CLINICAL PHARMACOKINETICS AND DISEASE PROCESSES

Clin. Pharmacokinet. 21 (5): 357-371, 1991 0312-5963/ 91/0011-0357/$07.50/ 0 © Adis International Limited. All rights reserved. CPKl83

Ofloxacin Pharmacokinetics in Chronic Renal Failure and Dialysis Norbert Larneire, Bernd Rosenkranz, Vitus Malerczyk, Karl-Heinz Lehr, Nic Veys and Severin Ringoir Renal Division, Department of Medicine, University Hospital, Gent, Belgium, and Clinical Research, Hoechst AG, Frankfurt, Federal Republic of Germany

Contents 357 359 359 364 365 367 369 370

Summary

Summary I. Assays 2. Results of a Study in Undialysed Patients with Chronic Renal Failure (CRF) 3. Review of Other Studies in Undialysed Patients 4. Dosage Adjustment in Undialysed Patients with CRF 5. Pharmacokinetics of Ofloxacin During Dialysis 5.1 Continuous Ambulatory Peritoneal Dialysis (CAPD) 5.2 Haemodialysis

Data on the pharmacokinetics of ofloxacin in chronic renal failure, in patients who were not dialysed or were receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), are reviewed. In addition, a large pool of data obtained in patients with a wide range of renal dysfunction is provided. The good absorption of ofloxacin after oral administration is not influenced by renal failure. Total plasma clearance (CL) is largely dependent on renal elimination of the drug, and renal clearance (CLR) and urinary recovery are reduced in parallel with reductions in renal function. Consequently, the serum half-life progressively increases when creatinine clearance decreases. Although there is wide variation in the published absolute values for the CL and CLR of ofloxacin, all studies show a similar pattern in the pharmacokinetic behaviour of the drug in chronic renal failure. A proposed protocol for ofloxacin dosage adjustment in chronic renal failure is reported which differs slightly but significantly from that recommended by the manufacturer. This new dosage regimen was derived from the pharmacokinetic results after single and multiple oral administration of the drug to patients with chronic renal failure. Since no clinically relevant losses of ofloxacin occur during haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), the same protocol should be fOllowed in these patients as in undialysed patients with terminal chronic renal failure.

358

Clin. Pharmacokinet. 21 (5) 1991

o

«WC~ H3C/N~

o~

CH3

Fig. 1. Chemical structure of ofloxacin.

The older quinolones, of which nalidixic acid was the prototype, are characterised by unfavourable pharmacokinetic profiles such as low serum concentrations and short elimination half-lives (t'l,). They were also known for the apparent ease with which organisms developed resistance to their antibacterial effects. This limited their use to infections of the urinary tract and the gut. Fortunately, the insertion of fluorine at the C6 position, and of different side chains at positions Cl and C7, has led to the development of a whole series of compounds which have become known generally as the 4-quinolones. These modifications broadened the antibacterial spectrum and increased the activity of these agents and also resulted in better pharmacokinetic properties with higher serum concentrations, longer tl;' values and excellent oral bioavailability (Hooper & Wolfson 1985; Wolfson & Hooper 1985). One of these newer quinolones, ofloxacin, possesses a quinoline nucleus and contains a fluorine atom, an oxazin ring and N-methylpiperazine (fig. 1). The oxazin ring formation increases both the hydrophilicity and metabolic stability, and decreases the toxicity of the agent. The N-methylpiperazine ring increases both the lipophilicity and activity against anaerobes and Gram-positive aerobes. As with all other quinolones, the antibacterial activity of ofloxacin is due to its inhibition of the bacterial enzyme DNA gyrase, a type II topoisomerase (Smith 1984). After its introduction into clinical practice, data on the antibacterial activity of ofloxacin revealed its potent activity against Gram-negative bacteria, many Gram-positive bacteria and some anaerobes (Monk & Campoli-Richards 1987). Comparative pharmacokinetics of the new quinolones have shown that after a single dose of

ofloxacin, 70 to 90% is eliminated from the body unchanged by the renal route and a very low amount is removed via the faeces. The proportion of a dose eliminated renally is higher for ofloxacin than for all other new 4-quinolones. The relatively small volume of distribution (Vd) of ofloxacin compared with other compounds in this class, together with excellent bioavailability (85 to 95%), explains the relatively high serum concentrations that can be achieved after oral administration (Lode et al. 1987). With its good tissue penetration, ofloxacin is consequently attractive for oral treatment of both urinary tract and systemic infections. Patients with chronic renal disease are frequently prone to systemic infections and could therefore profit from use of an orally administered antibiotic. However, since ofloxacin is mainly excreted via the kidneys, the elimination of the drug in patients with chronic renal failure (CRF) will be slowed and the dosage regimen will have to be adjusted from that recommended for patients with normal renal function. Several single-dose studies of the pharmacokinetic behaviour of ofloxacin in CRF have been performed, and dosage regimens have been proposed to account for differences in the severity of the renal functional impairment (Arosio et al. 1985; Bandai et al. 1989; Fillastre et al. 1987; FIor 1989; Homer 1987; Homer & Koeppe 1987; Hurle et al. 1989; Kuhn 1987; Navarro et al. 1990; Nawishy et al. 1986; Tsubakihara et al. 1989; Vulterini et al. 1985; White et a!. 1987). These studies have been published as isolated reports and the many proposed dosage regimens were not always consistent. This review summarises the pharmacokinetic studies that have been performed with ofloxacin in CRF. In addition, detailed data are included from an extensive single and multiple oral dose study and from a single-dose intravenous study of ofloxacin performed in our renal unit. A practical recommendation for ofloxacin dosage adjustments in these patients is presented. Pharmacokinetic data from patients undergoing haemodialysis or continuous ambulatory peritoneal dialysis (CAPO) are also reviewed.

Ofloxacin Kinetics in Renal Failure

1. Assays In all studies, ofloxacin concentrations in serum and urine were determined using high performance liquid chromatography (HPLC) or a microbial assay with either Bacillus subtilis, Proteus morganii or Escherichia coli as indicator organisms. In healthy volunteers, comparison between the 2 methods showed excellent correlation (Verho et al. 1986). Although ofloxacin is metabolised to only a very small degree «10%) in healthy volunteers (Monk & Campoli-Richards 1987), metabolites may accumulate in the presence of impaired renal function. If these metabolites were microbiologically active their activity would be measured by the microbial assay and this would interfere with the assay methods used to determine the concentrations of the parent drug. In addition, the effects of accumulation of antimicrobially-active metabolites on the microbial assay in patients with renal failure are not yet known. Therefore, in this review, a clear distinction is made between the studies using these 2 assay methods.

2. Results of a Study in Undialysed Patients with Chronic Renal Failure (CRF) A group of 41 subjects was studied, composed of 12 healthy volunteers and of 29 patients with various degrees of stable CRF who were not yet on dialysis. Patients who presented with gastrointestinal or liver diseases known to interfere with the absorption, distribution or metabolism of drugs were excluded from the study. The study was performed according to the Declaration of Helsinki, and informed consent was obtained from all volunteers and patients. Patients were selected for inclusion according to their creatinine clearance (CLcR), which was measured before the study. However, for the final analysis and grouping of patients the mean CLcR calculated throughout the study was taken. This led to different sample sizes in each individual group (table I). In groups I to V, 3 ofloxacin 100mg tablets were administered orally with 50ml of water after an

359

overnight fast of 8h. Breakfast was permitted 2h after drug administration. In group VI, ofloxacin 200mg was intravenously (IV) infused over 30 min. Blood samples were drawn from all patients at 0 (predose), 5, 15, 30,45, 60 and 90 min and at 3, 4, 6, 9, 12 and 16h. Further samples were drawn at 24, 30, 48, 54, 72 and 96h after drug administration. The blood was allowed to clot at 4·C; the serum was transferred into labelled tubes and immediately frozen and stored at - 20·C until analysis. Urine was collected, when possible, at Oh (predose), and at intervals between 0 and 2, 2 and 4, 4 and 6,6 and 12, and 12 and 24h for the first day. Urine was further collected at 24h intervals until day 3 after drug administration in all patients, and until day 4 in patients from groups IV and V (with most severe CRF). Two 10mi aliquots from each collection were stored immediately at - 20·C until analysis. Ofloxacin concentrations in serum and urine were determined by HPLC on 'Nucleosil C18' (125 X 4.6mm), particle size 5~m (Macherey-Nagel, Duren, Germany), with a mobile phase of 250 parts of 0.2 mol/L phosphoric acid, adjusted to pH 1.85 with tetraethylammonium hydroxide solution, 10 parts of tetrahydro-furane and 6 parts acetonitrile. The flow rate was 1.7 ml/min and column temperature 40·C. Detection was by an RF530 fluorescence detector (Shimadzu, Duisburg, Germany) at XEx = 298 nm and XEm = 458 nm. Quantification was based on the peak-height ratio of ofloxacin and the internal standard (DL-8357). Before assay, 0.1 ml of serum was deproteinated with a methanol mixture containing the internal standard DL-8357 (Daiichi Seiyaku, Tokyo, Japan) and 7% perchloric acid (I : I). Urine was diluted appropriately with mobile phase after addition of the internal standard. The imprecision between days of the assay in serum was 4% of the measured value ± 0.3 ~g/L and in urine was 3.5% of the measured value ± 0.1 mg/L. The lower limits of quantification were 0.03 and 0.2 mg/L for serum and urine, respectively. Peak serum ofloxacin concentrations (C max ) as well as time to peak (t max ) values were taken from lists of the raw data. The area under the serum

C/in. Pharmacokinel. 21 (5) 1991

360

Table I. Demographic data, renal function and underlying renal diseases in study subjects

Group and pt no. Group I (n = 12)

Age/Sex

Weight (kg)

34-59/M

60-86

49/F 35/F 50/F

59.0 76.6 70.0

48/F 46/F 57/F 51/F 56/F

75/M 54/F 51/M 75/M 70/F 79/F

sCR (I'moI/L)

CLcR (ml/min)

Renal diagnosis

89-152

Healthy volunteers

70.7 97.2 123.8

109.0 76.6 59.4

Membranous nephropathy Congenital atrophic kidney Renovascular disease

61.0 60.0 88.6 90.5 83.0

123.8 123.8 159.1 141.4 229.8

48.0 43.4 37.6 36.2 21 .9

56/F

49.0 67.3 63.0 68.2 69.7 45.5 56.0

309.4 247.5 397.8 256.4 274.0 265.2 335.9

19.5 19.0 t8.2 17.4 14.8 12.9 10.5

71/M 53/M 64/M 65/F 53/F

41.0 72.0 76.0 52.0 63.0

203.3 671 .8 866.3 680.7 866.3

9.7 9.3 7.1 5.5 3.3

52/F 59/M 64/F 70/F 74/F 49/M 45/M 68/M 64/M

72.4 57.7 74.8 67.8 63.5 68.8 57.9 82 71.5

859.2 548.1 577.2 631 .2 366.0 1043.1 517.1 754.1 630.3

6.7 12.2 5.85 8.7 13.1 4.4 11 .5 3.8 7.1

Group II

1 2 3 Group III

4 5 6 7 8

Analgesic nephropathy Analgesic nephropathy Hydronephrosis single kidney Chronic pyelonephritis Bilateral nephrolithiasis

Group IV

9 10 11 12 13 14 15

Renovascular disease Chronic pyelonephritis Nephroangiosclerosis Reflux nephropathy Single kidney (analgesic nephropathy) Analgesic nephropathy Analgesic nephropathy

Group V

16 17 18 19 20

Nephroangiosclerosis Diabetic nephropathy Malignant nephroangiosclerosis Analgesic nephropathy Analgesic nephropathy

Group VI

21 22 23 24 25 26 27 28 29

Abbreviations: sCR

= serum creatinine; CLCR = creatinine clearance;

concentration-time curve (AUC) was determined by the trapezoidal rule, extrapolated to infinity. The elimination rate constant, terminal half-life (t'l2)' apparent volume of distribution (Vd/t) and relative total plasma clearance (CLft) of the drug were calculated according to standard formulae, where

M

Analgesic nephropathy Chronic pyelonephritis Renovascular disease Chronic pyelonephritis Analgesic nephropathy Nephroangiosclerosis Chronic pyelonephritis Unknown Chronic glomerulonephritis

= male; F = female .

f is the systemic availability of oral drug. The renal clearance (CLR) was calculated as Ae/C where Ae is the amount of ofloxacin excreted into the urine during a given time interval, and C is the mean plasma ofloxacin concentration during the same interval. Table I summarises the demographic data

Ofloxacin Kinetics in Renal Failure

361

and the renal function of all subjects and the underlying type of renal disease in the 29 patients with CRF. Volunteers were 34 to 59 years of age and their CLcR varied from 89 to 152 ml/min (5.34 to 9.54 L/h). Patients were 35 to 79 years of age and had CLcR values of 3.3 to 109 ml/min (0.2 to 6.54 L/h). Table II summarises the pharmacokinetics of ofloxacin after administration to volunteers (group I) and in the different groups of patients with CRF (groups II to VI). After oral ofloxacin 300mg, Cmax and tmax are 4.6 ± 0.92 mgfL and 1.0 ± 0.7h, respectively, in group I, which is not different from the values for Cmax (4.07 ± 1.35 mgfL) and t max (1.35 ± 0.49h) observed in the patients with the lowest CLcR (group V). The similarity between these values suggests that absorption of the drug is unchanged in uraemia. As expected, a progressive increase in AVC and decrease in CL/f are noted with decreasing creatinine clearance. It should also be noted that the Vd remained stable when values from patients with CRF were compared with those observed in volunteers. The results (see table II) obtained after intravenous infusion of ofloxacin 200mg to group VI indicate similar but somewhat lower CL/fvalues [mean 39.9 ± 4.3 ml/min (2.39

L/h)] compared with those in group V after oral ofloxacin 300mg. Figure 2 depicts the indirect proportionality between the ofloxacin serum t'/2 and CLcR after oral administration to both patients with CRF and volunteers. With progressive deterioration of renal function, serum t'/2 increases from 6 ± 1.1 h in volunteers to 18.4 ± 12.1 h in the group V patients with the lowest CLcR. In the latter group, serum t'/2 ranges from 6.4 to 37. lh. In group VI, the mean t'/2 is 30.9 ± 3.lh. Table III summarises the cumulative urinary drug excretion (Ae) and also lists it as a percentage of the administered dose (fe) in the 6 study groups. It is clear that the Ae of ofloxacin is reduced dramatically when CLcR progressively decreases. The fe decreases from 98% in subjects with normal renal function to 10.5% in group V. Due to this prolonged urinary excretion, the urinary concentrations of ofloxacin remain high even in CRF. For example, in the patients with severely compromised CLcR (group V), the mean urinary concentrations were 8.91 ± 1.57 ~gfml after 48h. Thus, antimicrobially effective urinary concentrations of ofloxacin remain present for a sustained period, even in severe CRF.

Table II. Pharmacokinetic data after administration of single oral doses of ofloxacin 300mg to subjects in groups I to V and of single intravenous doses of ofloxacin 200mg to patients in group VI

Group I (n = 12) Group II (n = 3) Group III (n = 5) Group IV (n = 7) Group V (n = 5) Group VI (n = 9)

tv.

AUC mg/L · h

CL/f (ml/min)

Cmax ("Iml)

tmax (h)

Vd/f (L/kg)

28.46 ± 4.72

180.5 ± 32.1

4.6 ± 0.92

1.0 ± 0.7

1.23 ± 0.11

6.0 ± 1.1

174.4 ± 36.4

24.2 ± 10.1

227.7 ± 77.6

2.9 ± 0.4

2.3 ± 1.2

1.47 ± 0.16

4.6 ± 3.1

147.7 ± 34.7

43.9 ± 7.4

116.5 ± 18.4

4.4 ± 0.5

0.9 ± 0.4

1.27 ± 0.18

9.8 ± 1.8

41.6 ± 13.9

87.7 ± 47.2

70.3 ± 30.8

4.86 ± 2.09

1.39 ± 0.95

1.43 ± 0.49

15.9 ± 5.8

19.0 ± 12.2

98.1 ± 67.7

68.4 ± 35.1

4.07 ± 1.35

1.35 ± 0.49

1.55 ± 0.52

18.4 ± 12.1

6.7 ± 4.0

87.7 ± 7.8

39.9 ± 4.3

1.46 ± 0.01

30.9 ± 3.1

10.2 ± 5.1

(h)

CLR (ml/min)

Abbreviations: AUC = area under the plasma concentration-time curve; CL/f = relative plasma clearance; Cmax = peak plasma drug concentration; t max = time to Cmax ; Vd/f = apparent volume of distribution; tv. = terminal half-life; CLR = renal clearance.

...,a-

Table IV. Review of mean (± SO) phannacokinetic data for ofIoxacin in undialysed patients with chronic renal failure and in healthy voIl.IlIeers Study

tv

Dose

ClcR

Vd/f

AUC

c..-

tn-

(mg)

(ml/min)

(L/kg)

(mg/L-h)

(mg/L)

(h)

t.... (h)

3.8 ± 1.2

2.3 ± 1.3

5.1 ± 1.8

CL/f

C4IR

CLR

(mi/min)

(ml/min)

(ml/min)

fe (%)

174 ± 36,4

98

147.6 ± 34.7

66.9

HPlC _MayS Navarro

at al.

400 PO

104.8 ± 23.1

38.8 ± lp.3

(n = 9)

(1990)

>20

0.76

130.9

5.03

0.73

16.6

1.46 ± 0.21

315.5 ± 100

5.4 ± 0.8

1.53 ± 0.09

39.4 ± 11.8

(n = 3)

I:>

30 (n = 1) 14 (n = 1)

'"

;;. ~

HOffler & Koeppe (1987)

200 PO

115 ± 7.6 (n = 10)

1.27 ± 0.20

28.4 ± 32

1.16 ± 0.31

(n = 20)

16.6 ± 2.6 67.8 ± 32.9

2.42 ± 0.6 2.83 ± 0.59

1.41 ± 0.74

19.37 ± 7.97

57.4 ± 26.6

40 ± 15.6 30.9 ± 14.2

151 ± 19.3 26.5 ± 25.2

70.3 ± 4.8 24.9 ± 20.7

.... '" ~

.... '0 '0 ....

Fillastre at al. (1987)

Nawishy at 81. (1986)

Kuhn (1987)

200 PO

200 PO

200 PO

119.6 ± 20.8 (n = 12)

2.53 ± 0.78

13.18 ± 3.12

2.24 ± 0.9

0.83 ± 0.31

7.86 ± 1.81

241 .4 ± 53.8

44.9

196.5 ± 42.06

68.4 ± 11.9

45 ± 4.8 (n = 4)

2.14 ± O.SO

32.33 ± 4.18

2.18 ± 0.53

1.75 ± 1.66

15 ± 4.4

109.4 ± 18.3

48.8

60.0 ± 18.3

37.7 ± 3.5

262 ± 4.4 (n = 7)

2.15 ± 0.31

47.48 ± 14

1.84 ± 0.32

2.36 ± 1.60

25.37 ± 8.56

70.8 ± 15.9

39.9

30.9 ± 7.7

22.7 ± 6.2

11.5 ± 3.0 (n = 5)

2.02 ± 0.26

65.98 ± 15

1.71 ± 0.62

1.60 ± 1.34

34.84 ± 15.46

SO.6 ± 14.5

36.9

13.7 ± 6.2

11.8 ± 6.2

97-120 (n = 5)

4.68

7-44 (n = 10)

200 PO

(1985)

Bandai at al.

100 PO

(")

S· ~

::t

"g. '"S· :;e

2.7 (2.1-3.0)"

2.0 (1.5-2)"

17.8 (12.3-38.5)"

3.57

58.45 (38.2-104.1)"

2.7 (1 .8-4)"

2.0 (1 .5-4)"

38.5 (24.8-99)"

57

70-83 (n = 4)

1.07 (0.96-1.16)"

35.99 (24.88-44.91 )"

3.51 (2.82-3.99)"

1.2 (0.6-2)

9.6 (6.1-10.8)"

98.5 (74.2-134)"

2O-SO (n = 6)

2.64 (0.94-8.96)"

92.46 (54.51-152.67)"

4.09 (2.76-5.48)"

2.27 (0.6-6)"

SO (10.1-223)"

40.85 (21 .6-61 .1)"

3.49 2.87

6 6

18.6 12.1

17.34

Control" (n = 5)

17.17 ± 2.36

2.90 ± 027

0.73 ± 0.33

3.96 ± 0.62

22-2.6 mg/dib (n = 5)

66.89 ± 10.55

2.9 ± 0.53

3.67 ± 1.72

13.81 ± 12.59

1.22 ± 0.14

6.02 ± 1.05

0.95 ± 0.17

1.90 ± 023

2.9 ± 0.53

1.08 ± 0.17

67.34 ± 31 .4

1.73 ± 022

2.48 ± 0.59

23.06 ± 6.95

"!!!-::t

192

(11 .~19.4)"

106.6 ± 12.2

::!l 0

>< ~

14 (n = 1) (n = 1) NOsio at al.

0

'T1

e!. i:' til

130.8 ± 23

69.26

27 ± 112

36.71

284 ± 51.8

23 ± 17.8

261 ± 46.6

(1989) (n

= 5)

10.5 ± 5.32 (n = 9)

31.8 ± 18.1

23.8 ± 14.1

8.0 ± 4.7

a Control subjects were healthy volunteers with ClcR within normal ranges. b Serum aeatinine levels. c Mean (range). AbbnwiatIons: ClcR = creatinine clearance; Vd/f = apparent volume of distribution; AUC = area under the plasma drug OOlicelitratiol ..time curve; Cn.x = peak plasma drug oollcentration; !max z time to Cn.x; ty, = elimination half-life; Cl../f = relative clearance; CLNR = nonrenal clearance; C~ z renal clearance; f. - fraction of systemically available drug axcreted into urine; HPLC = high perfOrmance liquid chromatography; PO = oral; IV = intravenous.

w

0-

w

364

Clin. Pharmacokinet. 21 (5) 1991

50 40

s:



30

••• ••• •• :,

t 20 10



0

0

,.. . . .. .- •.. 50

100

• 150

CLcR (ml/min) Fig. 2. Inverse relationship between creatinine clearance (CLcR) and ofloxacin serum half-life (tolz) after oral administration of 300mg of the drug to patients with chronic renal failure.

3. Review 0/ Other Studies in Undia/ysed Patients Table IV summarises the most important pharmacokinetic data obtained with ofloxacin in patients with CRF who were not yet on dialysis. The 2 studies which used a single dose of ofloxacin 300mg and an HPLC assay yield very similar results for most of the parameters studied (Flor 1989; Lameire et aI., current study). In both studies, the decrease in CLR which paralleled the reduction in CLcR was a major contributor to the reduction in CL/f which occurred when renal function decreased. It is noteworthy that in all groups of patients in both studies, the nonrenal clearance Table III. Cumulative urinary ofloxacin excretion (Ae) in mg and as percentage of administered dose (fe) Study group

II II IV V

VI

fe

Ae (mg)

293.7 200.8 109.3 86.9 31 .4 42.6

(%)

± ± ± ± ± ±

23.7 27.6 38.1 38.8 12.5 13.8

98 66.9 36.4 28.9 10.5 21.3

Abbreviations: Ae = amount of unchanged drug excreted into

urine; fe urine.

= fraction of systemically available drug excreted into

(CLNR) remained more or less unchanged. The low CLNR observed in the healthy volunteers in our study was due to the rather high recovery of unchanged drug in urine, which is usually between 85 and 90% (Monk & Campoli-Richards 1987). Regarding other pharmacokinetic parameters, the main finding of both our study and Flor (1989) is that the serum t'12 of ofloxacin is prolonged in inverse relation to the decrease in CLcR. Whereas the serum t'l2 is around 6h in volunteers with normal GFR, this parameter rose to 18.4 ± 12.1h and 21.7h (range 17 to 28.4h) in our group V patients and in patients in the study by Flor (1989), respectively. On the other hand, t max and Cmax in CFR in both studies are similar to those in healthy volunteers, suggesting that absorption of the drug does not change when patients are uraemic. Furthermore, AUC increases and CL/f decreases as GFR decreases. This is further confirmed by the results in our group VI patients, in whom similar CL/f and t'12 values are seen after intravenous administration to those observed in studies involving oral administration. Due to the prolonged t'12, plasma concentrations of ofloxacin in patients with CRF remain high for a period up to 24 to 48h. The cumulative urinary excretion of ofloxacin is lower in patients with CRF than in healthy volunteers. Whereas in the latter about 80 to 90% of a dose of ofloxacin 300mg is excreted unchanged in the urine within 24h, the corresponding figure in severe CRF is only 8%. Consequently, persistently high urinary drug concentrations are achieved over a prolonged period and, in the group V patients, mean concentrations of 8.91 ± 1.57 mg! L were measured in the urine over the 48h after administration. It can therefore be concluded that anti microbially effective urinary concentrations of ofloxacin remain present for a sustained period, even in severe CRF. The second group of studies comprises those where a single oral dose of ofloxacin 200mg has been administered and a microbial assay has been used (Arosio et a1. 1985; Fillastre et a1. 1987; HOffler & Koeppe 1987; Kuhn 1987; Nawishy et a1. 1986). Although the results are qualitatively similar to those obtained in the 2 previous studies, the

Ofloxacin Kinetics in Renal Failure

results in this group are more varied. For example, comparing ofloxacin CL/f values in healthy volunteers, a range is found from as low as 131 ± 23 ml/min (7.86 ± 1.38 L/h) in the study by Arosio et al. (1985) to as high as 241 ± 53.8 ml/min (14.46 ± 3.20 L/h) in that by Fillastre et al. (1987). CLR values associated with normal renal function vary from 196.5 ± 42 to 151 ± 19.3 ml/min (11.79 ± 2.52 to 9.06 ± 1.16 L/h) in 2 studies (Fillastre et al. 1987; Hoffler & Koeppe 1987). It is remarkable that in these 2 studies the CLNR values are very similar to those obtained in the HPLC studies. Whereas in the studies of Fillastre et al. (1987) and Hoffler and Koeppe (1987) the serum t'l2 values in subjects with normal renal function are within the range obtained in the HPLC studies, the t'l2 values observed in the studies of Nawishy et al. (1986) [mean 17.8h] and Arosio et al. (1985) [mean 3.96h] are extremely high and low, respectively. In CRF, similar results to those in the HPLC studies are noted with t'l2 increasing and CL/f decreasing in tandem with a reduction in CLcR. The high mean t'l2 obtained by Kuhn (1987) in his patients with CLCR values of 20 to 50 ml/min (1.2 to 3.0 L/h) is skewed by I value of 223h. A possible explanation for this high value could be interference in the microbial assay by coadministration of another antibiotic. Ignoring this high value and recalculating the mean t'l2 yields a new mean t.;, of 15.4 ± 3.lOh. Finally, a third group of investigations are represented by the studies of Navarro et al. (1990), Vulterini et al. (1985) and Bandai et al. (1989), who administered single doses of ofloxacin 400mg and l00mg, respectively. The first study used HPLC and the latter 2 the microbial assay. Their results agree closely with the findings discussed above. The conclusions from all 3 groups of studies are, first, that ofloxacin is well absorbed after oral administration regardless of renal status. Secondly, in volunteers with normal renal function, the CL/ f of the drug is largely dependent on renal elimination. Thirdly, in the presence of progressively deteriorating renal function, renal elimination and urinary recovery also decrease. Thus, the serum t.;, of ofloxacin progressively increases as CLcR de-

365

300



250

.,.

..J

U

• • •

• y = 1.21x + 36

50

100

150

CLCR (ml/m.n)

Fig. 3. Regression line between total plasma clearance (CL) of ofloxacin and creatinine clearance (CLcR). For explanation see text (pooled data from Fillastre et al. 1987, Homer & Koeppe 1987, Kuhn 1987 and the current study).

creases and the role of the CLNR of the unchanged drug becomes progressively more important when renal function deteriorates. Lastly, although the results obtained with HPLC and microbial assays show some divergent results, particularly in the calculation of the absolute values ofCL/fand CLR, all studies show a similar pattern of pharmacokinetic behaviour for ofloxacin in CRF.

4. Dosage Adjustment in Undialysed Patients with eRE This section discusses the dosage adjustments required for patients with renal failure who are not yet on dialysis. Therefore, only published studies which included sufficiently detailed information were considered and the pharmacokinetic parameters most relevant to the CLCR were pooled. We examined the studies performed by our group (see section 2), Fillastre et al. (1987), Hoffler and Koeppe (1987) and Kuhn (1987). Figure 3 shows the pooled data on the relationship between CLcR vs CL/f. In calculating the dosage adjustment, it was agreed for safety reasons that a larger accumulation of the drug was not allowed in patients with CRF than in healthy volunteers. From figure 3 it can be derived that the relationship between CLcR and CL/f of ofloxacin is described by: CL/f = 1.21

X

CLcR

+ 36; r2

= 0.7155

366

C/in. Pharmacokinet. 21 (5) 1991

Table V. New proposal for maintenance dosages of ofloxacin in undialysed patients with chronic renal failure

(ml/min)

Dosage (mg/day)

>50 20-49 50 mil min (> 3.0 L/h) received a normal dose of ofloxacin 200mg every 12h, which resulted in a range of Cmin values between I and 2 mg/L (fig. 4). In 5

....

.............................

',_,0-

°0~----2--~3~~4~~5--~6~~7~~8~~9~10 Time (days)

Fig. 4. Trough ofloxacin plasma concentrations in a multiple dose study in 2 patients with normal creatinine clearance.

Ofloxacin Kinetics in Renal Failure

367

Table VI. Demographic data. renal function. underlying renal disease and maintenance dosage administered in multiple dose study

Group I

Group II

Group III

Age/sex (y)

Weight (kg)

sCR (I'moI/L)

CLcR (ml/min)

Dosage (mg/day)

Renal diagnosis

321M 351M 50/F 63/M 41/F 63/F 71/F 43/F 64/F 58/M 74/F 41/F 57/F 57/F 62/F 76/F

59.5 68.3 67.9 76.3 51 .1 56.7 48.5 45.3 53 91 52 69.5 44.5 54.5 69.5 61.2

106.1 97.2 247.5 253.6 150.3 265.2 288.2 221 209.5 1016.6 893.8 194.5 603.8 646.2 652.4 724.9

71 55 34 29 27 22 20 22 24 9 3.5 13.6 4 4 7.5 4

2 x 200 2 x 200 1 x 200 1 x 200 1 x 100 1 x 100 1 x 100 1 x 100 1 x 100 1 x 50 1 x 50 1 x 50 1 x 50 1 x 50 1 x 50 1 x 50

Wegener's disease Diabetic nephropathy Chronic interstitial nephritis Renovascular disease Chronic interstitial nephritis Analgesic nephropathy Obstructive nephropathy Analgesic nephropathy Analgesic nephropathy Polycystic disease Analgesic nephropathy Lupus ery1hematodes Analgesic nephropathy Single kidney + calculi Diabetic nephropathy Analgesic nephropathy

Abbreviations: sCR

= serum creatinine; CLcR = creatinine clearance;

the 7 patients with a CLcR ranging from 20 to 50 ml/min (1 .2 to 3.0 L/h), a dose of ofloxacin 200mg was administered once daily. One patient in this group showed progressive accumulation of the drug with Cmin values of up to 4.5 mg/L (fig. 5). Therefore, not everyone with this degree of CRF should receive a daily maintenance dose of ofloxacin 200mg. In the 7 patients with a CLcR

Ofloxacin pharmacokinetics in chronic renal failure and dialysis.

Data on the pharmacokinetics of ofloxacin in chronic renal failure, in patients who were not dialysed or were receiving haemodialysis or continuous am...
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