Pharmacokinetics of Gepotidacin in Renal Impairment.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. In this phase 1, nonrandomized, open-label, parallel-group, multicenter, multipart study, the pharmacokinetics, safety, and tolerability of a single intravenous (IV) dose of gepotidacin 750 mg over 2 hours were evaluated in subjects with normal renal function, in those with moderate and severe renal impairment, and in end-stage renal disease (ESRD) on and not on dialysis. Administration of IV gepotidacin 750 mg was safe and generally tolerated in the study subjects. Dosing in severe renal impairment with and without hemodialysis resulted in significant increases in plasma drug levels and decreases in clearance. The geometric mean elimination half-life (t½ ) was minimally impacted (range 9.45 to 11.5 hours) in all the renal-impairment groups relative to normal renal function. Regardless of renal function, urine gepotidacin concentrations remained considerably high over a 12-hour period. Saliva concentrations displayed a linear relationship with plasma concentrations. The t½ in saliva was not impacted in the moderate-impairment and ESRD subjects and was comparable to t½ in plasma. Over a 4-hour dialysis, approximately 6% of the gepotidacin dose was removed. Overall, subjects with severe renal impairment and ESRD with and without hemodialysis may require adjustment in dose or dosing frequency.

Clinical Pharmacokinetics of Sulfobutylether-ß-Cyclodextrin in Patients With Varying Degrees of Renal Impairment.

Delafloxacin, a fluoroquinolone, has activity against Gram-positive organisms including methicillin-resistant S aureus and fluoroquinolone-susceptible and -resistant Gram-negative organisms. The intravenous formulation of delafloxacin contains the excipient sulfobutylether-ß-cyclodextrin (SBECD), which is eliminated by renal filtration. This study examined the pharmacokinetics and safety of SBECD after single intravenous (IV) infusions in subjects with renal impairment. The study was an open-label, parallel-group, crossover study in subjects with normal renal function or mild, moderate, or severe renal impairment, and those with end-stage renal disease undergoing hemodialysis. Subjects received 300 mg delafloxacin IV or placebo IV, containing 2400 mg SBECD, in 2 periods separated by ≥14-day washouts. SBECD total clearance decreased with decreasing renal function, with a corresponding increase in area under the concentration-time curve (AUC0-∞ ). After IV delafloxacin 300 mg administration, SBECD mean total clearance was 6.28 and 1.24 L/h, mean AUC0-∞ was 387 and 2130 h·µg/mL, and mean renal clearance was 5.36 and 1.14 L/h in normal and severe renal subjects, respectively. Similar values were obtained after IV placebo administration. In subjects with end-stage renal disease, delafloxacin 300 mg IV produced mean SBECD AUC0-48 values of 2715 and 7861 h·µg/mL when dosed before and after hemodialysis, respectively. Total SBECD clearance exhibited linear relationships to estimated glomerular filtration rate and creatinine clearance. Single doses of IV delafloxacin 300 mg and IV placebo were well tolerated in all groups. In conclusion, decreasing renal function causes reduced SBECD clearance and increased exposures, but SBECD continues to exhibit a good safety and tolerability profile in IV formulations.

Pharmacokinetics of Intravenous Delafloxacin in Patients With End-Stage Renal Disease.

This was an open-label, parallel-group, crossover study that examined the pharmacokinetics and safety of delafloxacin, an anionic fluoroquinolone, after a single intravenous infusion in subjects with end-stage renal disease (ESRD; creatinine clearance <15 mL/min) undergoing hemodialysis compared with healthy subjects. Subjects received 300 mg delafloxacin containing sulfobutylether-ß-cyclodextrin in 2 periods separated by ≥14-day washouts. Blood and urine samples were collected, and pharmacokinetic parameters were calculated using noncompartmental methods. The mean total exposure (area under the curve) of delafloxacin was about 2.1 and 2.6 higher for subjects with ESRD compared to healthy subjects when dosed 1 hour before or 1 hour after hemodialysis, respectively. Compared to subjects with normal renal function, the maximum exposure to delafloxacin was 13% and 33% higher for ESRD subjects given delafloxacin 1 hour before and 1 hour after hemodialysis, respectively. The mean clearance was 13.7 L/h for healthy subjects and was lower for subjects with ESRD when given before (7.39 L/h) or after (5.69 L/h) hemodialysis. The clearance of delafloxacin in dialysate was 4.74 L/h with about 19.2% of the delafloxacin dose recovered after a 4-hour dialysis session. Delafloxacin was well tolerated in both healthy and ESRD subjects, with diarrhea being the most reported treatment-emergent adverse event.

Delafloxacin Pharmacokinetics in Subjects With Varying Degrees of Renal Function.

Delafloxacin, a fluoroquinolone, has activity against gram-positive organisms including methicillin-resistant Staphylococcus aureus and fluoroquinolone-susceptible and -resistant gram-negative organisms. This study was conducted to determine delafloxacin pharmacokinetics after a single intravenous infusion or oral dose administration in subjects with varying degrees of renal function. The study was an open-label, parallel-group crossover study in subjects with normal renal function or with mild, moderate, or severe renal impairment. Subjects received 300 mg delafloxacin intravenously, placebo intravenously, and 400 mg delafloxacin orally in 3 periods separated by ≥14-day washouts. Blood and urine pharmacokinetic parameters were calculated using noncompartmental methods. Delafloxacin total clearance decreased with decreasing renal function, with a corresponding increase in AUC0-∞ . After intravenous administration, mean total clearance was 13.7 and 7.07 L/h, and mean AUC0-∞ was 22.6 and 45.0 µg·h/mL in normal and severe renal subjects, respectively. Mean renal clearance as determined by urinary excretion was 6.03 and 0.44 L/h in normal and severe renal impairment subjects, respectively. Total clearance exhibited linear relationships to eGFR and CLCR . Similar observations were found after oral administration of delafloxacin. Single doses of delafloxacin 300 mg intravenously and 400 mg orally were well tolerated in all groups. In conclusion, renal insufficiency has an effect on delafloxacin clearance; a dosing adjustment for intravenous dosing is warranted for patients with severe renal impairment (eGFR < 30 mL/min).

Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics.

PURPOSE: The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728. METHODS: A single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration (C max), area under the concentration-time curve (AUC) from time of dose to 72 h (AUC72), AUC extrapolated to infinity (AUC∞), AUC to last measurable concentration (AUClast), half-life (t ½ h), volume of distribution (V z), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD. RESULTS: Isavuconazole C max values were 4% higher in mild RI and 7, 14, and 21% lower in participants with moderate RI, severe RI, or ESRD versus the healthy control group, respectively. When hemodialysis occurred post-dose (day 15), participants with ESRD had a 30% increase in AUC72 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC∞ and AUClast) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t1/2 (day 1) was 125.5 ± 63.6 h (healthy control group), 204.5 ± 82.6 h (ESRD group) in part 1, and 140.5 ± 77.7 h (healthy control group), 117.0 ± 66.2 h (mild RI), 158.5 ± 56.4 h (moderate RI), and 145.8 ± 65.8 L/h (severe RI) in part 2. CL was 2.4 ± 0.8 L/h (healthy control group) and 2.9 ± 1.3 L/h (ESRD group) in part 1 and 2.4 ± 1.2 L/h (healthy control group), 2.5 ± 1.0 L/h (mild RI), 2.2 ± 0.8 L/h (moderate RI), and 2.4 ± 0.8 L/h (severe RI) in part 2. The V z was 382.6 ± 150.6 L in the healthy control group and 735.6 ± 277.3 L in ESRD patients on day 1 in part 1 of the study. In part 2 of the study, V z was 410.8 ± 89.7 L in the healthy control group, 341.6 ± 72.3 L in mild RI, 509.1 ± 262.2 L in moderate RI, and 439.4 L in severe RI. CONCLUSIONS: Based on the findings of this study, dose adjustments of isavuconazole are unlikely to be required in individuals with RI or in those with ESRD who receive hemodialysis.

Special Populations in Clinical Pharmacology Studies: Evolving Challenges.

The clinical research industry is changing, and the number of protocols requiring specialty populations for early-phase clinical studies is increasing. In particular, the demand for studies on renal specialty populations has grown, given the prominent role of the renal system in excreting drugs from the body. Understanding the challenges associated with the use of specialty populations is critical to ensure that the study design will allow for the timely and successful completion of the project, while minimizing costs and safety risks.

Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus.

BACKGROUND: Uremic pruritus is a common and deleterious condition among hemodialysis (HD) patients. Central gating of µ/κ opiate circuitry plays an important role in mediating and countering pruritogenic sensation. The objective of this study was to assess the safety and pharmacokinetics (PK) of the mixed µ-antagonist/κ-agonist nalbuphine, administered orally as nalbuphine HCl extended release (ER) tablets in HD patients, and explore its effect on pruritus. METHODS: In this open-label multiple escalating dose study, 15 HD patients with pruritus and 9 matched healthy subjects were enrolled. Nalbuphine HCl ER dose was escalated from 30 mg QD to 240 mg BID over 15 days. A full PK profile was obtained under dialysis and non-dialysis conditions as a function of dose. Clearance during dialysis was determined by sampling dialysate and arterial/venous blood during dialysis. Pruritus severity was assessed twice daily using a Visual Analog Scale (VAS). Safety monitoring included extensive monitoring of EKG, blood pressure, and pulse oximetry. RESULTS: In HD patients, nalbuphine concentration peaked within 4-9 hours and attained steady state within 2-3 days, with no significant accumulation. Mean half-life was 14.2 hours, mean Cmax and AUCtau ranged between 13 and 83 ng/mL and 118 and 761 ng∙h/mL, respectively, with exposure increasing in a nearly dose-proportional fashion. Exposure in HD patients was about 2-fold higher than in healthy subjects. There was no meaningful difference between exposure on dialysis and non-dialysis days with 1% or less of the dose removed by dialysis. Nalbuphine suppressed itch in a dose-dependent manner, reducing mean VAS score from 4.0 to 1.2 at 180 mg and 0.4 at 240 mg. CONCLUSIONS: Nalbuphine HCl ER tablets can be safely administered to HD patients without dose adjustment up to 240 mg BID and may hold promise in treating uremic pruritus.

Pharmacokinetics and pharmacodynamics of pegloticase in patients with end-stage renal failure receiving hemodialysis.

AIMS: Phase 3 trial data indicate that treatment of chronic tophaceous gout with pegloticase, a recombinant uricase conjugated to polyethylene glycol, does not reduce estimated glomerular filtration rate in chronic kidney disease (CKD) patients and that pegloticase therapeutics are independent of CKD stages 1 - 4. We determined the pharmacokinetics/pharmacodynamics of pegloticase after a single-dose in non-gout subjects with stage 5 CKD receiving hemodialysis. METHODS: In this open-label phase 1 study, 12 subjects received a single intravenous dose of pegloticase 8 mg 3 hours prior to hemodialysis. Blood samples for determination of serum pegloticase concentrations and serum uric acid (SUA) levels were collected immediately predose and at regular intervals before, during, and after hemodialysis. RESULTS: Mean serum pegloticase concentrations remained stable and were unaffected by dialysis sessions. Mean SUA fell to undetectable levels within 3 hours and remained undetected for up to 72 hours postdose. CONCLUSION: Our findings indicate no significant effect of hemodialysis on either the stability of serum pegloticase concentrations after a single dose or the capacity of pegloticase to lower SUA. No new safety signals were detected. Administration of pegloticase in patients with comorbid chronic tophaceous gout and endstage renal failure requiring hemodialysis appears feasible.

Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment.

BACKGROUND: Daclatasvir (DCV) is a pangenotypic inhibitor of the HCV NS5A replication complex approved in Japan and Europe for combination treatment of HCV. AI444-063 was an open-label, two-stage, adaptive study assessing DCV pharmacokinetics and safety in HCV-uninfected subjects with renal impairment. METHODS: Stage 1 included 12 subjects with end-stage renal disease (ESRD) on dialysis and 12 healthy controls (creatinine clearance [CLcr]≥90 ml/min, Cockcroft-Gault) matched by sex, age and weight. All participants received a single DCV 60-mg dose on day 1. DCV plasma levels were measured through day 4. Prespecified criteria for study expansion (ESRD versus control area under the curve extrapolated to infinite time [AUC∞] geometric mean ratio [GMR] upper 90% CI>1.5) were met; therefore, 12 subjects with moderate or severe renal impairment (estimated glomerular filtration rate, 30-59 and 15-29 ml/min/1.73m(2), respectively) were included in stage 2. RESULTS: All 36 participants (30 male, mean age 54 years) completed the study. DCV AUC∞ was higher in ESRD subjects versus controls (GMR 1.264, 90% CI 0.989, 1.616). Compared with normal CLcr (90 ml/min), GMR and 90% CI for unbound DCV AUC∞ at CLcr 60, 30 and 15 ml/min were 1.18 (1.07, 1.30), 1.39 (1.14, 1.70) and 1.51 (1.18, 1.94), respectively. DCV was generally well tolerated in subjects with normal renal function, ESRD, or moderate or severe renal impairment. CONCLUSIONS: Observed DCV exposure increases were within the normal range of variability and were not associated with an elevated risk of adverse events. DCV can be administered in subjects with renal impairment, including ESRD, without dose modification. ClinicalTrials.gov NCT01830205.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects.

INTRODUCTION: The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models. METHODS: Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively. RESULTS: Nebulized sodium nitrite was well tolerated following 6 days of every 8 h administration up to 90 mg, producing significant increases in circulating Hb(Fe)-NO, R-SNO, and FENO. Pulmonary absorption of nitrite was rapid and complete, and plasma exposure dose was proportional through the MTD dosage level of 90 mg, without accumulation following repeated inhalation. At higher dosage levels, DLTs were orthostasis (observed at 120 mg) and hypotension with tachycardia (at 176 mg), but venous methemoglobin did not exceed 3.0 % at any time in any subject. Neither the tolerability nor pharmacokinetics of nitrite was impacted by conditions of mild hypoxia, or co-administration with sildenafil, supporting the safe use of inhaled nitrite in the clinical setting of PAH. CONCLUSION: On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients.

Pharmacokinetics of vilazodone in patients with mild or moderate renal impairment.

BACKGROUND AND OBJECTIVE: In patients with impaired renal function, the pharmacokinetics of a drug may be altered, resulting in decreased renal excretion or metabolism, and altered absorption, plasma protein binding or distribution. Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder. Vilazodone is extensively hepatically metabolized with minimal renal excretion. The primary objective of this study was to assess the pharmacokinetics of a single 20-mg dose of vilazodone in subjects with mild or moderate renal impairment. METHODS: This was a Phase 1, open-label, single-dose study of vilazodone in community-dwelling subjects with renal impairment and in healthy subjects to evaluate the pharmacokinetics of vilazodone in the presence of renal impairment. Thirty-two subjects were enrolled: eight subjects with mild (estimated glomerular filtration rate [est GFR] >50-80 mL/min) renal impairment matched individually by age, sex and body mass index to eight control subjects with normal renal function (est GFR >80 mL/min), and eight subjects with moderate (est GFR ≥30-50 mL/min) renal impairment matched with eight control subjects with normal renal function. Subjects received a single, 20-mg dose of vilazodone and pharmacokinetics, safety and plasma protein binding were assessed for 14 days. The pharmacokinetic parameters calculated were maximum plasma concentration (Cmax), time to maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time zero to 24 h, AUC from time zero to the last measurable concentration, AUC from time zero to infinity estimated by linear trapezoidal rule and extrapolation, oral clearance, terminal elimination rate constant, elimination half-life (t½), free fraction in plasma, apparent free drug clearance, amount of vilazodone recovered in urine 0-96 h following drug administration, percent of dose recovered in urine over 96 h following drug administration, renal clearance and volume of distribution. Safety assessments were adverse events, clinical laboratory test results, 12-lead electrocardiograms and vital signs. RESULTS: Vilazodone pharmacokinetic parameters in renally impaired subjects were variable but not substantially different from healthy controls. Mean values for vilazodone Cmax and AUC were similar among groups. Mean t½ (35.7 and 34.8 h mild and moderate vs. 37.0 and 34.8 h matched controls), total drug clearance (19.9 and 25.1 L/h vs. 26.4 and 26.9 L/h), and mean vilazodone recovery in urine (1.21 % and 0.58 % vs. 0.95 % and 0.81 %) were similar for mild and moderate renally impaired subjects and matched controls with normal renal function. There were no apparent systematic trends in vilazodone pharmacokinetic parameters associated with decreasing renal function. Protein binding was variable (coefficient of variation, 29-65 %) but not substantially different among the three groups, and total drug clearance was not affected. Safety and tolerability of vilazodone were comparable in all groups of subjects. CONCLUSION: This study suggests that systemic exposure of vilazodone is not affected by mild or moderate renal impairment. No dose adjustments are recommended in patients with mild or moderate renal impairment.

The pharmacokinetics of PF-734200, a DPP-IV inhibitor, in subjects with renal insufficiency.

AIMS: PF-734200 is a potent, selective inhibitor of DPP-IV. This two-part study evaluated the pharmacokinetics (PK) of oral 20mg PF-734200 in subjects with varying degrees of renal insufficiency or with end-stage renal disease (ESRD) requiring chronic haemodialysis (HD). The study also assessed the HD clearance of PF-734200 in ESRD. METHODS: Part 1 included subjects with normal renal function or renal insufficiency but not on HD. Subjects received a single dose of 20mg PF-734200 while fasting and serum and urine samples were collected. In part 2, period 1, 1h after HD, a single 20-mg dose was given to subjects with ESRD and serum samples were collected. After a 7-day washout, subjects received another dose followed by collection of serum samples (period 2), during which HD was initiated 4h after dosing. Dialysate samples were collected to quantify amount of drug removed, from which HD clearance was calculated. The fraction of drug dialysed was calculated using an AUC-based method. RESULTS: Systemic exposures of PF-734200 increased approximately 1.5-, 2.2-, 2.1- and 2.8-fold in subjects with mild, moderate, or severe renal insufficiency or ESRD, respectively, compared with subjects with normal renal function. The terminal half-life increased from 16.2h in subjects with normal renal function to 36.6h in subjects with ESRD. Approximately, 29% of PF-734200 in the body after a single-dose administration was dialysed by 4h HD. CONCLUSIONS: Systemic exposure of PF-734200 increases with decreasing renal function. The effect of HD on drug removal is modest.

Analytical and biological variation in measures of anemia and iron status in patients treated with maintenance hemodialysis.

BACKGROUND: To make informed decisions in dosing erythropoiesis-stimulating agents and intravenous iron therapy, clinicians must determine whether differences between current and previous test results for anemia and iron status markers reflect expected variation, a significant change, or an actual trend. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 30 patients undergoing thrice-weekly in-center hemodialysis. PREDICTOR: Within-patient biological variations in hemoglobin (Hb) level, hematocrit (Hct), reticulocyte Hb content, transferrin saturation (TSAT), and ferritin level were determined over 12 consecutive treatment days. OUTCOMES & MEASUREMENTS: We separately measured same-sample analytical variation and within-patient biological variation (coefficient of variation), then calculated the number of sampling days needed to determine the true or homeostatic value for each analyte with 95% probability. We also evaluated whether results differed among the first, second, and third dialysis days of the week. RESULTS: Biological variation differed by analyte. Hb level (4.0%), Hct (4.0%), and reticulocyte Hb content (4.8%) showed much lower variation than TSAT (38.2%) or ferritin level (15.1%). Analytical variation ranged from 2.0%-6.9% for all analytes. We found that one sample day would be sufficient to establish the true mean Hb level or Hct within a level of closeness+/-20% and 95% probability. For the same levels of closeness and probability, one sample day would be needed for reticulocyte Hb content, 15 for TSAT, and 3 for ferritin level. No pairwise comparison for any of the 5 analytes yielded a significant difference between results obtained on the first, second, or third dialysis day of the week. LIMITATIONS: These findings may not apply to other patient populations. CONCLUSIONS: Low biological variation renders Hb level, Hct, and reticulocyte Hb content, but not TSAT and ferritin level, suitable for trend analysis using results from 2 successive samples. TSAT and ferritin test results, unlike reticulocyte Hb content, have limited value in evaluating changes in iron status within individual hemodialysis patients.

Examination of association with candidate genes for diabetic nephropathy in a Mexican American population.

BACKGROUND AND OBJECTIVES: Diabetic nephropathy (DN) is a multifactorial complication characterized by persistent proteinuria in susceptible individuals with type 1 and type 2 diabetes. Disease burden in people of Mexican-American descent is particularly high, but there are only a few studies that characterize genes for DN in this ethnic group. Two genes, carnosine dipeptidase 1 (CNDP1) and engulfment and cell motility 1 (ELMO1) previously showed association with DN in other ethnic groups. CNDP1 and ELMO1 were examined along with eight other genes that are less well characterized for DN in a new study of Mexican-Americans. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The target sample was patients of Mexican-American ancestry collected from three centers: 455 patients with DN and 437 controls with long-term diabetes but no incident nephropathy. Forty-two, 227, and 401 single nucleotide polymorphisms (SNPs) in CNDP1, ELMO1, and the other eight genes, respectively, were examined. RESULTS: No region in CNDP1 or ELMO1 showed significant P values. Of the other eight candidate genes, an association of DN with a SNP pair, rs2146098 and rs6659783, was found in hemicentin 1 (HMCN1) (unadjusted P = 6.1 x 10(-5)). Association with a rare haplotype in this region was subsequently identified. CONCLUSIONS: The associations in CNDP1 or ELMO1 were not replicable; however, an association of DN with HMCN1 was found. Additional work at this and other loci will enable refinement of the genetic hypotheses regarding DN in the Mexican-American population to find therapies for this debilitating disease.

A pharmacokinetics evaluation of a new, low-volume, oral sulfate colon cleansing preparation in patients with renal or hepatic impairment and healthy volunteers.

The pharmacokinetics (PK) of an oral sulfate solution (OSS) for bowel cleansing preparation was studied. OSS (30 g of sulfate) was split between 2 doses, 12 hours apart. Safety measures included electrocardiography, vital signs, adverse events, hematology, blood chemistry, and urinalysis. Six adult patients with moderate renal disease (MRD), 6 with mild-moderate hepatic disease (M/MHD), and 6 normal healthy volunteers (NHVs) completed the study. Adverse events were mild to moderate in severity and were mainly limited to headache and expected gastrointestinal symptoms. Serum sulfate levels were highly variable at all times, even after adjusting for baseline. Sulfate was higher in MRD in comparison to the other groups. The C(max) and AUC were higher in the patients, but no statistically significant differences emerged. Sulfate levels returned to predose values within 54 hours after dosing. No electrolyte disturbances occurred. Urinary sulfate excretion was approximately 20% of the dose. OSS was well tolerated. The types and severity of adverse events were similar to those seen in large phase III trials. While patients with MRD had elevated sulfate, the levels were less than those in renal failure and did not alter biochemical parameters that are associated with hypersulfatemia.

Pharmacokinetics of telbivudine in subjects with various degrees of hepatic impairment.

This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.

Pharmacokinetic profile of rizatriptan 10-mg tablet and 10-mg orally disintegrating tablet administered with or without water in healthy subjects: an open-label, randomized, single-dose, 3-period crossover study.

This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC(0-2h) than ODTs and that ODTc has a greater geometric mean AUC(0-1h) than tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (t(max)) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC(0-2h) compared with ODTs (33.84 h x ng/mL vs 18.83 h x ng/mL; P < .001). ODTc had a slightly, but not statistically significantly, greater geometric mean AUC(0-1h) compared with rizatriptan tablet (17.07 h x ng/mL vs 13.32 h x ng/mL). The median t(max) was 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting.

Revisiting mortality predictability of serum albumin in the dialysis population: time dependency, longitudinal changes and population-attributable fraction.

BACKGROUND: Hypoalbuminaemia is a marker of malnutrition-inflammation complex syndrome (MICS) and a strong predictor of cardiovascular (CV) death in maintenance haemodialysis (MHD) patients. However, serum albumin may change over time. Hence, its time-varying associations with outcome may be different. METHODS: Associations between 3-month averaged serum albumin levels, measured in a single laboratory using bromocresol green, and CV mortality were studied longitudinally in a 2-year cohort of 58,058 MHD patients. Mortality predictability of fixed baseline and trimonthly-varying serum albumin concentrations were compared. RESULTS: Hazard ratios (HRs) of CV death strictly increased across decrements of baseline serum albumin, whereas the HR for time-varying serum albumin decrements below 3.8 g/dl did not differ. A drop in serum albumin in the first 6 months was associated with increasing all-cause and CV death risks in the subsequent 18 months, while a rise in serum albumin was a predictor of better survival independent of baseline serum albumin. The multivariate adjusted population-attributable fraction of death due to baseline serum albumin <3.8 g/dl was 19%. CONCLUSIONS: Time-varying hypoalbuminaemia predicts all-cause and CV death differently from fixed measures of serum albumin in MHD patients. An increase in serum albumin over time is associated with better survival independent of baseline serum albumin or other MICS surrogates. If this association is causal, an intervention that could increase serum albumin >3.8 g/dl might reduce the number of MHD deaths in the USA by approximately 10,000 annually. Nutritional interventions examining benefits of increasing serum albumin in MHD patients are urgently needed.

Pharmacokinetics of etoricoxib in patients with renal impairment.

The effect of renal insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was examined in 23 patients with varying degrees of renal impairment (12 moderate [creatinine clearance between 30 and 50 mL/min/1.73 m2], 5 severe [creatinine clearance below 30 mL/min/1.73 m2], and 6 with end-stage renal disease requiring hemodialysis) following administration of single 120-mg oral doses of etoricoxib. Even the most severe renal impairment was found to have little effect on etoricoxib pharmacokinetics. The low recovery of etoricoxib in dialysate (less than 6% of the dose) supports that hemodialysis also has little effect on etoricoxib pharmacokinetics, and binding of etoricoxib to plasma proteins was generally unaffected by renal disease. Single doses of etoricoxib were generally well tolerated by patients with renal impairment. Based on pharmacokinetic considerations, dosing adjustments are not necessary for patients with any degree of renal impairment. However, because patients with advanced renal disease (creatinine clearance below 30 mL/min/1.73 m2) are likely to be very sensitive to any further compromise of renal function, and there is no long-term clinical experience in these patients, the use of etoricoxib is not recommended in patients with advanced renal disease.