Pharmacokinetics of sparfloxacin in patients with renal impairment

CLINICAL

THERAPEUTICS

Pharmacokinetics Impairment

“/VOL. 2 I, NO. 7, I999

of Sparfloxacin in Patients with Renal

Mary Beth Dorr, PhD,’ Robert D. Johnson, PhD,‘J Bradford Jensen, PhD,’ David Magner, MS,‘J Thomas Marbury, MD: and George H. Talbot, MD1 ‘RhBne-Poulenc Rarer, Collegeville, Pennsylvania, 2Lilly Laboratory jbr Clinical Research, Indianupolis, Indiana, -‘Astra Pharmuceuticals, Wayne, Pennsylvaniu, and 40rlando Clinical Research Center, Orlando, Florida

ABSTRACT 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 (I 5 men, 17 women) with (1) normal renal function (creatinine clearance [CL,,] 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 (CL,, 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 lo-29 mL/min per 1.73 m2) and a mean age of 50.8 years and Accepted for publication April 26. 1999. Prlnted in the USA. Reproduction in whole or part IS not permitted.

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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 spaffloxacin and its glucuronide metabolite were determined after the last dose. All subjects were monitored for changes in the corrected QT (QTJ 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 0119.2918/99/$19.00

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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 postdose 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. Key words: sparfloxacin, pharmacokinetics, renal impairment, maximum plasma concentration. INTRODUCTION The fluoroquinolones are broad-spectrum synthetic antibiotics whose inhibition of DNA gyrase represents a unique mechanism of antibacterial action. Although highly active against most Enterobacteriaceae, fastidious gram-negative bacilli, and gram-negative cocci,‘,* older fluoroquinolones such as ofloxacin, ciprofloxatin, and norfloxacin have significant limitations. In particular, their activity is relatively poor against clinically important streptococci, enterococci, and anaerobes,lm3 and their elimination half-lives (t,,,) are relatively short, necessitating multiple daily dosing! This requirement may significantly reduce compliance with

oral regimens and thus potentially compromise therapeutic outcome.5” Sparfloxacin is a fluoroquinolone antimicrobial agent with characteristics that distinguish it from older drugs in its class. Excellent antibacterial activity has been observed against Enterobacteriaceae6,7 and clinically important gram-positive aerobes, particularly Streptococcus pneumoniue.7*x Sparfloxacin exhibits excellent tissue penetration, with tissue-to-serum ratios generally >l 9,10; its 16- to 22-hour t,,, permits once-daily dosing.” The pharmacokinetic characteristics of sparfloxacin have been studied extensively in patients and healthy volunteers.” In persons with normal kidney function, plasma concentrations of sparfloxacin reach a peak of 1.2 to 1.5 mg/L between 3 and 6 hours after a single 400-mg dose, with a t,,, of between 16 and 22 hours. Approximately 10% of an administered dose is excreted in urine as unchanged drug and 21% to 38% as its glucuronide metabolite. Biliary excretion of sparfloxacin and its metabolite account for 1.5% and 11 .O%, respectively, of the dose administered. The most likely pathways of elimination for the remaining administered dose are transintestinal secretion, followed by fecal excretion. Similar results have been reported after multidose administration.” Only 1 single-dose study’* has assessed the effects of renal impairment (creatinine clearance [CLJ ~30 mlimin) on the pharmacokinetics of sparfloxacin. In that study, the terminal elimination t,,, in patients with CLcr ~30 mL/min was shown to be twice that in subjects with normal renal function. However, the study was noncomparative and did not include patients with CLcr >30 mL/min. The present study was undertaken to compare the multidose pharmacokinetics 1203

CLINICAL

of sparfloxacin in healthy volunteers with those in patients with various degrees of renal impairment. Based on results of the earlier study,t2 patients with severe renal impairment were dosed every 4X hours in an attempt to provide a concentration-time profile that would be similar to that in normal volunteers. PATIENTS AND METHODS Thirty-two volunteers (15 men, 17 women) aged 218 years were enrolled in this open-label, multidose, single-center trial. The women were neither pregnant nor lactating and were either postmenopausal, surgically sterilized, or using an accepted form of birth control. Participants had stable renal function and no contraindications to sparfloxacin based on the results of a detailed medical and surgical history and complete physical examination. The examination included measurement of vital signs (systolic and diastolic blood pressure, heart rate, temperature), a 12-lead electrocardiogram (ECG), hematology (hemoglobin, total and differential white blood cell [WBC] counts, platelet count), blood chemistry (creatinine, blood urea nitrogen, glucose, total protein, albumin, total bilirubin, alkaline phosphatase, aminotransferase, calcium, magnesium, sodium, chloride, potassium, HIV- 1 antibody, hepatitis A surface antigen, hepatitis C antibody, serum beta human chorionic gonadotropin [in women], amylase, lipase, lactic dehydrogenase), urinalysis (dipstick for protein and glucose, casts, epithelial cells, WBCs, red blood cells, crystals), and urine screen for drugs of abuse. Body weights were within + 30% of normal, as determined from the 1983 Metropolitan Life Bulletin.‘” 1204

THERAPEUTICS”

All volunteers provided written informed consent, and the protocol and informed-consent statement were approved by the local institutional review board. Exclusion criteria were as follows: history of or positive results on serologic testing for hepatitis B surface antigen or HIV antibody; evidence of active hepatitis C infection, congenital long-QT syndrome, seizures, neoplastic disease, or any other chronic disease that could adversely affect safety or interfere with study conduct; current drug addiction or alcoholism; participation in any investigational drug study or donation of blood within the preceding 8 weeks; history of intolerance, allergy, or phototoxic reaction to any quinolone product; unwillingness or inability to complete all treatment days; baseline corrected QT (QTJ interval >500 milliseconds; use of antiarrhythmic or other drugs known to cause QT prolongation; need for hemodialysis or chronic ambulatory peritoneal dialysis; salt-losing nephritis; and need for sucralfate or medications containing bivalent cations within 8 hours before and 4 hours after each dose of sparfloxacin. Volunteers were withdrawn from the study after enrollment for protocol deviation, QTc interval >550 milliseconds, deterioration in renal function, or a treatment-limiting adverse event. Subjects were admitted to the research unit for 24 hours during the screening phase for collection of urine for CLcr determination and for approximately 36 hours during the study for pharmacokinetic sampling and ECG assessments. Ambulatory 24hour CLcr was determined at screening and on day 9 (subjects with severe renal insufficiency) or day 10 (control subjects and those with moderate renal insufficiency). Participants were confined to the study unit for this measurement and were instructed

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to void completely and collect all urine over the subsequent 24 hours. Total urine volume was recorded for each sub-ject,and a IO-mL aliquot was retained for creatinine determination; blood was obtained on the same day for determination of serum creatinine. The observed CLc, (mL/min) was calculated as: Urine

creatinine Serum

(mg/dL)

creatinine

x 24-h urine volume (mg/dL)

(mL)

x 1440 min

On the basis of screening values for CLcr (corrected to a body surface area of 1.73 m*), subjects were assigned to 1 of 3 groups: normal renal function (CLc, 2.50 mL/min per 1.73 m2), moderate renal insufficiency (CLcr 30 to 49 mL/min per 1.73 m2), or severe renal insufficiency (CLcr 10 to 29 mL/min per 1.73 m2). Each control volunteer was matched by age (+ 5 y), weight (+ lo%), and sex to a subject with moderate or severe renal insufficiency. Spaffloxacin 200-mg tablets were taken in the morning with 240 mL of water according to the following schedule: subjects with normal renal function and those with moderate renal insufficiency 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. Water was allowed as desired throughout the study; milk and yogurt products were excluded from breakfast and lunch on dosing days. On days 9 and 10 (patients with severe renal insufficiency) and on day 10 (control subjects and those with moderate renal insufficiency) a standardized continental breakfast was served 1 hour before dosing; lunch and dinner were

served 4 and 10 hours after dosing. Snacks were available at approximately 3 PM and 10 PM. All standardized meals and snacks, which were selected by patients and approximated the normal American diet, were served after any concurrently scheduled phlebotomy or ECG. Blood samples for determination of sparfloxacin and spaffloxacin glucuronide pharmacokinetics were obtained by direct, individual venipuncture (no indwelling catheters were used) before and 2 and 4 hours after dosing on days 1 and 5; before drug administration on days 3 (subjects with severe renal insufficiency only), 7 (all groups), and 8 and 9 (controls and subjects with moderate renal insufficiency only); and at the following times relative to the final dose: predose and 0.5, 1,2,3,4,6,8,12,16,24,36,48, 72, and 96 hours postdose in all groups and 120 hours postdose in subjects with severe renal insufficiency. Heparinized blood samples (10 mL) were centrifuged for 10 to 15 minutes at 4°C and 2000 to 3000 ‘pm. The plasma fraction was then stored at -2OOC until assayed. Urine samples for determination of sparfloxacin and sparfloxacin glucuronide pharmacokinetics were obtained before drug administration on day 1 and at 24hour increments through 96 hours after the last dose (controls and subjects with moderate renal insufficiency) or through 120 hours after the last dose (those with severe renal insufficiency). Urine (10 mL) was stored at -2O’C until assayed. Plasma and urine samples were assayed for spaffloxacin concentrations by means of validated high-performance liquid chromatography with ultraviolet detection at 360 nm.‘* The total sparfloxacin concentration (free sparfloxacin plus sparfloxacin glucuronide) was measured us1205

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ing the same method after alkaline hydrolysis of sparfloxacin glucuronide.‘* Plasma sparfloxacin glucuronide concentrations were reported as the difference between the total and unchanged sparfloxacin concentrations. The linearity range for the plasma assay was 0.025 to 20 kg/mL, and the lower limit of quantitation was 0.025 pg/mL. The accuracy of the assay, determined by the percentage of difference between the measured and nominal concentrations, varied within the range -3.8% to -0.87%. The precision of the assay, established by the coefficients of variation of control samples, ranged from 2.8% to 7.4%. The linearity range for the urine assay was 0.25 to 100 kg/mL, and the lower limit of quantitation was 0.25 FgimL. Accuracy varied within the range -6.5% to 4.2%, and precision ranged from 4.6% to 15.8%. The maximum steady-state plasma concentrations (C,,X) for sparfloxacin and sparfloxacin glucuronide and the time to Cmax(T,,,) were determined directly from the observed plasma concentration-time profile after the last dose. Terminal elimination rate constants (km,,,) were determined by linear regression of the logarithm of the terminal portion of the plasma sparfloxacin concentration-time profile. The harmonic mean terminal t,,* was calculated as 0.693imean kterm.Linear trapezoidal summation was used to calculate the area under the steady-state plasma sparfloxacin and sparfloxacin glucuronide concentration-time profile over a specific dosing interval (7) (AUC&. Average steady-state concentrations (Cay,) for spaffloxacin and sparfloxacin glucuronide were calculated as AU&/r. For control subjects and those with moderate renal insufficiency, r = 24 hours; for those with severe renal insufficiency, r = 48 hours. 1206

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Steady-state renal clearance (CLJ for sparfloxacin and sparfloxacin glucuronide was calculated as Ae,JAUC,-7, where was the amount of unchanged Ae0-7 sparfloxacin and sparfloxacin glucuronide excreted in the urine at steady state over the dosing interval. Complete physical examinations were performed at screening and at the end of the study. Systolic and diastolic blood pressure and heart rate were assessedmanually from the same arm after ~10 minutes of seated rest at screening; on days 1 (predose), 9 (subjects with severe renal insufficiency), or 10 (controls and those with moderate renal insufficiency); and at discharge or dropout. Laboratory assessments, including serum chemistry, hematology, and urinalysis, were performed at the same times. A 12-lead ECG, double speed (50 mm/s) and double amplitude (20 mV), was performed at screening and at the end of the study or dropout, as well as before and 1.5, 3.5, and 5.5 hours after the sparfloxacin dose on days 1,5, and 9 (subjects with severe renal insufficiency) or 10 (controls and those with moderate renal insufficiency). Each ECG was performed by machine after the subject had been at undisturbed supine rest for 210 minutes. The predose ECG was performed before scheduled phlebotomy; postdose tracings were made ~20 minutes afterward. A 30-second rhythm strip (lead II) was also obtained. QT interval, the primary ECG variable analyzed, was corrected for heart rate (QTJ using Bazett’s correction,‘” which adjusts the QT interval by dividing it by the square root of the RR interval. The formula is as follows: QTc-,, = QT/(RR)“*

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All adverse events reported during study therapy were recorded. Use of concomitant medications was also recorded. Compliance was assessed by accounting for all unused study medication at the conclusion of the study. Statistical Analysis Statistical analysis of steady-state sparfloxacin and spaffloxacin glucuronide pharmacokinetic variables in plasma and urine was performed by multiple stepwise regression using the General Linear Models procedure within SAS version 6.08 (SAS Institute, Cary, North Carolina). Pharmacokinetic variables were regressed against body weight, sex, and CLc,, and the significance of these independent variables was assessed from the P value by means of the type III sum of squares at an CL level of 0.10. Descriptive statistics (mean + SD, range) were used to #summarize vital signs, ECG findings, and clinical laboratory data. Because of the small size of each group, ECG results were not compared statistically. RESULTS Demographic Characteristics There were a total of 14 subjects with normal renal function (6 men and 8 women; mean age, 52.6 years; mean weight, 70.4 kg); 8 subjects with moderate renal insufficiency (4 men and 4 women; mean age, 54.4 years; mean weight, 67.8 kg); and 8 subjects with severe renal insufficiency (3 men and 5 women; mean age, 50.8 years; mean weight, 73.1 kg). Of the 32 enrolled subjects, 30 completed all study procedures. One subject with moderate renal insufficiency discontinued pre-

maturely-on day 1 -because of an adverse event (moderate anaphylactic reaction) after administration of the sparfloxacin loading dose. Another subject was discontinued after 1 day of study participation because he was a normal match for the subject who withdrew. Demographic characteristics were comparable in each group (Table I). Two subjects with normal renal function and 1 subject with mild renal insufficiency did not appear to be at steady state on or before the day of the last multiple oral dose of study drug (based on trough sparfloxacin concentrations) and were, therefore, excluded from pharmacokinetic analyses. Pharmacokinetics After multiple doses of sparfloxacin, the plasma concentration-time profile for subjects with severe renal insufficiency who received the drug at a 48-hour dosing interval was similar to that for control subjects with normal renal function who received the drug at a 24-hour dosing interval (Figure 1). Mean plasma sparfloxacin concentrations were approximately 2 to 3 times higher in those with moderate renal impairment than in control volunteers who received the same dose. Steady-state plasma pharmacokinetic variables for each group are summarized in Table II. The mean AUC,, for subjects with severe renal insufficiency was -67% higher than that for control subjects, although mean Cmaxvalues were comparable in the 2 groups. The 48-hour dosing interval in subjects with severe renal insufficiency produced a plasma sparfloxacin concentration-time profile comparable to that with the standard 24-hour dosing interval in subjects with normal renal function. Steady-state values of AUC,, and 1207

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THERAPEUTICS’

Table I. Demographic characteristics of enrolled subjects. Moderate Renal

Renal Function* (n = 14)

Normal

Variable

Severe Renal Insufficiency* (n = 8)

Insufficiency*

(n = 8)

Age (Y) Mean Range Sex, no. Male Female Weight at screening (kg) Mean Range Creatinine clearance (mL/min per 1.73 m2) at screening Mean Range

52.6 22-69

SO.8 36-67

54.4 28-72

6 8

4 4

3 5

70.4 52.2-87.5

67.8 45.8-85.3

73.1 57.2-96.6

82.9 50-106

38.6 33-47

17.0 IO-28

*Normal renal function: creatinine clearance 30 to 49 mL/min

(CLJ ~50 mL/min per I .73 m2: moderate renal insufficiency: renal insufficiency: CLcr 10 to 29 mL/min per 1.73 m?.

per 1.73 m2; severe

CLcr

+

Normal renal function (n = 12; T= 24 h) A Moderate renal insufficiency (n = 7; T = 24 h)

Severe renal insufficiency (n = 8; T = 48 h)

n

0

10

20

30

40

50

Time

60

70

80

90

100

110

120

(h)

Figure 1. Mean plasma sparfloxacin concentrations at the last 200-mg dose. T = dosing interval. 1208

M.B. DORR ET AL.

Table II. Mean (% coefficients of variation) steady-state plasma pharmacokinetic variables for sparfloxacin, by renal function status.

‘Variable

Normal Renal Function** (n = IZ)

i-w AUCsr (Fg/mL.h)

24 11.502 (32.2)

Cave QvWJ Cmax b4WJ “r,,, W km 0) bz (h)

0.479 (32.2) 0.750 (29.3) 5.9 pT.Uj 0.037 (34.4) 18.7

Moderate Renal Insufficiency*+ (n = 7) 24 25.397 (19.5)5 1.06 (19.5)5 1.46 (17.2)s 4.9 (3K4j 0.025 (32.6) 27.7

Severe Renal

Insufficiency’$ (n = 8) 46 19.2 (35.2)s 0.40 (35.2)s 0.800 (27.8) 6.3 (s^S.Uj+ 0.034 (53.9) 20.4

tion rateconstant;t,,* = eliminationhalf-life. “Mean values up to 24 h. ‘Normal renal function: creatinine clearance (CLo) z-50 mL/min per 1.73 m2; moderate renal insufficiency: 30 to 49 mL/min per 1.73 m*; severerenalinsufficiency:CLcrIOto 29 mL/min per 1.73 m2. ‘Mean vahes q7 x7 4% h. 8Significantlydifferentfrom the groupwith normal renal function(P < 0.05).

C mayfor subjects with moderate renal in-

sufficiency were approximately twice those noted in the control group. The t,,, was 18.7 hours in normal subjects, 20.4 hours in those with severe renal insufficiency, and 27.7 hours in subjects with moderate renal impairment. The surprisingly short t,,, in the group with severe renal insufficiency resulted from 2 subjects having unusually rapid sparfloxacin elimination rates of 9.7 and 13.6 hours. Subjects with severe renal insuftlciency excreted 4.0% sparfloxacin, compared with subjects with normal renal function (8.3%) or moderate renal insufficiency (9.2’%). The CLr of sparfloxacin decreased with a reduction in renal function (Table III). The t1,2 values derived from the urinary excretion rate data were comparable to those determined from the plasma concentration data. Figure 2 illustrates the cumulative urinary excretion of sparfloxacin in the 3 groups.

CLcr

Regression analysis of the steady-state values (Figure 3) demonstrated that AUCs7 was related to CLcr, and C,, was related to body weight. No other significant relations were observed between any subject characteristics and pharmacokinetic variables. The pharmacokinetic variables for sparfloxacin glucuronide are summarized in Table IV. Mean C,,, and AUC& in subjects with severe renal insufficiency were about 2 and 5 times higher, respectively, than those in normal volunteers. In subjects with moderate renal insufficiency, the Cmax was 2.3 times higher and the AU& was more than 2 times higher than in the control group. The t,,* values for the metabolite decreased with increasing renal impairment. The ratio of the metabolite to the parent drug in plasma increased with declining renal function. This effect was most pronounced in the subjects with severe renal insufficiency. 1209

CLINICAL THERAPEUTICS”

Table III. Mean (% coefficients of variation) steady-state urinary pharmacokinetic variables for sparfloxacin, by renal function status. Normal Renal

Function’+ (n = 12)

Variable

t 04

Moderate Renal Insufficiency’+ (n = 7)

Severe Renal Insufficiency” (n = 8)

27.7

48 4.0 (55.4)s 0.42 (38.1)s 0.035 (40.3) 19.8

24 8.3 (35.3) 1SO (32.4) 0.040 (39.9) 17.3

% excreted CLT (L/h) kterm 0-l ) t,,, (h)

5 = dosing interval; CL, = renal clearance; k,r,,, = terminal elimination rate constant; t,!? = elimination half-life. *Mean values up to 24 h. ‘Normal renal function: creatinine clearance (CL,,) 250 mL/min per I .73 m*; moderate renal insufficiency: CLcr 30 to 49 mL/min per I .73 m*; severe renal insufficiency: CLcr IO to 29 mL/min iMean values up to 48 h. §Significantly different from the group with normal renal function (P < 0.05).

+ Normal renal function (n = 12) A Moderate renal insufficiency (n = 7) m Severe renal insufficiency (n = 8)

50g

45 -

s .5 t

4035-

Lz 2

30 -

.-2 5

25-

a, .z 3 5 E 3

per 1.73 tn’.

20154

lo-

s s

5o0

,

I

I

I

I

20

40

60

80

100

Time

I 120

(h)

Figure 2. Mean cumulative urinary excretion of sparfloxacin at the last 200-mg dose. 1210

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;;:i:,

A

O-

~~~~

I

I I I 25 50 75 100 125 1501:50 CL,, (mUmin.73 m*)

0

I

0.00 0

25

I 50

CL,,

I 75

I 100

(mUmin-

I 125

I 150

I 175

I 200

.73 m2)

0.0% 0.07 5

0.06

!z 0.05 J .G m” 0.04 :: E g cn

A

A

2.5 -

i A t

A

A

0.03

=t,

0.02

3

2.0 -

A 4

1.1 -

** aA

A A

A

1.0 0.5 -

0.0 j., 0

25

50

CL,,

75

100

(mUmin-

125

1500

0

.73 m2)

25

50

CL,.

75

100 125

(mUmin-

.73

150

175 200

m*)

Figure 3. Scatter plots of steady-state values for sparfloxacin in 27 subjects, including area under the concentration-time curve (AUC,,) (13 = 0.31; P < 0.05); maximum plasma concentration (C,,,) (r2 = 0.07); terminal elimination rate constant (k,,,) (r2 = 0.02); and renal clearance (CL,) versus creatinine clearance (CL,,) (9 = 0.77; P < 0.05). The CL1 of sparfloxacin glucuronide was 3.06 L/h in subjects with severe renal insufficiency, compared with 16.5 L/h in subjects with normal renal function and 17.6 L/h in subjects with moderate renal insufficiency (Table V). As with the parent drug, only a small portion of metabolite was excreted in the urine in each group.

Regression analysis showed that AU(&, C,,, and kterm for sparfloxacin glucuronide were a function of CLcr. Tolerability All ECG results were within normal limits, with no adverse changes from base1211

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THERAPEUTICS”

Table IV. Mean (% coefficients of variation) steady-state pharmacokinetic variables for sparfloxacin glucuronide in plasma, by renal function status.

Variable t 04 AUC&

(l&mL.h)

Cave WmL) Cmax (k&W Tmax (h) kterm @-‘I G/2

(h)

Normal Renal Function*.’ (n = 9)

Moderate Renal Insufficiency*+ (n = 6)

Severe Renal Insufficiency+* (n = 8)

24 2.069 (72.4) 0.090(72.4) 0.181 (57.2) 6.0 (71.2) 0.026 (66.3)11 26.7

24 4.659(64.7) 0.194(64.7) 0.408 (78.7)a 14.1 (139) 0.031 (44.l)l 22.4

48 I I.333 (74.2)” 0.236 (74.2)s 0.5 1 I (59.6)s 12.6(53.7) 0.037 (50.8)# 18.7

z = dosing interval; AUCs7 = area under the plasma concentration-time curve over average concentration: Cmar = maximum plasma concentration; T ma\ = time to Cmai; tion rate constant; t,,2 = elimination half-life. *Mean values up to 24 h. +Normal renal function: creatinine clearance (CL,,) 250 mL/min per 1.73 ml: moderate 30 to 49 mL/min per I .73 m’: severe renal insufficiency: CLcr 10 to 29 mL/min per ‘Mean values up to 48 h. %ignificantly different from the group with normal renal function (P < 0.05). n = 5. yn = 4. ‘n = 6.

a dosing interval; Ca,c = krcn,, = terminal elimina-

renal insufficiency: I .73 m?.

CLcr

Table V. Mean (% coefficients of variation) steady-state urinary pharmacokinetic variables for sparfloxacin glucuronide, by renal function status.

Variable x- (h) ‘% excreted CLr (L/h) k term (h-‘) 5/2

(h)

Normal Renal Function*+ (n = 9)

Moderate Renal Insufficiency*’ (n = 6)

Severe Renal Insufficiency+: (n = 8)

24 8.79(49.3) 16.5 (103) 0.038 (41.2) 18.2

24 15.9 (54.3)"11 17.6 (164) 0.029(25.3) 23.9

48 10.5 (37.3) 3.06(69.2) 0.028 (30.1) 24.8

T = dosing interval; CLr = renal clearance: k,crm = terminal elimination rate constant; t,,? = elimination half-life. *Mean values up to 24 h. *Normal renal function: creatinine clearance (CL,,) 250 mL/min per 1.73 m2; moderate renal insufficiency: CLcc 30 to 49 mLimin per I .73 m’; severe renal insufficiency: CLcr IO to 29 mL/min per I .73 rn?. ‘Mean values up to 48 h. §n = 7. #‘Significantly different from the group with normal renal function (P < 0.05).

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line. The mean change in QTc interval was greatest 5.5 hours after the last sparfloxacin dose in all 3 groups and appeared to be similar regardless of renal function: 14 milliseconds with normal renal function and moderate renal insufficiency and 6 milliseconds with severe renal insufficiency. Additional analysis of ECC records failed to reveal any clinically significant changes in heart rate or in RR or QRS intervals. QRS axes were normal in all groups. Spaffloxacin was generally well tolerated in all 3 groups, with 6 of 32 (19%) safety-assessable subjects reporting adverse events, none of which was severe or serious. In the group with normal renal function, 1 subject reported a tooth disorder. In the subjects with moderate renal insufficiency, 1 reported nausea., 1 reported hypoglycemia, and 1 reported an anaphylactic reaction. In subjects with severe renal insufficiency, 1 experienced prolonged QT interval (465 milliseconds), and 1 experienced peripheral edema. The subject with moderate renal insufficiency was prematurely discontinued from the study because of a moderate anaphylactic reaction probably related to sparfloxacin. DISCUSSION The results of this study indicate that the clearance of sparfloxacin is reduced and that plasma levels of unchanged drug and its glucuronide metabolite are raised in the presence of moderate or severe renal insufficiency. These increases did not appear to augment the effects of the drug on the QTc interval or enhance the risk for adverse events. The unexpectedly short t,,, in subjects with severe renal dysfunction was due primarily to 2 subjects having a t,,, within the normal range.

Our results in subjects with normal renal function agree with those reported by Ritz et a1,15who used a similar multidose design. In addition, our results in subjects with renal impairment were generally similar to those of Fillastre et al.12 After administration of single 400-mg doses of sparfloxacin to patients with CLcr >lO to 30 mL/min or ~10 mL/min, those investigators observed a near doubling of t1,2 in both groups relative to values in normal volunteers. Marked decreases also were reported in the CLr of sparfloxacin and its glucuronide metabolite. Corroborating previous pharmacokinetic assessments,” our results point to primarily nonrenal elimination of sparfloxacin, which distinguishes it from ofloxacin and levofloxacin, which are eliminated primarily through the kidneys.2,16 Both renal and nonrenal routes are involved in the elimination of ciprofloxacin and norfloxacin.2 The accumulation of glucuronide in patients with renal insufficiency is not associated with safety risks, since this metabolite is pharmacologically inactive (ie, it has no antimicrobial activity).t7 Assessing ciprofloxacin pharmacokinetics in patients with various degrees of renal impairment, Shah et altx noted that both the C maxand AUC for the parent drug and its primary metabolite were significantly increased in subjects with reduced CLcr. Yu et all9 reported that the AUC for ciprofloxacin was tripled and its renal clearance reduced to 10% of normal in patients with renal impairment; a 100% increase m tu2 was also observed. VanceBryan et al*O recommended changes in ciprofloxacin dosing in patients with CLcr ~20 to 30 mL/min per 1.73 m2 to achieve plasma drug concentrations comparable to those in patients with normal renal function. Review of the literature indi1213

CLINICAL

cates altered pharmacokinetics of norfloxacin, ofloxacin, lomefloxacin, and levofloxacin in the presence of renal dysfunction,2~16~21.22 and Blum2’ has recommended reducing doses of lomefloxacin, temafloxacin, and norfloxacin in patients with renal insufficiency. Although the pharmacokinetics of sparfloxacin are altered in patients with renal dysfunction, no significant change has been observed in healthy elderly individuals with age-appropriate renal function.” Sparfloxacin slightly increased the QTC interval in the present study, but this elevation was not associated with the development of arrhythmias and was not greater in individuals with impaired renal function. In their review of safety data, Jaillon et al*’ reported that sparfloxacin treatment was associated with an approximately 3% mean increase in the QTC interval, with no enhanced risk for this change in patients with either renal or hepatic impairment. Sparfloxacin, however, should not be prescribed for individuals with known QTC prolongation or in patients receiving medications known to produce an increase in the QTC interval and/or

torsades

de pointes.*”

CONCLUSIONS In conclusion, sparfloxacin clearance is reduced and plasma levels increased in subjects with moderate or severe renal insufficiency. These changes, however, do not augment the effects of sparfloxacin on ECG findings in a clinically meaningful way. The decreased elimination of spar-

floxacin in the setting of renal impairment suggests that an adjustment in dosing from a 24- to 48-hour interval may be appropriate in patients with either moderate or severe renal insufficiency. 1214

THERAPEUTICS”

ACKNOWLEDGMENTS The authors thank Aesculapius Communications, Inc., East Brunswick, New Jersey,for preparation

of the manuscript

and Frances

McDermott for administrative assistance. Address correspondence to: Mary Beth Dorr, PhD, RhBne-Poulenc Rorer, 500 Arcola

Road, Collegeville,

PA 19426-o 107.

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