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.

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.

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.

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.