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Delafloxacin Pharmacokinetics in Subjects With Varying Degrees of Renal Function.

ABSTRACT: 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 ?g·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).

SUBMITTER: Hoover RK

PROVIDER: S-EPMC5901045 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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Delafloxacin Pharmacokinetics in Subjects With Varying Degrees of Renal Function.

Hoover Randall K RK Alcorn Harry H Lawrence Laura L Paulson Susan K SK Quintas Megan M Cammarata Sue K SK

Journal of clinical pharmacology 20171218 4

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, ...[more]

PMID: 29251785

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Project description:Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobin A1c (HbA1c), body weight, BP, and albuminuria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies suggest that the HbA1c-lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascular risk factors at different eGFR levels are incompletely understood.This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creatinine ratio with placebo (n=2178) or dapagliflozin 10 mg (n=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR?45 to <60 ml/min per 1.73 m2, eGFR?60 to <90 ml/min per 1.73 m2, and eGFR?90 ml/min per 1.73 m2).Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecutive lower eGFR subgroup (P value interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects potentially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ?30 mg/g, placebo-adjusted reductions in urinary albumin-to-creatinine ratio were larger in the lowest eGFR subgroup (P value interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebo-treated patients.The HbA1c-lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albumin-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for volume contraction, suggest that the effects of dapagliflozin are partly mediated via nonglucosuric-dependent mechanisms.

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Delafloxacin Pharmacokinetics in Subjects With Varying Degrees of Renal Function.

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Delafloxacin Pharmacokinetics in Subjects With Varying Degrees of Renal Function.

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