DRUG DISPOSITION

C1in. Pharmacokinet. 22 (I): 32-46, 1992 0312-5963/ 92/000 1-0032/ $07. 50/0 © Adis International Limited. All rights reserved. CPKI

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Ofloxacin Clinical Pharmacokinetics Kenneth C. Lamp, Elaine M. Bailey and Michael J. Rybak Department of Pharmacy Practice, College of Pharmacy and Allied Health Professions and Division of Infectious Diseases, School of Medicine, Wayne State University and the Antiinfective Research Laboratory, Department of Pharmacy Services, Detroit Receiving Hospital, Detroit, Michigan, USA

Contents 32 33 33 34 35 36 36

39 39 40 40 40 41 41 41 41

42 43 43

Summary

Summary I. Chemistry 2. Analytical Methods 3. Mechanisms of Action and Resistance 4. Pharmacokinetics 4.1 Absorption 4.2 Distribution 4.3 Metabolism 4.4 Elimination 5. Pharmacokinetics in Renal Dysfunction 5. 1 Haemodialysis 5.2 Continuous Ambulatory Peritoneal Dialysis 6. Pharmacokinetics in the Elderly 7. Drug Interactions 7.1 Methylxanthines 7.2 Ion-Containing and Antiulcer Agents 7.3 Probenecid 7.4 Anticoagulants S. Therapeutic Considerations

Ofloxacin is a new fluoroquinolone with a spectrum of activity similar to other fluoroquinolones with activity which includes Chlamydia trachomatis, Mycobacterium spp., Mycoplasma spp. and Legionella pneumophila. Through its additional mechanisms of action, ofloxacin may be less susceptible to the development of resistance from Staphylococcus aureus commonly seen with currently available fluoroquinolones. The impact of these findings cannot be evaluated without further clinical experience. The pharmacokinetics of ofloxacin are characterised by almost complete bioavailability (95 to 100%), peak serum concentrations in the range of 2 to 3 mg/L after a 400mg oral dose and an average half-life of 5 to Sh. In comparison with other available quinolones, elimination is more highly dependent on renal clearance, which may lead to more frequent dosage adjustments in patients with impaired renal function. Ofloxacin appears less likely to atTect the pharmacokinetics of drugs (e.g. theophylline) which commonly interact with fluoroquinolones such as ciprofloxacin and enoxacin. The properties of ofloxacin make it a therapeutic alternative to currently available fluoroquinolones.

Ofloxacin Pharmacokinetics

The development of fluoroquinolone derivatives over the past decade has renewed interest in this group of antibiotics. Nalidixic acid and most analogues suffered from poor antibacterial activity, poor oral availability and the rapid emergence of resistance (Moellering et al. 1989; Wolfson et al. 1989). Fluoroquinolones are highly effective against Gram-positive and Gram-negative bacteria both in vivo and in vitro with few of the problems of their predecessors (Andriole 1990). The spectra of activity of the fluoroquinolones against these organisms appear comparable; however, differences emerge against other microorganisms, such as Chlamydia trachomatis, Mycobacterium spp. and Mycoplasma pneumoniae (Wolfson et al. 1985). Ofloxacin has a broad spectrum of activity against Gram-negative and Gram-positive bacteria with poor activity against anaerobes (Chau et al. 1986; Griineberg et al. 1988; Rubinstein et al. 1986; Sato et al. 1986; Smith 1986; Torres et al. 1986). The ofloxacin minimum inhibitory concentration (MIC) for 90% (MIC90) of Enterobacteriaceae isolates (range 0.6 to 4 mgfL) would indicate inferior activity compared with ciprofloxacin (Smythe et al. 1990). This may not be clinically significant since ofloxacin achieves higher serum concentrations. Gram-positive bacteria are similarly sensitive to ofloxacin and ciprofloxacin, with Staphylococci spp. more sensitive than Streptococci spp. As with other available fluoroquinolones, streptococci are only moderately sensitive to ofloxacin with MIC values ranging from 1 to 4 mgfL (Fuchs 1989). Pseudomonas spp. exhibit differing susceptibilities. Pseudomonas aeruginosa and non-aeruginosa species are less susceptible to ofloxacin than to ciprofloxacin; however, ofloxacin is at least as active against Xanthomonas maltophilia (Chau et al. 1986). Ofloxacin is active against Clostridium perjringens but few other anaerobes are inhibited at obtainable serum concentrations. Legionella pneumophila and Mycobacterium tuberculosis are also susceptible to ofloxacin. C. trachomatis is very sensitive to ofloxacin with Ureaplasma urealyticum and Mycoplasma hominis only moderately susceptible. In situations of comparable serum concentration to

33

MIC ratios and efficacy, the choice of quinolone may be more influenced by dosage intervals and drug interactions than minor differences in in vitro activity.

1. Chemistry Ofloxacin is a new pyridonecarboxylic acid derivative of nalidixic acid, chemically known as 9fluoro-2, 3-dihydro-3-methyl-l 0-( 4-methyl-I-piperazinyl)-7-oxo-7H-pyrido-[1, 2, 3-de]-1,4-benzoxazine-6-carboxylic acid (fig. 1). Ofloxacin differs from other quinolones in having a tricyclic structure. The attachment of the methyl group at the C3 position of the oxazine ring produces an asymmetric centre and its spatial orientation affects antibacterial activity. (-)-Ofloxacin is as much as 100 times more active than (+ )-ofloxacin and about twice as active as the racemic mixture against Gram-positive and Gram-negative bacteria (Hayakawa et al. 1986). The combination of a piperazinyl ring at position 7 and a fluorine at position 6 improves oral bioavailability and antibacterial activity. Substitution of a methyl group at the C4 position of the piperazinyl group increases the Gram-positive activity of ofloxacin and slightly decreases activity against Gramnegative bacteria, especially P. aeruginosa. In addition, the entire side-chain increases bioavailability, half-life and serum concentrations (Chu et al. 1989).

2. Analytical Methods Microbioassay and high performance liquid chromatography (HPLC) are the only methods which have been described to determine ofloxacin

F~O

J : -. I

H3C- N

o

COOH

I

CH3

Ofloxacin

Fig. 1. Chemical structure of ofloxacin.

34

concentrations in various biological fluids. There appears to be a fairly good correlation between ofloxacin concentrations measured by these 2 techniques. Serum and bile concentrations assayed by both methods had a correlation coefficient of 0.99 (Kazmierczak et al. 1987). Similar results were noted when assaying ofloxacin concentrations in cere!'rospinal fluid by both methodologies (Stahl et al. 1986). However, there is a need to standardise assay procedures in order to directly compare pharmacokinetic studies, particularly in patients with renal failure, due to active metabolites which cannot be separated by bioassay. Additional clinical problems with bioassay include assay interference caused by the presence of other antibiotics. As with other fluoroquinolones no fluorescence polarisation immunoassay or radioimmunoassay has been described. Microbiological assay has been used to analyse ofloxacin in serum, blister fluid, sputum, bronchial secretions and bile (Davies et al. 1987; Kalager et al. 1986; Symonds et al. 1987) with Klebsiella aerogenes and Escherichia coli used as indicator organisms. Standard curves were constructed from assays performed on Mueller-Hinton agar using undiluted pooled human serum and serum diluted 1 : 1 with saline for assay in blister fluid. Special problems encountered in the assay of sputum concentrations included the need to increase the size of the well diameter in order to assay purulent sputum. Although this assay has an acceptable limit of sensitivity (0.1 to 12 mg/L), it lacks specificity and may not be useful clinically in patients receiving other antibiotics which might interfere with this process. An HPLC method to determine several fluoroquinolone concentrations (including ofloxacin) in serum has been evaluated (Griggs et al. 1989). Proteins were precipitated with perchloric acid before assay. A Microbondapak C18 Radia-Pak (8 X 100mm) column was used for analysis. The mobile phase consisted of 18 mmoljL potassium dihydrogen phosphate with 0.13 mmoljL heptane sulfonic acid, methanol and concentrated phosphoric acid (the latter 3 in a ratio of700: 300: 1).

Clin. Pharmacokinet. 22 (J) 1992

Coefficients of variation for the standards were less than 2.5%. A similar methodology was evaluated using a mobile phase consisting of water, acetonitrile and triethylamine (850: 150: 1.4). The coefficients of variation (between-day and within-day) in serum, saliva and blister fluid were less than 3.6% (Warlich et al. 1990). Specificity for ofloxacin in the presence of its metabolite was not performed in either study mentioned previously. Ofloxacin, demethyl-ofloxacin and ofloxacin-N-oxide separation has been described (White et al. 1987). A Microbondapak C 18 column was utilised with a mobile phase of 0.1 molj L citric acid: methanol (75: 25) with a flow rate of 2 mljmin. Serum preparation consisted of acidification with 0.16 N HCl and fluorescence of all 3 compounds was measured at 294nm. Using this methodology, recovery of the metabolites in spiked control samples was 100%. If quinolone concentrations are to be monitored in the future, new methods are needed. The technical expertise and expense required for HPLC assays precludes their widespread clinical use. The technology involved in the production of fluorescence polarisation immunoassays will have to be applied to the quinolones before clinical use of quinolone serum concentrations can be accomplished. Selected patient populations may benefit from serum quinolone concentration monitoring.

3. Mechanism of Action and Resistance Quinolone antibiotics are rapidly bactericidal to a wide range of bacteria. At least 3 mechanisms are responsible for this antibacterial action, but only 2 are clearly defined. Inhibition of DNA gyrase is believed to be common to all quinolones and the degree of inhibition is related to bactericidal activity (Lewin et al. 1988; Sato et al. 1986). DNA gyrase (topoisomerase II) is responsible for introduce ing negative superhelical twists into double-stranded DNA allowing DNA replication and facilitating DNA synthesis, repair, recombination and transposition (Crumplin et al. 1987; Wolfson et al. 1985).

35

Ofloxacin Pharmacokinetics

A second mechanism has been termed the 'SOS' response. This is a complex reaction inducing DNA repair and delaying cell replication, producing filamentous shaped bacteria in response to conditions which may damage DNA, including exposure to quinolones. The reason for the rapid bactericidal effect of quinolones is not known but may involve a combination of mechanisms. Ciprofloxacin and ofloxacin have been shown to exert 2 bactericidal mechanisms against E. coli. Ciprofloxacin appears to possess only 1 mechanism against staphylococci, whereas ofloxacin employs 2 mechanisms. This may account for the higher MIC values for ciprofloxacin against staphylococci (Lewin et aI. 1988). Through numerous mechanisms, bacteria develop resistance remarkably quickly after the introduction of new antibiotics. Quinolone resistance appears to occur primarily through single step mutations in the structure of DNA gyrase (Crumplin et al. 1987). Resistance to new quinolones such as ofloxacin occurs less frequently than with the older quinolones (Crumplin et al. 1987; Kaatz et al. 1990; Torres et al. 1986). Resistance may also develop from decreased drug permeation, increased efflux or a combination of the two. AI-

though plasmid-mediated resistance is common with many antibiotics, it has not been encountered with the quinolones (Courvalin 1990; Wolfson et al. 1985). Ofloxacin-resistant strains can be selected in the laboratory and probably arise as a result of 2 independent mutations, which may explain the lower frequency of resistance seen with the newer quinolones. These mutants quickly lose their resistance in the absence of antibiotics and their clinical significance is unknown (Crumplin et al. 1987). The rabbit model of staphylococcal endocarditis indicates that resistance during ofloxacin therapy occurs at a lower frequency than seen with ciprofloxacin and fleroxacin (Kaatz et al. 1990). Further study of Gram-positive infections is warranted.

4. Pharmacokinetics Ofloxacin is well characterised pharmacokinetically in healthy volunteers (tables I and 11). Less thorough investigations have been conducted in patients. Differences in study design, pharmacokinetic model and patient populations give rise to an inherent variability in pharmacokinetic parameters obtained.

Table I. Comparative pharmacokinetics of single oral doses of selected quinolones in healthy volunteers

Dose (mg)

F (%)

Cmax (mg/L)

Ciprofloxacin

500 750

52-84

1.5-2.8 2.0-4.2

Enoxacin

600

87-91

Norfloxacin

400

Ofloxacin

Pefloxacin

a

Vd (L/kg)

Reference

3.3-4.8

2.5-4.4

Berl/an et al. (1986) Borner et al. (1986b) Hoffken et al. (1985) Ullmann et al. (1986)

2.9-4.3

4.3-7.6

1.6-2.9

Chang et al. (1988) Wise et al. (1984)

_8

1.5-1.6

3.5-7.0

200 400 600

95-100

1.6-2.2 3.2-4.3 6.7-8.1

5-8

400

90-100

3.2-4.5

t~

(h)

10.5-12.7

Unable to determine, intravenous formulation not available. = bioavailability; Cmax = peak plasma drug concentration;

Abbreviations: F

Adhami et al. (1984) Swanson et al. (1983)

t~

1.0-1.5

See text

1.5-1.9

Frydman et al. (1986) Barre et al. (1984)

= elimination half-life; Vd = volume of distribution.

Clin. Pharmacokinet. 22 (1) 1992

36

Table II. Pharmacokinetics of ofloxacin

Dose (mg)

Vd (L/70kg)

CLR (ml/min)

CL (ml/min)

Ae(24) (%)

AUC (I'g' h/ml)

Reference

(h)

111 102

5.6 4.9

197 202

230 a 240 a

74 73

14.6 28.0

Lode et al. (1987)

4.5 4.3-5.4

185 140-190

235 235-280

73 66-77

7.3 14-14.4b 13.4c

Lode et al. (1987) Farinotti et al. (1988) Lode et al. (1987)

tV2~

Oral

200 400

Intravenous

100 200

a

90 86-108

Apparent total clearance.

b AUC(O-oo). c AUC(O-12). Abbreviations: CLR = renal clearance; CL = total body clearance; Ae(24) = amount of drug excreted unchanged in urine over 24h; AUC = area under the concentration-time curve; for other abbreviations, see table I.

4.1 Absorption Ofloxacin and the newer quinolones are well absorbed orally with the exception of norfloxacin. Oral bioavailability of ofloxacin appears to be complete, with 95 to 100% absorbed (Lode et al. 1987). Peak serum concentrations are attained rapidly (range 0.5 to 3h) [Bitar et al. 1989; Leroy et al. 1987; Lode et al. 1987; Verho et al. 1985; Warlich et al. 1990]. The administration of ofloxacin with food delays the time to maximum concentration (tmax) but does not alter the extent of absorption (H6ftken et al. 1988; Leroy et al. 1987). Increasing the dose prolongs the tmax slightly and produces linear increases in peak serum concentrations (Cmax) [Lode et al. 1987; Verho et al. 1985). Mean Cmax values following single doses of 200, 400 and 600mg range from 1.6 to 2.2, 3.2 to 4.3 and 6.7 to 8.1 mg/L, respectively (Bitar et al. 1989; Flor 1989; Leroy et al. 1987; Lockley et al. 1984; Lode et al. 1987; Verho et al. 1985). Multiple doses of 200mg orally every 12h produce mean Cmax values of 3 mg/L (Warlich et al. 1990). Steady-state Cmax values after 400mg orally twice daily are approximately 5 mg/L (Flor 1989). The serum concentrations are generally well in excess of the MIC values for Gram-positive and Gram-negative bacteria within the spectrum of activity of ofloxacin.

4.2 Distribution Ofloxacin is widely distributed into bodily secretions and inflammatory exudates. The volume of distribution (Vd) varies between 1.0 and 1.5 L/ kg after oral or intravenous administration (Farinotti et al. 1988; Flor 1989; Lode et al. 1987; Warlich et al. 1990)_ Vd values as large as 3 L/kg have been reported after oral administration, but oral data may be less accurate for determination ofVd than intravenous data (Leroy et al. 1987). Low protein binding is common to all fluoroquinolones. Mean ofloxacin serum protein binding is 25% and is not affected by drug concentration (Lode et al. 1987). Ofloxacin achieves inhibitory concentrations in saliva, blister fluid, pancreatic juice, bile, sputum, lung tissue, prostatic tissue and secretions, urine, cerebrospinal fluid, bone and tonsillar tissue, and intracellularly (table III). Blister fluid is a useful model for determining passive diffusion drug characteristics into extracellular fluid. A single oral dose of ofloxacin 600mg was given to 6 healthy volunteers to assess serum and cantharides blister concentrations_ The maximum mean blister and serum concentrations were 5.2 and 8.2 mg/L, respectively. Penetration into blister fluid was slow (tmax = 5.3h), but concentrations above 4 mg/L were obtained within 3h.

Ofloxacin Pharmacokinetics

Alternatively, the ratio of blister fluid to serum area under the concentration-time curves (AVC) was 1.25, mainly because blister fluid concentrations exceeded those in serum from 4 to 12h post-dose. This indicates a high degree of tissue penetration. Elimination half-lives (t'l2) from serum and blister fluid were comparable (Lockley et al. 1984). Tissue penetration after multiple doses may be a more realistic model of passive diffusion (Warlich et al. 1990). Oral ofloxacin 200mg twice daily for 3 days was evaluated using both cantharides and suction blisters. Peak serum, cantharides and suction blister concentrations were 3, 2.3 and 2.9 mg/ L, respectively. Remarkably similar results for t1h, AVC ratio and blister fluid concentration in excess of serum concentrations were obtained compared with the abovementioned singie-dose study. On the basis of these results, blister concentrations exceed the MIC90 for a variety of pathogens including Staphylococcus aureus, Enterobacteriaceae spp. and Neisseria gonorrhoeae. Quinolones penetrate bronchial secretions and tissue to a higher degree than penicillins, cephalosporins or aminoglycosides, possibly due to active secretion (Gerding et al. 1989). Sputum to serum Cmax ratios ranged from 0.72 to 0.86 and sputum to serum AVC ratios (from administration to lIh post-dose) were 0.78 to 1.03. Sputum and serum Cmax values after single oral doses of 400, 600 and 800mg were 2.7 and 3.7,6.1 and 7.1, and 6.3 and 8.8 mg/L, respectively (Davies et al. 1987). Bronchial secretion and serum concentrations at bronchoscopy after 11 singie oral 400mg dose were studied by Symonds et al. (1987). Individual variation was pronounced. Over the 1 to 6h post-dose period, bronchial secretion concentrations ranged from l.l to 4.5 mg/L and concentrations above 1.5 mg/L were maintained in 14 of 16 patients. Ratios of bronchial secretion concentrations to serum concentrations ranged from 0.53 to 0.92. Lung tissue concentrations have been evaluated in singleand multiple-dose designs. Tissue concentrations exceeded plasma concentrations by an average of 200 to 400% (Couraud et al. 1987; Davey et al. 1991; Wijnands et al. 1988). After single oral doses of 200mg, tissue concentrations are maintained

37

above 2 mg/kg dlfring the interval between 2 and 6h, and 200mg orally twice daily maintains concentrations above 2 mg/kg over the entire dosage interval (Davey et al. 1991). In general, high sputum concentrations in relation to the MIC of the pathogen result in greater efficacy (Davies et al. 1987). The efficient penetration of ofloxacin into sputum and tissue correlates with the favourable results of therapy for respiratory tract infections. For pathogens such as Haemophilus injluenzae, Moraxella (Branhamella) catarrhalis and the Enterobacteriaceae spp., ofloxacin in daily doses of 400 to 800mg in 2 divided doses has shown bacterial eradication rates of 80 to 90% (Grassi et al. 1987). Lower response and eradication rates are obtained against Streptococcus pneumoniae and P. aeruginosa, though these can be improved by higher dosages (Maesen et al. 1987; Grassi et al. 1987). Vrine concentrations greatly exceed the MIC values of potential urinary pathogens despite the adverse effect that urine and low pH have on MIC values (Hooper et al. 1985). Vrine concentrations of 250 to 700 mg/L are easily obtained after 200 to 800mg doses (Farinotti et al. 1988; Neuman 1988). Intracellular antibiotic penetration is essential in treating atypical pneumonias due to L. pneumophila or C. trachomatis and mycobacterial infections. Ofloxacin maintains activity intracellularly and rapidly enters and exits polymorphonuclear neutrophils depending on the extracellular concentration. In vitro cellular to extracellular (C/E) ratios at 2 and 5 mg/L were 8.3 and 6.7, respectively (Pascual et al. 1989). Ofloxacin penetration into tissue culture epithelial cells and fibroblasts is lower, but C/E ratios remain above 2.0 (Pascual et al. 1990). Alveolar macrophages are also penetrated by ofloxacin, ciprofloxacin and pefloxacin, with C/E ratios of 7.1, 8.1 and 6.9, respectively (Carlier et al. 1987). The high intracellular penetration of ofloxacin supports clinical evaluation of the drug in the therapy of intracellular organisms. Although not presently indicated, the spectrum of activity, complete bioavailability and high bone penetration would support the use of ofloxacin for

Clin. Pharmacokinet. 22 (1) 1992

38

Table III. Penetration of ofloxacin into bodily secretions and tissues

Tissue

Dose (mg)

Ratio site: serum concentration ("!o)

Reference

Sputum

400 600 800 200

73 86 72 120

Davies et al. (1987)

SO SO SO MOB

Bronchial secretions

400 SO

Lung, healthy

200 MO

350

200 MO

390

diseased

Lam et al. (1986)

53-92

Symonds et al. (1987) Couraud et al. (1987)

Warlich et al. (1990) Lockleyet al. (1984)

Blister fluid

200 MO 600 SO

Bile, GB

200 MO 400 MO

950 230

Kazmierczak et al. (1987) Chin et al. (1990)

200 MO 300 SO

390 192-311

Kazmierczak et al. (1987) Pederzoli et al. (1989)

Bone

200 SO 400 SO

30-120 17-61

Meissner et al. (1990) Wittmann et al. (1986)

Cartilage

200 SO

70-440

Meissner et al. (1990)

Prostate secretions

400 SO

117

Naber et al. (1987)

200 SO 200 SO

112 317

Claes et al. (1986)

CBO

tissue

76-177 80-183

Pancreatic juice

300 SO 400 SO

33-92 92

Pederzoli et al. (1989) BrattstrOm et al. (1988)

CSF, normal

300 SO

40

Orancourt et al. (1988)

47 87 47-65 28 18-45

Stjjbner et al. (1986b )

purulent

SO MO MO SO SO

Aqueous humor

200 200 200 300 200

PMN

NA

670-830 210

Alveolar macrophage

NA

710

Stahl et al. (1986) Orancourt et al. (1988) Fisch et al. (1987) Pascual et al. (1989) Carlier et al. (1987)

a Three times daily. b Patient mixture of infected and noninfected CSF. Abbreviations: SO single dose; MO multiple dose (twice daily unless otherwise noted); GB polymorphonuclear neutrophil; NA not applicable. duct; CSF cerebrospinal fluid; PMN

=

=

= =

=

= gall bladder; CBO = common bile

Ofloxacin Pharmacokinetics

osteomyelitis and related infections (Gentry et al. 1991). The determination of bone concentrations has several methodological difficulties, but the quinolones overall achieve concentrations in bone which are 30 to 60% of serum concentrations (Gerding et al. 1989). Few studies have evaluated ofloxacin bone concentrations. After a single 400mg oral dose, bone concentrations remained above 0.5 mg/L from 2 to 8h post-dose (Whitmann et al. 1986). Bone concentrations ranged from 0.75 to 9.77 mg/L and serum concentrations ranged from 1.0 to 5.0 mg/L in 12 patients receiving 200mg orally twice daily for chronic osteitis (Etesse et al. 1988). After a single 200mg intravenous dose, concentrations over the 1 to 12h period in cortical bone ranged from 0.59 to 0.86 mg/L; in cancellous bone the values were 0.99 to 1.7 mg/L and in cartilage 1.38 to 2.19 mg/L (Meissner et al. 1990). Ofloxacin bone concentrations are above the MIC90 of staphylococci and the Enterobacteriaceae spp., but the treatment of less susceptible bacteria such as P. aeruginosa may be less successful or require larger doses. The quinolones are effective agents against bacterial prostatitis, a finding consistent with the significant penetration into prostatic tissue and secretions. The ratio of ofloxacin concentrations in prostatic tissue to those in plasma was 3.17 2h after a single 200mg oral dose (Claes et al. 1986). Prostatic and vesical fluid concentrations 2h after the final dose of 400mg/day orally for 3.5 days were 2.44 and 2.5 mg/L, respectively. Quinolone concentrations in prostatic fluid remain high over 24h despite falling serum concentrations (Dalhoff et al. 1984). 4.3 Metabolism Ofloxacin undergoes a limited degree of biotransformation. In individuals with normal renal function, less than 5% of ofloxacin is excreted in the urine as metabolites (Lode et al. 1987). Three metabolites have been identified: ofloxacin glucuronide, demethyl-ofloxacin and ofloxacin-N-oxide (Borner et al. 1986a). Demethyl-ofloxacin has moderate antibacterial activity and can represent

39

2 to 20% of ofloxacin concentrations. Such low metabolite concentrations are present even in renal failure that it is of negligible clinical importance (White et al. 1987, 1988). 4.4 Elimination The mean t'l2 ranges from 5 to 8h (Farinotti et al. 1988; Flor 1989; Lockley et al. 1984; Lode et al. 1987; Verho et al. 1985). Some investigators have found shorter t'l2 values after intravenous administration, but overall there appears to be no difference when compared with oral administration (Lode et al. 1987). Renal excretion accounts for approximately 75 to 80% of ofloxacin elimination over 24 to 48h (Leroy et al. 1987; Lockley et al. 1984; Lode et al. 1987; Verho et al. 1985). This indicates a small degree ofnonrenal clearance (CLNR) which is confirmed by clearance data. Total body clearance (CL) after oral administration ranges from 230 to 290 mljmin (13.8 to 17.4 L/h) [Leroy et al. 1987; Lode et al. 1987]. Similar values are obtained for CL after intravenous administration (Farinotti et al. 1988; Lode et al. 1987). Renal clearance (CLR) ranges from 150 to 250 ml/min (9.0 to 15.0 L/h) [Farinotti et al. 1988; Lode et al. 1987]. As previously stated, oral bioavailability appears complete. Almost identical metabolite excretion data following oral and intravenous administration corroborate the lack of a first pass effect (Lode et al. 1987). Most ofloxacin pharmacokinetic data have been obtained from single dose studies and may not be applicable to clinical situations. However, multiple dose administration of ofloxacin does not appear to result in significant accumulation (Farinotti et al. 1988). The choice of model can affect the calculation of pharmacokinetic parameters and, in addition to population variability, may explain the differences seen among subjects. Although investigators have used 1-, 2- and 3-compartment models, a 2-compartment model appears to characterise ofloxacin pharmacokinetics best (Lode et al. 1987; Verho et al. 1985).

40

Clin. Pharmacokinet. 22 (1) 1992

5. Pharmacokinetics in Renal Dysfunction Ofloxacin has been well studied in patients with diminished renal function. Since ofloxacin is primarily eliminated renally, decreased glomerular filtration rates (GFR) would be expected to have profound effects on its disposition. Values of t'/2 are linearly related to creatinine clearance (CLcR) until CLcR falls below 20 mljmin (1.2 L/h), when t'/2 rises sharply (Fillastre et al. 1987). The t max of ofloxacin may be delayed in patients with a GFR of less than 30 mllmin (1.8 L/h), though this has not been a universal finding (Fillastre et al. 1987; Navarro et al. 1990). Vd does not appear to alter in the presence of renal dysfunction (Fillastre et al. 1987). The choice of pharmacokinetic model used to interpret data may explain apparent differences (such as seemingly altered Vd) in patients with decreased renal function (Navarro et al. 1990). Oral bioavailability has not been directly assessed in patients with renal dysfunction but does not appear to be altered (Navarro et al. 1990). Studies of blister fluid concentrations after oral administration also indicate that distribution characteristics are not modified (Navarro et al. 1990). For patients with CLcR of >80, 20 to 80, and <20 mljmin (>4.8, 1.2 to 4.8, and <1.2 L/h), a dose of ofloxacin 200mg can be administered every 12, 24, and 36 to 48h, respectively (Fillastre et al. 1987). Other formulas advocated for dosage adjustment have not been adequately evaluated (Hoffler et al. 1987). 5.1 Haemodialysis Ofloxacin is eliminated to a varying degree, usually 15 to 25%, by haemodialysis (Dorfier et al. 1987; Fillastre et al. 1987; Kampf et al. 1990). Ofloxacin elimination occurs almost entirely during the first 2h of dialysis and the first haemodialysis period after beginning ofloxacin has the greatest effect of lowering drug concentrations (Dorfier et al. 1987). Longer haemodialysis treatments should not have any greater effect on ofloxacin clearance. An initial dose of 200mg followed by 100mg after the first dialysis treatment with a maintenance dosage

of 100mg daily maintains adequate serum concentrations and has been effective in a small group of patients (Dorfier et al. 1987). Kampf et al. (1990) evaluated a loading dose of 200mg, followed by 100mg daily administered after dialysis on dialysis days. No significant difference was seen when trough concentrations (Cmin) were compared between dialysis and nondialysis days, suggesting that additional doses are not required when ofloxacin is given after dialysis sessions. Ofloxacin after haemodialysis treatments in a dosage of 200mg every 36 to 48h may also be an acceptable regimen. Further work is needed to clarify the proper dosage adjustments during haemodialysis treatment. The effect of continuous arteriovenous haemofiltration (CAVH) on the pharmacokinetics of quinolones has not been evaluated. 5.2 Continuous Ambulatory Peritoneal Dialysis Patients maintained on continuous ambulatory peritoneal dialysis (CAPD) represent a unique problem with regard to dosage. Not only must therapeutic serum concentrations be maintained, but concentrations of the drug in peritoneal dialysis solution must be adequate if the site of infection is the peritoneum. Chan et al. (1987) investigated the pharmacokinetics of a single dose of ofloxacin 300mg and those of a longer regimen with a 400mg loading dose followed by 200mg daily for 7 days. Patients received peritoneal dialysis 3 times daily with 2L exchanges of 1.5% dialysis solution. The t max was delayed at 3.7h but the mean Cmax of 2.44 mg/L after the 300mg dose was comparable with those seen in otherwise healthy patients. Peritoneal dialysis solution concentrations were below the M1C90 of staphylococcal isolates for 2h following dialysis exchange but then rose to near serum concentrations. Cmin values during the 7-day treatment regimen ranged from 1.75 to 7.0 mg/L (mean 3.71 mg/L). This same group of investigators evaluated 2 oral regimens of ofloxacin for peritonitis. Success was defined as negative peritoneal cultures and the resolution of signs and symptoms of infection at least 7 days following antibiotic treat-

Ofloxacin Pharmacokinetics

ment. The higher oral dosage with a 400mg loading dose followed by 300mg daily for 9 days produced an overall success rate of 83% while 400mg followed by 200mg daily for 6 days was successful in only 50%. It was uncertain if the higher concentrations of ofloxacin in peritoneal dialysis fluid (4.9 vs 2.8 mg/L at 7 days with higher and lower daily doses, respectively) or the greater treatment length were responsible for the improved efficacy. Cmin values continued to increase for the entire treatment length with the larger dosage (Chan et al. 1988). Further study is warranted especially if longer treatment lengths are considered.

6. Pharmacokinetics in the Elderly Healthy elderly volunteers (65 to 85 years) with normal renal function receiving single 400mg doses or 400mg every 12h were evaluated at steady-state (Flor 1989). Cmax , AVC, t max and Vd were similar to values obtained in healthy young volunteers. Only the t'l2 was slightly delayed (7.4h compared with 5.4h). Accumulation of approximately 20% occurred, but steady-state was achieved within 48h of beginning ofloxacin administration. No dosage alteration appears to be needed for healthy elderly patients without renal dysfunction.

7. Drug Interactions Previous experience with the quinolones has increased the awareness of the possibility of drug interactions with this antibiotic class. As a result, a considerable amount of data has accumulated for most quinolones. Several quinolones such as ciprofloxacin are capable of inhibiting the metabolism of drugs transformed by the cytochrome P450 enzyme system. The following is a brief review of drug interactions with fluoroquinolones. 7.1 Methylxanthines Of the quinolones studied, enoxacin appears to cause the greatest inhibition of theophylline metabolism, followed in order by ciprofloxacin, pefloxacin, norfloxacin and ofloxacin (Edwards et al.

41

1988; Wijnands et al. 1987) [table IV]. Enoxacin decreases theophylline clearance by 40 to 75% (Edwards et al. 1988). Ofloxacin has little or no effect on theophylline clearance (Fourtillan et al. 1986; Gregoire et al. 1987; Niki et al. 1987; Sano et al. 1987; Wijnands et al. 1986, 1989). Caffeine clearance and half-life are also unaffected by ofloxacin although most quinolones which alter theophylline metabolism produce comparable effects on caffeine (Staib et al. 1987). Patients receiving theophylline do not appear to be at an increased risk of toxicity with concomitant ofloxacin administration. 7.2 Ion-Containing and Antiulcer Agents Quinolone bioavailability is affected by polyvalent metal ions such as magnesium, aluminium, iron and possibly calcium. Antacids containing aluminium or magnesium salts appear to affect the bioavailability of all quinolones. The simultaneous administration of magnesium-aluminium hydroxide (MAH) with ofloxacin 200mg or ciprofloxacin 500mg in single doses reduced AVC by 73 and 91%, respectively. The proposed mechanism of this interaction is chelation of the quinolone, forming an unabsorbable complex. A recent study evaluated the administration of MAH 24h and 2h prior to and 2h after a single dose of ofloxacin 400mg (Flor et al. 1990). Only MAH 2h before ofloxacin produced a significant 20% reduction in relative bioavailability. The influence of calcium carbonate was also investigated using the same dosage schedule and no significant interaction was detected. Ranitidine and pirenzepine (an anticholinergic agent) caused varying degrees of lowering of Cmax and delay of t max but did not alter the total extent of ofloxacin absorption (H6f1ken et al. 1988). Sucralfate has been shown to inhibit the absorption of ciprofloxacin and norfloxacin (Nix et al. 1989; Parpia et al. 1989). Administration of sucralfate Ig 6 and 2h before a single dose of ciprofloxacin 750mg decreased relative bioavailability by 30%; however, one-third of the subjects had decreases greater than 50%. Sucralfate reduced the relative bioavailability of norfloxacin 98.2% and 43.4% when given si-

42

Clin. Pharmacokinet. 22 (1) 1992

Table IV. Summary of influence of quinolones on theophylline clearance (Cl) [after Edwards et al. 1988] Drug

Subjects

Enoxacin

14 severely ill COPO patients, 41-86y 8 stable COPO patients, 51-69y 6 healthy subjects

Decrease in Cl (%)

References

42.4

Wijnands et al. (1985) Wijnands et al. (1986) Beckmann et al. (1987)

63.6 74.0

8 stable COPO patients, 51-69y 8 healthy men 8 young healthy men

33

Wijnands et al. (1986) Nix et al. (1987) Schwartz et al. (1988)

Pefloxacin

8 stable COPO patients, 51-69y

29.4

Wijnands et al. (1986)

Ofloxacin

8 stable COPO patients, 51-69y 15 healthy men, 18-34y 5 healthy subjects, 24-39y 12 healthy men, 18-3Oy

5.1 12.1

5

Wijnands et al. (1986) Gregoire et al. (1987) Sano et al. (1987) Fourtillan et al. (1986)

7.4 11.3 14.9

Sano et al. (1987) Bowles et al. (1988) Ho et al. (1988)

Ciprofloxacin

Norfloxacin

5 healthy subjects, 24-39y 10 healthy men, 24-34y 8 healthy subjects, 21-34y

30.4

17.8

o

Abbreviation: COPO = chronic obstructive pulmonary disease.

multaneously with and 2h before norfloxacin, respectively. This interaction is most likely to be due to the aluminium content of sucralfate and a comparable effect could be expected with other quinolones including ofloxacin. In summary, administration of antacids within at least 2h ~fore or after the administration of ofloxacin should be avoided. Ofloxacin with low doses of calcium carbonate do not appear to be problematic although concurrent administration and larger doses have not been evaluated. Concomitant sucralfate with ofloxacin therapy is not advisable until more information is available regarding this combination. Polk et al. (1989) administered a single dose of ciprofloxacin 500mg to subjects receiving ferrous sulfate 325mg 3 times daily or a multivitamin with zinc every morning in a randomised crossover study. Ciprofloxacin bioavailability was reduced 64% by the ferrous sulfate and 24% by the multivitamin with zinc. A crossover single-dose study found similar effects on both ciprofloxacin and ofloxacin (Lode et aI. 1989). Ciprofloxacin 500mg or ofloxacin 400mg were administered concomitantly with placebo or 1135.4mg offerrous-glycine-sulfate

complex. Bioavailability of ciprofloxacin and ofloxacin was reduced 48 and 36%, respectively. The mechanism appears to be the same as with MAH antacids: chelation of the quinolone with the cation. Administration of ciprofloxacin, ofloxacin and probably other quinolones with iron- and zinccontaining products should be avoided. 7.3 Probenecid CLR values of ofloxacin and other quinolones exceed the GFR, suggesting tubular secretion is an important elimination pathway. Probenecid blocks tubular secretion of uric acid, penicillin and other drugs, including quinolones. Probenecid 2.5g prolonged the t'/2 and increased the AUC of a single dose of enoxacin 600mg and decreased CLR from 374 to 171 ml/min (22.44 to 10.26 L/h) [Wijnands et al. 1988]. A single dose study with ciprofloxacin 500mg and probenecid Ig noted reduced ciprofloxacin CLR with no difference in AUC or t'/2' possibly due to increased CLNR. The combination of ofloxacin and probenecid has not been evaluated,

Ofloxacin Pharmacokinetics

but its high reliance on CLR supports the possibility of this drug interaction. 7.4 Anticoagulants The possibility of an interaction with warfarin has been reported (Leor et al. 1988). A 40-year-old woman received a mitral valve replacement and was being maintained on warfarin 5mg daily with digoxin, furosemide (frusemide), spironolactone, prednisone and verapamil. Ofloxacin 200mg 3 times daily was begun and 2 days later the degree of anticoagulation had increased as measured by the International Normalised Ratio. The patient was not rechallenged. The mechanism has been postulated to be inhibition of metabolism, displacement from albumin or the elimination of gastrointestinal bacteria producing vitamin K. Ofloxacin has little effect on hepatic metabolism and is only 15 to 25% protein bound, leaving the final possibility more likely. Until more data are available this drug interaction should be monitored closely.

8. Therapeutic Considerations Ofloxacin is a fluoroquinolone with pharmacokinetic characteristics which include essentially 100% bioavailability, relatively high serum concentrations compared with MIC values and a prolonged half-life. Minimal drug interactions with of· loxacin make it a useful alternative in patients with complicated medication regimens. In vivo and in vitro data support the reduced susceptibility of ofloxacin to the development of resistance by S. aureus. More information in carefully controlled human studies is needed to clarify the proposed advantage in the treatment of Gram-positive infections. The high dependence of ofloxacin on renal clearance makes dosage adjustments in mild renal dysfunction necessary. However, its half-life of 5 to 8h and sustained tissue concentrations in patients with normal renal function may allow the use of single or once-daily administration of ofloxacin for certain indications, improving patient compliance and cost-effectiveness.

43

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Clin. Pharmacokinet. 22 (1) 1992

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Correspondence and reprints: Dr Michael J. Rybak. Wayne State University, College of Pharmacy and Allied Health, Department of Pharmacy Practice, 328 Shapero Hall, Detroit, MI 48201, USA.