Pharmacokinetics of sparfloxacin in patients with renal impairment.
Sparfloxacin is a fluoroquinolone antimicrobial agent with a broad spectrum of activity and long elimination half-life. Because its single-dose pharmacokinetics are altered by renal impairment, the present study was undertaken to determine the effects of moderate or severe renal insufficiency on the multidose pharmacokinetic characteristics of and tolerance to sparfloxacin. The pharmacokinetic characteristics of sparfloxacin were assessed in 32 subjects (15 men, 17 women) with (1) normal renal function (creatinine clearance [CLcr]> or = 250 mL/min per 1.73 m2) and a mean age of 52.6 years and mean weight of 70.4 kg; (2) moderate renal insufficiency (CLcr 30-49 mL/min per 1.73 m2) and a mean age of 54.4 years and mean weight of 67.8 kg; and (3) severe renal insufficiency (CLcr 10-29 mL/min per 1.73 m2) and a mean age of 50.8 years and mean weight of 73.1 kg. The first 2 groups received a 400-mg loading dose on day 1 followed by 200 mg once daily for 9 days; subjects with severe renal insufficiency received a 400-mg loading dose on day 1 followed by 200 mg every 48 hours on days 3, 5, 7, and 9. The plasma and urinary pharmacokinetics of sparfloxacin and its glucuronide metabolite were determined after the last dose. All subjects were monitored for changes in the corrected QT (QTc) interval and for adverse events. Renal insufficiency altered the steady-state pharmacokinetic variables of sparfloxacin and its glucuronide metabolite, reducing their renal clearances and increasing both maximum plasma concentration and area under the plasma concentration-time curve. Mean steady-state plasma sparfloxacin concentrations in subjects with severe renal insufficiency (48-hour dosing interval) were comparable to those in subjects with normal renal function (24-hour dosing interval). However, mean plasma sparfloxacin concentrations in patients with moderate renal insufficiency were 2 to 3 times greater than the corresponding concentrations in subjects with normal renal function receiving the same dosage regimen. The QTc interval was slightly increased in all groups (the greatest increases were 14, 14, and 6 milliseconds in the groups with normal renal function and moderately and severely impaired renal function, respectively, at 5.5 hours post-dose on day 9 or 10) but similar among subjects with normal renal function or with renal insufficiency. Sparfloxacin was well tolerated. Thus sparfloxacin clearance is reduced and plasma concentrations raised by moderate or severe renal insufficiency. These increases do not appear to augment drug effects on the QTc interval or enhance the risk for adverse events. These results suggest that alternate-day dosing (48-hour dosing interval) following a double loading dose on day 1 should be used in patients with severe renal insufficiency and may be appropriate for patients with moderate renal insufficiency.
Dorr
M B
MB
Rhône-Poulenc Rorer, Collegeville, Pennsylvania 19426-0107, USA.
Johnson
R D
RD
Jensen
B
B
Magner
D
D
Marbury
T
T
Talbot
G H
GH
D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones; D020719:Glucuronides / Q000032:analysis* / Q000097:blood / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000145:classification / Q000378:metabolism*; D013997:Time Factors
D000890:Anti-Infective Agents; D000995:Antitubercular Agents; D024841:Fluoroquinolones; D020719:Glucuronides; C061363:sparfloxacin