 h) and the highest values reported for the 10.0-mg/kg dose (206.4 ± 12.4 h). Future studies are needed to confirm the safety of this cαStx2, and innovative clinical trials will be required to measure its efficacy in preventing or treating HUS.
PMCID: PMC1087672  PMID: 15855500

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