DRUG DISPOSITION

Clin. Phormacokinet. 27 (6): 418446, 1994 0312-5963/94/0012-Cl418/S 14.50/0

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Pefloxacin Clinical Pharmacokinetics Fram;oise Bressolle,l,2 Fatima Gonc;alves,2 Anne Gouby3 and Marc Galtier2 1 Laboratoire de Pharmacocinetique, Faculte de Pharmacie, Montpellier, France 2 Laboratoire de Pharmacocinetique, Centre Hospitalier Universitaire Caremeau, Nimes, France 3 Laboratoire de Bacterioiogie, Centre Hospitaiier Universitaire G. Doumergue, Nimes, France

Contents Summary ........... . 1. Chemistry . . . . . . . . . . . . 2. Pharmacodynamic Properties 2.1 Mechanism of Action .. 2.2 In Vitro Antibacterial Activity 2.3 Postantibiotic Effect and Cellular Penetration 2.4 Resistance . . . . . . . . 3. Pharmacokinetic Properties 3.1 Absorption. 3.2 Distribution. 3.3 Metabolism 3.4 Elimination . 4. Effects of Age and Various Disease States on Pharmacokinetics 4.1 Age . . . . . . . . . .. . 4.2 Impaired Renal Function. . . . . . . . . . . 4.3 HepatiC Dysfunction . . . . . . . . . . . . . 4.4 Other Altered Pathophysiological States . 5. Pharmacokinetic Interactions with Other Drugs 6. Penetration into Body Fluids . 6.1 Saliva . . . . . . . . . . . . 6.2 Otolaryngological Fluids . 6.3 Sweat . . . . . . . . ... . 6.4 Blister Fluid . . . . . . . . . 6.5 Bronchial Secretions and Sputum 6.6 Cerebrospinal Fluid . . . . . . . 6.7 Cervical Secretions . . . . . . . 6.8 Prostatic and Ejaculate Fluids . 6.9 Ocular Fluids. ....... . 6.10 Bile 6.11 Other Fluids . . . . 7. Penetration into Tissues 7.1 Heart . . . . . . . . 7.2 Lung . . . . . . . . 7.3 Muscle, Fat and Skin 7.4 Bone . . . . . . . . . 7.5 Gynaecological Tissues 7.6 Ocular Tissues . . . . . . 7.7 Otolaryngological Tissues 7.8 Prostatic Tissue and Epididymis 7.9 Other Tissues. . . . . . . 8. Therapeutic Considerations. . , . .

418 419 419 419 420 421 421 421 421 423 425 425 427 427 427 428 429 429 430 430 431 431 431 431 431 434 434 435 435 436 436 436 436 437 437 440 440 441 441 441 441

419

Pefloxacin Clinical Pharmacokinetics

Summary

Pefloxacin has a broad spectrum of activity against a great number of Gramnegative and Gram-positive bacteria. It is also capable of penetration into cells, yielding high tissue : serum ratios, with implications for the treatment of infections caused by intracellular pathogens. Pefloxacin is well absorbed from the gastrointestinal tract. Its elimination half-life ranges from 6.2 to 12.4 hours. After repeated administration, a major change in pharmacokinetic parameters is observed. Pharmacokinetic parameters are minimally altered or not altered in patients with impaired renal function. Altered plasma pharmacokinetics in patients with liver insufficiency and in elderly patients are observed, so dosage adjustments are necessary. In addition, pefloxacin interacts with a number of other compounds at hepatic (e.g. theophy lline and cimetidine) and gastrointestinal (e.g. antacids) sites. With the exception of saliva, cerebrospinal fluid, aqueous humor, vitreous fluid and amniotic fluid, body fluid concentrations reach plasma concentrations. Studies on tissue penetration show that concentrations exceeding plasma concentrations are obtained in most tissues. The highest tissue: plasma concentration ratios are achieved in lung and kidney, whereas concentrations in fat are considerably lower than those in plasma.

The quinolone antimicrobial agents are a new and expanding class of oral drugs that are effective in the treatment of a variety of bacterial infections. The first drug of this class to be used clinically was nalidixic acid. This drug and most of its analogues had poor antibacterial activity, poor oral availability and caused the rapid emergence of resistance. [IJ Subsequently, fluoroquinolones were found to be highly effective against Gram-positive and Gramnegative bacteria both in vivo and in vitro with few of the problems of their predecessors. 12 ] In this paper we review data published in the literature regarding the pharmacokinetics and tissue and fluid distribution of pefloxacin.

1. Chemistry Pefloxacin is a fluorinated piperazinyl-substituted quinolone derivative of nalidixic acid (fig. I). The piperazine substituent was found to be primarily responsible for the totallipophilicity of the molecule)3] 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 at the C4 position of the piperazinyl group increases the Gram-positive activ© Adis International Limited. All rights reserved.

ity of pefloxacin and slightly decreases activity against Gram-negative bacteria, especially Pseudomonas aeruginosa. In addition, the entire sidechain increases oral bioavailability, elimination half-life (tJ;2) and serum concentrations.[4,5]

2. Pharmacodynamic Properties 2.1 Mechanism of Action

Quinolone antibiotics are rapidly bactericidal to a wide range of bacteria. They are active against bacteria whether in the rapid growth phase or stationary phase. At least 3 mechanisms are responsible for this antibacterial action, but only 2 are clearly defined)6] The primary event in the bactericidal action of quinolones is the inhibition of DNA synthesis due to the interaction with DNA gyrase, a prokaryotic type II topoisomerase that converts relaxed closed-circular DNA to negatively supercoiled DNA, in an adenosine triphosphate (ATP)-dependent manner. Gyrase consists of two A and B subunits encoded by the gyrA and gyrB genes, respectively.[7-9] DNA gyrase is responsible for introducing negative superhelical twists into double-stranded DNA, allowing DNA Clin. Phormacokinet. 27 (6) 1994

Bressolle et al.

420

o

F~COOH

0",11~I. ) 0-

H3C

/N~

C2HS

~ __ M_'~~ IN

Pefloxacin glucuronide

~.,) 0N

:,e/N~ __ e,I H, ~ F~COOH IN

N H/

I

~

~.,) 0N

I

C2HS

N-demethyl-pefloxacin (Norfloxacin)

~

/

~

Oxo-pefloxacin

Oxo-norfloxacin

Fig_ 1. Metabolic pathways for pefloxacin.

replication and facilitating DNA synthesis, repair recombination and transposition.! 10] Fluoroquinolones interact with either the A subunit itself or a complex of DNA gyrase and DNA to inhibit enzymatic function'! II] Mutations affecting the B subunit can also alter bacterial sensitivity to 4-quinolones.! 12] It has also been suggested that induction of the 'SOS' response may be involved in the bactericidal mechanism of quinolones. The 'SOS' response is a complex reaction inducing © Adis International Limited. All rights reserved.

DNA repair and delaying cell replication, producing filamentous shaped bacteria in response to conditions that may damage DNA. The reason for the rapid bactericidal effect of quinolones may involve a combination of mechanisms.[13] 2.2 In Vitro Antibacterial Activity

Pefloxacin presents a broad spectrum of activity against a great number of Gram-negative and Gram-positive bacteria. In vitro activity of peClin. Pharmacokinet. 27 (6) 1994

Pefloxacin Clinical Pharmacokinetics

tloxacin against Gram-negative aerobes, Grampositive aerobes and anaerobes is summarised in table r.[14-16] Organisms may be considered susceptible if the minimum inhibitory concentration (MIC) is <2 mg/L, while MIC values between 2 and <4 mg/L may indicate moderate susceptibility for petloxacin. Petloxacin has a good antibacterial activity against Gram-negative bacteria including most species of Enterobacteriaceae and the genera Haemophilus, Neisseria and Legionella. There is no difference between the activity of petloxacin and its metabolite, nortloxacin, against N. gonorrhoeae and H. injluenzae. Petloxacin is more active than nortloxacin against Moraxella catarrhalis'! I 0] Against P. aeruginosa, petloxacin is less active than ciprofloxacin; furthermore, strains resistant to all quinolones are isolated with an increasing frequency. Against Acinetobacter baumannii there is a significant risk of clinical failure with all fluoroquinolones. Other Gram-negative species including Aeromonas hydrophila, Plesiomonas, Capnocytophaga, Agrobacter and Vibrio spp. are susceptible to pefloxacin. Methicillin-sensitive staphylococcal strains, including Staphylococcus aureus and S. epidermidis isolates are susceptible to petloxacin, which is more active than nortloxacin and as active as ofloxacin and ciprofloxacin against these strains. Clinical resistance to quinolones has emerged quickly among methicillin-resistant staphylococci. Streptococcus and Enterococcus spp. have only moderate sensitivity to pefloxacin.! II] Petloxacin, in common with otloxacin and ciprotloxacin, is inactive against most anaerobic species, including Bacteroides, Clostridium and Fusobacterium spp. Pefloxacin is moderately or poorly active against Gardnerella vaginalis, Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum. 2.3 Postantibiotic Effect and Cellular Penetration

A postantibiotic effect has been demonstrated with petloxacin. However, the clinical importance © Adis International Limited. All rights reserved.

421

of this effect remains to be fully established, and further studies are needed in this area) 17] Available data show that petloxacin and all other tluoroquinolones accumulate in phagocytic cells and even in nonphagocytic cells such as fibroblasts. However, it is not known for certain whether there is subcellular localisation of quinolones. Cellular uptake of tluoroquinolones is rapid. The consequence of the short half-life of quinolones within macrophages is that the pharmacokinetics of quinolones inside phagocytes are highly dependent on extracellular concentrations of the drugs. [18] Fluoroquinolones have been shown to be effective agents against some typical obligatory intracellular pathogens, such as Legionella spp., and have been shown to be effective in macrophages against S. aureus and Salmonella spp) 19,20] 2.4 Resistance

Outside the hospital environment, resistance to quinolones is still rare. Less than 5% ofthe isolates of common pathogens such as H. injluenzae, Escherichia coli, Salmonella spp., and methicillin sensitive S. aureus are resistant. However, the increasing frequency of quinolone-resistant nosocomial pathogens (e.g. methicillin-resistant S. aureus, P. aeruginosa, extended-spectrum ~-lactamase-pro­ ducing Klebsiella spp., etc.) is a matter for concern. In a French hospital the percentage of petloxacinresistant Serratia marcescens increased from 14.2 to 68% between 1984 and 1992)12] Two principal mechanisms of resistance have been characterised: (i) alteration of DNA gyrase, which results in decreased affinity for the quinolones; and (ii) decreased drug accumulation as a result of lower uptake or enhanced eftlux.!12] Resistance by mutations in gyrA or gyrB genes or mutations impairing the permeability, usually by modification of the OmpF porin, are chromosomally encoded. 3. Pharmacokinetic Properties 3.1 Absorption

Dose-dependent increases in petloxacin plasma concentrations were obtained over the range from Clin. Pharmacokinet. 27 (6) 1994

Bressolle et a/.

422

Table I. Activity of pefloxacin against Gram-negative aerobes, Gram-positive aerobes and anaerobes[14.16] Organism (number of isolates)

Concentration range for activity (mg/L)

MIC (mglL) MICso

Escherichia coli (50)

0.06-4

0.125

Klebsiella spp. (50)

0.06-2

0.12

MIC90

1

Citrobacter koseri (40)

0.06-1

0.12

C. freundii (25)

0.06-4

0.25

2

Enterobacter aerogenes (30)

0.06-0.25

0.125

0.25

E. cloacae (35)

0.06-16

0.125

2

Hafnia alvei (15)

0.03-0.125

0.06

0.06

Serratia spp. (25)

0.25-4

0.5

Proteus mirabilis (40)

0.06-1

0.25

1

P. vulgaris (25)

0.125-0.25

0.125

0.25

Morganella morganii (20)

0.06-1

0.125

0.25

Providencia alcalifaciens (10)

0.06-0.5

0.25

0.25

P. rettgeri (20)

0.03-2

0.25

0.5 4

0.25

P. stuartii (40)

0.125-8

0.5

Acinetobacter spp. (35)

0.03-2

0.25

Aeromonas spp. (10)

0.008-0.03

0.016

Non-mucoid Pseudomonas aeruginosa (60)

0.25-4

Mucoid P. aeruginosa (56)

0.12-4

Pseudomonas spp. (35)

0.06-4

2

4

Gardnerella vaginalis (20)

2-8

4

8

Haemophilus influenzae (50)

0.015-0.06

0.03

0.06

Moraxella catarrhalis (20)

0.125-0.25

0.125

0.016 2 4

Neisseria gonorrhoeae (40)

0.016-0.125

0.016

0.25 0.06

MS Staphylococcus aureus (20)

0.06-0.5

0.5

0.5

MS S. epidermidis (15)

0.25-0.5

0.5 >64

MR Staphylococcus spp.

0.5 >64

Groups A, C & G p-haemolytic Streptococcus spp. (40)

4-128

8

16

Streptococcus agalactiae (25)

8-32

16

32

S. pneumoniae (50)

4-16

8

16

a- and non-haemolytic Streptococcus spp. (20)

4-64

16

32

S. faecalis (20)

2-8

4

4

Enterococci spp. (20)

2-8

4

8

Bacteroides fragilis group (30)

4-32

16

32

B. melaninogenicus!oralis group (40)

2-16

8

16

B. ureolyticus (10)

0.125-2

0.25

0.5

Peptostreptococcus spp. (20)

1-8

2

8

Peptococcus spp. (20)

1-32

4

8

Clostridium spp. (20)

0.5-64

2

64

Fusobacterium spp. (10)

1-64

16

32

Eubacterium spp. (10)

1-16

4

8

Veillonella spp. (10)

0.25-2

1

2

Mobiluncus spp. (20)

4-16

8

16

=

Abbreviations: MIC minimum inhibitory concentration ; MICso MR methicillin-resistant; MS methicillin-sensitive.

=

=

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=MIC for 50% of tested strains; MIC90 =MIC for 90% of tested strains;

Clin. Pharmacokinet . 27 (6) 1994

423

Pefloxacin Clinical Pharmacokinetics

200 to SOOmg for oral and intravenous administration of single doses of the drug in healthy volunteers.[16,21] Following oral administration of single 200 to SOOmg doses of pefloxacin, the rate of absorption from the gastrointestinal tract is rapid,l22] peak plasma concentrations (Cmax ) occurred between 1.2 and 2.2 hours (table II), resulting mean Cmax values were 1.5 to 2.5 mg/L for the 200mg dose, 3.6 to 4.6 mg/L for the 400mg dose, 5.4 mg/L for the 600mg dose and 6.06 mg/L for the SOOmg dose. C max values increased roughly proportionally with the dose. After a single 400mg dose of pefloxacin was administered intravenously, C max values of 3.9 to 5.8 mg/L were achieved in healthy volunteers.[ 16,26,27] Plasma concentrations I to 1.5 hours after single intravenous and oral doses of 400mg were similar. After repeated intravenous and oral administration (400mg twice daily), plasma concentrations increased equivalently for both routes (5 to 10.1 vs 4 to II mg/L; table I); steady-state concentrations were achieved within 4S hours. After 7 to 10 days of treatment, the Cmax values ranged from 7.9 to 10 mg/L after oral administration and from 9.6 to 10.1 mg/L after intravenous administration of 400mg twice daily.[16,26] Trough plasma pefloxacin concentrations following oral administration rose from 1.5 to 2.1 mg/L on day I to a steady-state concentration of 3.8 mg/L on days 5 and 6 of treatment,[33] 5.9 mg/L on day 11[30] and 3.2 to 5.S mg/L on days 3 to 16.[26] Repeated intravenous or oral administration of pefloxacin produced slight accumulation, as shown by the overall increases in Cmax values and minimum plasma concentrations (Cmin) and the area under plasma concentrationtime curve (AUC) compared with those observed after administration of a single dose. The mean value of accumulation ratio computed from AUCO-12h on day 10 to AUCo-oo on day 1 or from AUCO-12h on day 16 to AUCo-oo on day I averaged 1.4)26] Following repeated intravenous and oral administration of pefloxacin 400mg twice daily, Cmax and Cmin values for N-demethyl-pefloxacin (norfloxacin) averaged 0.25 and 0.2 mg/L, respec© Adis International Limited. All rights reserved.

tively; for the N-oxide metabolite these values were 0.34 and 0.33 mg/L, respectively)26] Pefloxacin absorption was complete, and was not influenced by the dose administered. 3.2 Distribution

The pharmacokinetics of pefloxacin have been descri bed using a 2-compartment open model [21] or a 3-compartment model.[27,34] The diffusion of a drug into the extravascular space is determined by its protein binding, its lipophilicity, its acid-base properties and its molecular size. The quinolones penetrate well into body fluids. Passage to tissues occurs through passive diffusion of the drug across the capillary bed.f3 5] Gruber et al)36] demonstrated that the lipophilicity of quinolones is greatest at a neutral pH, suggesting that a blood pH of 7.4 increases the passage of these compounds through capillary membranes. The pH dependence of lipophilicity may also cause 'ion-trapping' of quinolones in body fluids and tissues with a slightly acidic or basic pH (e.g. inflamed tissues). Because the molecule is more ionised in these compartments, the consequence is a reduction in the movement of the molecule back into plasma. This can lead to higher tissue concentrations than those in plasma. Although low protein binding, high lipophilicity at blood pH and the relatively small molecular size of quinolones are certainly important factors for intensive distribution of drug into body fluids and tissues; other factors, such as binding at the outer or inner cell membranes, may be of equal importance. Pefloxacin, which has a molecular weight of 333.4D and pKa values of 6.3 and 7.6, is 20 to 30% bound to serum proteins and has an isoelectric point of 6.9. Pefloxacin is extensively distributed throughout the body, producing high tissue concentrations. The volume of distribution (V d) varies between 1.0 and 2.6 Llkg (table III). Pefloxacin, like other fluoroquinolones, accumulates in macrophages and several other types of nucleated cells (but not in erythrocytes»)20,40,41] The alveolar macrophages can accumulate pefloxacin in vivo to concentrations lO-fold greater Clin. Pharmacokinet. 27 (6) 1994

Bressolle et al.

424

Table II. Pefloxacin absorption pharmacokinetic parameters

Dose (mg) [route and dosage regimen]-

No. of individuals

400 [PO SO]

6

400 [PO M03]

6

Sampling time

Cmin

(mglL)

7th dose

400 [PO M08]

6

17th dose

400 [IV M08]

12

17th dose

200 [PO SO]

3

Cmax (mglL)

tmax (h)

References

4.3

1.3

23,24

10 4.0

1.4

7.0 9.55

1

1.5

1.83

400 [PO SO]

3.63

2.16

600 [PO SO]

5.43

1.16

800 [PO SO]

6.06

1.61

21

400 [PO SO]

6

3.84

400 [IV SO]

8

3.9 to 5.8

27

5.8

26

400 [IV M01O]

400 [PO M016]

12

12

1st dose 03 am , pm

1.33,1.91 b

4.38,5.44b

04 am, pm

2.42, 2.8b

5.48,6.55b

05 am, pm

3.16,3.4 b

6.97,8.08b

06 am , pm

3.31 , 3.36 b

7.35, 7.66b

07 am , pm

3.55,3.54 b

7.35, 8.21 b

08 am, pm

3.64,4.03 b

7.17,8.12b

09 am, pm

3.78,4.09 b

6.99,7.59 b

010am

4.22

9.55

1st dose

25

4.13

1.5

3.23

1.5

4.08 b

5.64

1.5

010am, pm

4.56b

7.86

1.5

011 am, pm

4.05b

8.58

1.5

012am, pm

4.90b

8.07

1.5

013am, pm

4.41 b

7.98

1.5

014am , pm

4.94 b

8.61

1.5

015am , pm

6.52 b

8.07

1.5

016am

5.87

9.67

1.5 1.3

08 am, pm

3.35b

09 am , pm

400 [PO SO]

8

4.3

400 [IV SO]

10

6.85

29

400 [PO M010]

12

4.62

30

1st dose

1.62

21st dose

5.9

10.9

200 [PO SO]

12

2.5

1.2

400 [PO SO]

30

4.25

1.4

400 [PO M07]

18

400 [IV SO]

24

15th dose

400 [IV M07]

12

15th dose

10

04

800 [IV SO]

16

a

Dosage interval of 12 hours.

b

Result from evening sampling time.

10

16

1.4

5.8

400 [PO M03] 400 [IV M01]

28

10.1 6.0

11.2 12.1

1st infusion

1.8

6.5

2nd infusion

2.8

7.4

1.4

31 32

Abbreviations: am =morning; em;n =minimum plasma concentration; em_x =maximum plasma concentration; On =nth day; IV =intravenous administration; MOn =multiple dose administration for n days; pm =afternoon; PO =oral administration; SO =single dose; t m_x =time taken to achieve em_x.

© Adis International Limited. All rights reserved.

Clin . Pharmacokinet. 27 (6) 1994

425

Pefloxacin Clinical Pharmacokinetics

than serum concentrations.l42 ] In vitro experiments have shown that the ratio of the intracellular to the extracellular concentration is high (6.9 for human alveolar macrophages;[40] 9.3 for peritoneal macrophages, with an intracellular concentration of 85.9 mglL[41]). Uptake and release of drug are rapid. [43] Pefloxacin concentration in polymorphonuclear leucocytes is approximately 4-fold greater than the extracellular concentration.l40 ] The distribution patterns are compatible with either a true distribution of the drug in the cytoplasm of the cell, or their reversible association with organelle(s) or constituent(s) from which they may elute during cell homogenisation and/or fractionation.l 40 ] This is made plausible by the rapid rate of efflux of pefloxacin from uninfected macrophages. In contrast to uninfected cells, from which pefloxacin was quickly released, macrophages infected with a Legionella sp. retained approximately 20 to 30% of the accumulated pefloxacin after a 60-minute washout period. Cell fractionation studies indicated that the drug remaining in cells was associated with fractions containing [3HJ-labelled pathogens, if cells had been incubated with [3HJ-Iabelled Legionella sp., suggesting that part of the intracellular pefloxacin becomes associated with the bacteria.l40 ] Pefloxacin seems to be active intracellularly;[40] however, Raoult et al.l 44 ] suggested that pefloxacin had a bacteriostatic rather than bactericidal effect on intracellular pathogens. The available literature on body fluids and tissue penetration of pefloxacin are reviewed and discussed in sections 6 and 7. 3.3 Metabolism

Biotransformation of pefloxacin is extensive (85 to 90%), mainly oxidation by hepatic microsomes[45] to form the principal metabolites Ndemethyl-pefloxacin and pefloxacin N-oxide.[25.26] Other pathways of minor importance are N-acetylation, N-formylation and N-sulphate conjugation resulting in the formation of oxo-pefloxacin, oxonorfloxacin and pefloxacin glucuronide (fig. 1). The liver is the predominant organ of metabolism © Adis International limited. All rights reserved.

for pefloxacin. Two sites of the molecule were identified as metabolically unstable: the 3-carboxyl- and the 7-piperazinyl-substituent. Following oral administration, there is no hepatic firstpass metabolism of pefloxacin. 3.4 Elimination

After administration of single intravenous or oral doses, the terminal tl/2 (tY2~) ranged from 6.2 to 13.8 hours; total and renal clearances ranged from 6 to 9.54 Llh and 0.4 to 1.31 Llh, respectively (table III). However, after repeated administration, a major change in pharmacokinetic parameters of pefloxacin was found . Total clearance decreased from 7.4 to 8.9 Lih for the first dose to 5.2 to 6.4 Llh for the last dose, which was a statistically significant decrease, and was associated with a statistically significant increase in the tl/2 from 7.2 to 12 hours for the first dose to 13.9 to 15.9 hours after the last dose.l 16 ,23,24,26,31 ,37] These data suggested that multiple administration saturated a nonrenal clearance pathway for pefloxacin. In the study of Frydman et al.,[26] the concentrations of N-demethyl and N-oxide metabolites in the plasma were determined. The tl/2 ~ values for these 2 metabolites were very close to that of pefloxacin. An average of 13% of parent pefloxacin was recovered in the urine unchanged. Pefloxacin is mostly excreted as its metabolites (table III). Over the 72 hours following administration of a 800mg dose, the total urinary recovery of the parent compound plus metabolites accounted for 60% of the administered dose. Urinary recovery of norfloxacin, pefloxacin N-oxide, oxo-norfloxacin and oxopefloxacin was 20.2, 23.2, 5.4 and 0.75%, respectively; moreover, traces of pefloxacin glucuronide were recovered in urine.[25] Frydman et al.[26] reported tY2~ values for norfloxacin and the N-oxide metabolite of pefloxacin of 9.75 and 12 hours, respectively. The contribution of renal clearance to the elimination ofpefloxacin was low; 0.4 to 1.9 Llh (table III). The renal clearance of this drug was lower than the glomerular filtration rate [i.e. 80 to 120 ml/min (4.8 to 7.2 Llh) in healthy volunteers], sugClin. Phormacokinet. 27 (6) 1994

Bressolle et al.

426

Table III. Pefloxacin distribution and elimination pharmacokinetic parameters Dose (mg) [route and dosage regimenj"

No. of patients

400 [PO SO]

6

400 [PO M03]

6

200 [PO SO]

3

Sampling time

Ae(24h) (%)

(Uh)

CL (Uh)

0.40

6.9

CLR

7th dose

\1,., (h)

Vd (Ukg)

References

12.3

1.7

23.24 21

15.5 11.8

0.92

8.11

11 .7

1.86

400 [PO SO]

11.1

0.77

7.54

10.5

1.56

600 [PO SO]

14.0

0.88

6.68

11 .0

1.54

800 [PO SO]

17.0

1.31

7.84

12.6

1.93

200 [IV SOj

13.7

1.18

9.38

9.7

1.55

400 [IV SO]

NO

NO

7.39

10.7

1.00

600 [IV SO]

12.5

0.91

7.63

11.8

1.28

10.8

0.72

6.29

13.8

1.00

800 [IV SO]

9.3

400 [PO SO]

6

400 [IV SO]

12

400 [PO M08]

6

17th dose

400 [IV M08]

12

17th dose

400 [IV SO]

12

400 [IV SO]

8

400 [IV M01O]

12

400 [PO M016]

0.72

8

400 [IV SO]

10

25

8.8

37

15.4 11.3 to 13.9 8.2

11.0 6.2 to 10.5

1.9

38

1.7to 2.6

27 26

1st dose

8.91

11

1.9

last dose

6.41

13.9

1.7

1st dose

0.45

7.4

12.0

1.7

last dose

0.39

5.2

14.8

1.3

6.85

12.3

0.69

6.9

11 .17

12

400 [PO SO]

8.7

8.6

28 1.46

14.9

400 [PO M01O]

12

200 [PO SO]

12

21st dose 0.51

9.42

6.7

1.4

400 [PO SO]

30

0.4 to 0.76

7.8 to 9.54

7.2 to 12.3

1.5to 1.8

0.69

8.8 8.9

13.9

400 [PO M07]

18

400 [IV SO]

24

400 [IV M07]

12

15th dose

NO

7th dose

1.9

400 [PO M03]

10

400 [IV SO]

11

800 [IV SO]

16

15th dose

30 16

14.8 to 15.4

400 [IV MOl] a

29

8.7 to 11.3

1.4 to 2.1 2.1

4.3

15.9

1.4

31

6.0

11.3

1.5

39

6.0

12.2

1.5

32

5.77

12.4

1.4

Dosage interval of 12 hours.

= = = = administration; SO =single dose; t,., =elimination half-life; Vd =volume of distribution.

=

Abbreviations: Ae(24h) percentage of pefloxacin eliminated in urine in 24 hours; CL total plasma clearance; CLR renal clearance; On nth day; IV intravenous administration ; MOn multiple dose administration for n days; NO not determined; PO oral

=

gesting that pefloxacin is predominantly reabsorbed. The observed pH-dependence of renal clearance of pefloxacin supports the hypothesis that this drug undergoes extensive reabsorption in the kidney tubules)46) The available renal clearance values for the metabolites are higher than those for the parent drug, suggesting that the metabolites undergo more extensive secretion or © Adis International limited. All rights reserved.

=

=

less reabsorption in the kidney tubules than pefloxacin. Biliary excretion ofpefloxacin, either as parent drug or metabolites accounted for 20 to 30% of an oral dose (see section 6.10). High concentrations of pefloxacin were found in the faeces (645 mg/kg on day 7). In the faecal flora, members of the family Enterobacteriaceae Clin. Pharmocokinet. 27 (6) 1994

Pefloxacin Clinical Pharmacokinetics

were eliminated between days 2 and 8. Recolonisation with enterobacteria was seen 1 week after the cessation of treatment. The number of E. faecalis decreased slightly and the number of Candida spp. did not change during the observation period.[47-S0] The period of observation was the 21 days after cessation of pefloxacin 400mg twice daily treatment.

4. Effects of Age and Various Disease States on Pharmacokinetics 4.1 Age

The pharmacokinetics of single and multiple oral doses of pefloxacin 400mg were studied in elderly individuals with normal hepatic and renal function for their ageJSl] Following administration of single oral doses of pefloxacin, C max values in the plasma and AVC values were increased (about 2-fold); while plasma clearance and Vd were decreased compared with values observed in healthy volunteers. There was no change in the tYz in the elderly. The authors proposed that treatment should be started with a loading dose of 400mg twice daily on the first day, followed by 200mg twice daily thereafterJSl] 4.2 Impaired Renal Function

In contrast with other 4-fluoroquinolones, the AVC and tl/2 ofpefloxacin are subject to few, if any, changes in patients with impaired renal function. In a multiple-dose study, patients with renal impairment received pefloxacin 12 mg/kg given by a I-hour infusion twice daily or orally as 800mg twice daily for 5 days . Although the steady-state plasma concentration of pefloxacin was not modified by renal impairment, accumulation of N-demethyl-pefloxacin and in particular of Noxide-pefloxacin was noted.l5 2,S3] Vsing a lower intravenous dosage (8 mg/kg/day), there was no difference in distribution and elimination of pefloxacin between patients with moderate and severe renal impairment. No accumulation of N-demethylpefloxacin was observed.[S4] Pefloxacin clearance was correlated with creatinine clearance. © Adis International Limited. All rights reserved.

427

The renal clearance of the demethylated metabolite (norfloxacin) greatly exceeds that of pefloxacin (5.14 vs 0.31 LIh). Hoffler et alJ sS] and Le Roux et aU 29 ] demonstrated that after a single intravenous infusion of pefloxacin 400mg there was a significantly higher AVC in the patients with renal failure than in the healthy volunteers. However, the tJi2 values were similar for both groups in one of the studiesJ5S] while in the other study[29] the tl/2 was significantly increased. The investigators attributed the increase in AVC to a significantly lower extrarenal clearance in the patient with renal failure . Drug monitoring may be necessary if nonrenal elimination is also impaired. Renal failure alone will induce only a transient increase in the concentration of norfloxacin because this will be further metabolised to oxo-norfloxacin. Pefloxacin is partly removed by haemodialysis. The dialysis extraction ratio of pefloxacin across the dialyser is 0.17 to 0.26 and dialysis clearance ranges from 2.1 to 3.6 Lih. Repeat administration of pefloxacin after a period of haemodialysis may therefore be unnecessary.l9] In patients undergoing continuous ambulatory peritoneal dialysis (CAPD), the mean serum and dialysate concentrations of pefloxacin were similar for up to 48 hours after the oral or intravenous dose (table IV). The peritoneal clearance of pefloxacin averaged 2.5 ml/min (0.15 Llh).[S8-60] Following repeated administration, the overall plasma concentrations of pefloxacin were in a range similar to those observed in studies undertaken in human volunteers. Vnlike those normal volunteers who demonstrated no accumulation of metabolites, CAPD patients accumulated the Noxide metabolite.l611 After repeated intravenous and oral administration, Benzakour et al.l S7 ] reported a mean Cmax in the dialysate close to the Cmin values in serum; the C max in dialysate was 50 to 88 0/0 of the Cmax in serum. Similar results were reported by other investigators.[S6,61] In patients undergoing CAPD, the serum tl/2 (17 to 21 hours), was higher than that reported by several authors for healthy controls or uraemic paClin. Pharmacakinet. 27 (6) 1994

Bressolle et al.

428

Table IV. Pefloxacin concentrations during continuous ambulatory peritoneal dialysis Dose (mg) [route and dosage regimen]a

No. of patients

800 [IV SO] + 400 [IV M02] + 400 [PO M03-14]

15

Sampling time (hours

Concentration (mg/L) Dialysis fluid : S or PReferences -S-o-r-P----'-=--'--d-ia-Iy-Si-S-fl-Ui-d--- concentration ratio

postdose)

800 [IV SO] + 400 [IV M02] + 200 [PO M014]

3

(mg/L)

24

11.2 (Cmax). 5.5 (Cm;n)

5.7 (Cmax). 4.5 (Cm;n)

0.51 (Cmax). 0.83 (Cm;n)

72

9.96 (Cmax). 4.7 (Cm;n)

5.0 (Cmax). 4.0 (Cm;n)

0.5 (Cmax), 0.78 (Cm;n)

336

5.57 (Cmax). 2.6 (Cm;n)

2.9 (Cmax), 2.4 (Cm;n)

0.53 (Cmax), 0.94 (Cm;n)

336

8.17 (Cmax). 5.47 (Cm;n)

7.2 (Cmax). 5.77 (Cm;n)

0.88 (Cmax). 1.05 (Cm;n)

400 [IV SO]

5

6

3.1b • 4.5c • 3.7d

2.5b , 2.6c , 16.5d

0.8b , 0.6c , 4.5d

400 [PO SO]

4

12

2.4 b • 3.9c• 2.6d

2.0 b, 1.6c• 3.4 d

0.83b , 0.41 c , 1.3d

400 [IP SO]

4

400 [IV SO]

5

6

3.1b • 4 f. 3.5d

2.8b , 1.8c , 13.6d

0.9b , 0.43c , 3.9d

400 [PO SO]

5

12

2.4 b • 3.0c • 2.5d

1.6b , 1 f . 2.9d

0.7b • 0.6c • 1.2d

400 [IP SO]

5

18

1.8b • 2.6c , 1.9d

1.2b , 2.4c • 1.9d

0.7b , 0.9c • ld

24

1.5b , 2.0c , 1.4d

l.l b , 1.5c , 1.3d

0.7 b , 0.75c , 0.9d

48

0.6 b • of, 0.7d

0.64b , 0.9c • 0.6d

l.l b • 1.3c , 0.86d

a

Dosage interval of 12 hours.

b

Measured after administration of 400mg IV SO.

c

Measured after administration of 400mg PO SO.

d

Measured after administration of 400mg IP SO.

56.57

58

59

Abbreviations: Cm_x = maximal concentrations; Cm;n = minimal concentration; IP = intraperitoneal route; IV = intravenous administration; MOn = multiple dose administration for n days; P = Plasma; PO = oral administration; S = serum; SO = single dose.

tients on haemodialysis.£56,59] The reduction in the inflammatory condition of the peritoneum does not interfere with the diffusion of the antibiotic in the blood to dialysis fluid direction.£57] After a single intravenous and oral dose of 400mg, mean overall dialysis fluid: plasma ratio was above 0.8, reflecting high diffusion from blood to the peritoneal cavity.£62,63] Intraperitoneal administration yields high concentrations of pefloxacin in the dialysis fluid for up to 12 hours, and this can ensure effective treatment of peritonitis at the early phase of treatment. Furthermore, intraperitoneal administration resulted in plasma concentrations comparable to those obtained 6 hours after intravenous or oral administration.f 59 ] Since peritoneal clearance contributes insignificantly to the elimination of pefloxacin during CAPD, administration of 400 mg/day orally or intravenously seems to be a reasonable treatment option for infections in patients requiring CAPD.f 60 ] © Adis International Limited. All rights reserved.

4.3 Hepatic Dysfunction

Few studies on the pharmacokinetics of pefloxacin in patients with hepatocellular insufficiency have been published in the literature. In liver disease, pefloxacin shows altered plasma pharmacokinetics. Plasma clearance is decreased while the tt;2, AVC and urinary excretion of parent drug are increased. Danan et aJ.l38] found that the mean tt;2 in patients with hepatic cirrhosis was 3-fold higher than the value reported in healthy volunteers. Renal clearance was unchanged, while total body clearance was markedly decreased. Vd was slightly decreased, but ascites did not significantly modify this parameter. The investigators reported a significant correlation between nonrenal clearance and prothrombin time. There was no significant correlation between total clearance and any of tests of liver function. Similar results were reported by other investigators (fig. 2).[28,39,64,65] The proClln. Pharmacokinet. 27 (6) 1994

429

Pefloxacin Clinical Pharmacokinetics

longed elimination of pefloxacin is due to decreased hepatic clearance.£28] It was suggested that a reduced penetration of pefloxacin into patients' red blood cells (RBC) could partly explain the decrease in Vd. Indeed, after a single 400mg oral dose, the mean RBC : plasma ratio was 0.18 in patients with hepatic cirrhosis compared with 0.30 in healthy volunteers, 1.5 hours postdose. Similarly, ratios of 0.19 and 0.26, respectively, were reported 12 hours postdose .f661 Cardley et al.[28] and Galtier et al.[39] stressed the importance of the accumulation of pefloxacin after repeated administration. Moreover, in the results reported by Galtier et al.,[39] a practical tool is proposed for estimating the most likely values of pharmacokinetic parameters for a given patient, taking into account the values of the Child-Pugh score or the prothrombin time (fig. 3). The tl/2 tended to increase according to the presence of ascites or jaundice Uaundice alone: 28 hours; ascites alone: 34.4 hours; jaundice and ascites: 48. 1 hours) .l38] The concentration of unchanged pefloxacin in urine was higher and that of Ndemethyl pefloxacin was lower than in healthy volunteers; 4-oxo-N-demethyl pefloxacin was not detectable.£38,64,65] Pefloxacin enters the ascitic fluid. Ascitic fluid penetration was 68 % after a single oral or intravenous dose and significant accumulation of pefloxacin in ascites was obtained after repeated administration, a ratio of 72% after the administration of multiple oral doses of 400mg twice daily was reported,l28,64,65,67,68] Concentrations in ascitic fluid were higher than the MIC inhibitory to 90% of strains (MIC90) of Enterobacteria.

o o

Controls Grade B • Grade C

10

8

6

4

2

0

AUC n (mglL ' h)

Cmaxn (mglL)

CL (Uh)

160

120

80

40

o t •., (h)

MRT

Vd

(h)

(L)

Fig. 2. Pharmacokinetic parameters of pefloxacin in healthy volunteers (control group) and in patients for whom the severity of liver disease was graded B or C according to the Child-Pugh classification . Abbreviations: C max n = peak plasma concentration normalised to a 100mg dose; AUCn = area under the plasma concentration-time curve normalised to a 1mg dose; CL total body clearance; t'/2 elimination half-life; MRT mean residence time; Vd volume of distribution (from Galtieret al.,[39] with permission).

=

=

=

=

4.4 Other Altered Pathophysiological States

Pefloxacin pharmacokinetics are not altered in patients with cystic fibrosis.f 27 ]

5. Pharmacokinetic Interactions with Other Drugs Combinations of pefloxacin and other antibacterial agents have been used to: © Adis International Limited. All rights reserved.

• prevent chromosomal resistance to the drug; • exploit additive or synergistic properties of the combination; and • extend the antibacterial spectrum of activity. The most frequent use of combination therapy is for the additive effects found when pefloxacin is combined with the aminoglycosides (e.g. amiClin. Pharmacokinet. 27 (6) 1994

Bressolle et al.

430

twice daily for 9 days.[n] The investigators suggested that the interaction may be caused, not by the parent drug, but by its 4-oxo metabolite. The interaction is caused by the effect of the 4-oxo metabolite on cytochrome P450-related isoenzymes, with a reduction in the N-demethylation of theophylline predominantlyV 3] An antagonistic interaction between nitrofurantoin and pefloxacin has been reported.[9] Cimetidine inhibits the hepatic metabolism of pefloxacin, increasing its tl/2 and reducing its total clearance. The Vd and the renal clearance of pefloxacin were unchanged by cimetidineP4] Concomitant administration of pefloxacin with certain antacids containing aluminum and magnesium hydroxides may delay and reduce the absorption of pefloxacin. [75] The proposed mechanism of this interaction is chelation of the quinolone, forming a nonabsorbable complex .

10

•

8

"2

~6 Q)

•

(.)

c:

~

'" Q)

4

(3

2

0 120

•

90

• • •• • •

"2 ~60 ;£

30

6. Penetration into Body Fluids

0 0

20

40

60

80

100

Prothrombin time (%)

Fig. 3. Relationship between total body clearance of pefloxacin and prothrombin time, and between elimination half-life (t1,;,) of pefloxacin and prothrombin time in patients (from Galtier et al.,{39] with permission).

kacin).f 69 ] Ceftazidime and pefloxacin have been used in combination against the enterobacteria and Pseudomonas and Acinetobacter spp. However, this combination for the treatment of pseudomonal infections is more controversial.[69] There has been no reported interaction between pefloxacin and ceftazidime, metronidazole, piperacillin or tobramycin.!70,71] In a comparative study on the effects of fluoroquinolones on the clearance of theophylline, plasma theophylline concentrations were significantly increased (19.6%) and total body clearance of theophylline was significantly decreased (29.4%) following coadministration of pefloxacin 400mg © Adis International Limited. All rights reserved.

Table V summarises the distribution of pefloxacin into fluids following oral or intravenous administration. 6.1 Saliva

Penetration of pefloxacin into saliva was studied in healthy volunteers after administration of a single oral dose of 400mg. The concentration ratios of saliva: plasma averaged 0.61,0.65 and 0.70, respectively, 9, 24 and 32 hours postdose. Mean pefloxacin tl/2 was 11.2 hours from plasma and 11.8 hours from saliva.!76] Similar results were found in healthy volunteers and patients with cystic fibrosis.!77] After repeated oral administration of pefloxacin 400mg twice daily for 7 days, the concentration in saliva was closely related to the serum concentration. Two days after the last dose, pefloxacin concentrations in serum and saliva were 0.46 and 0.26 mg/L, respectively.[48] elin. Phormacokinet. 27 (6) 1994

431

Pefloxacin Clinical Pharmacokinetics

6.2 Otolaryngological Fluids

Penetration of pefloxacin into maxillary sinus cavity and nasal secretions was studied after oral administration of 2 doses of 400mg twice daily. Pefloxacin plasma concentrations were measured just before the second dose and 3, 6, 9 and 12 hours after this dose. The fluids: plasma concentration ratios averaged 1.37 for sinus aspirate fluid, 1.5 for cystic fluid and 1.3 for nasal secretions)78.79] The investigators concluded[79] that the concentrations of pefloxacin in sinus secretions, which are higher than the simultaneous concentrations in the plasma, could reflect uptake of drug by phagocytic cells. After administration of a single dose of 400mg orally or intravenously, to patients with cystic fibrosis, concentrations of pefloxacin in nasal secretions remained below the simultaneously measured plasma concentrations. The fluids: plasma concentration ratios ranged from 0.7 to 0.8VI .77] 6.3 Sweat

All quinolones were found to penetrate into sweat to a lesser degree than into saliva, nasal secretions or tears. Pefloxacin and f1eroxacin are the quinolones that exhibit the highest penetration into sweat.[IIO] After oral and intravenous administration of pefloxacin 400mg to healthy volunteers, the mean sweat: plasma concentration ratio averaged 0.4.[77] 6.4 Blister Fluid

The mean percentage penetration into cantharides-induced blister fluid was 70% for intravenous pefloxacin.f22] The blister concentrations exceeded those in serum from about 3 hours postdose until 12 hours postdose. In blister fluid the t'!2 (11. 7 hours) was similar to that in serum (l0.5 hours). After oral administration of pefloxacin 400mg, the concentrations of pefloxacin in blister and plasma were similar) III] Quinolones equilibrate slowly between blister fluid and plasma, the time of the C max in blister fluid was later than that in plasma. © Adis International limited. All rights reserved.

6.5 Bronchial Secretions and Sputum

Penetration of pefloxacin into bronchial secretions was studied following intravenous administration of 6 doses of 400mg twice daily for 3 days. The ratio of AVC for bronchial secretions to AVC for the serum averaged 1.7.[112] At all times the mean concentration of pefloxacin in bronchial secretions was similar to, or higher than, the corresponding concentration in serum. The mean C max in bronchial secretions was 15.3 mg/L, occurring 0.5 hours postdose. A good correlation was observed between the values obtained in serum and bronchial secretions.!80] The sputum: plasma concentration ratios ranged from 0.7 to 2.7.[81-83.113.114] Penetration of pefloxacin in the sputum of patients with cystic fibrosis was similar.!77] 6.6 Cerebrospinal Fluid

For many drugs, the rate of diffusion into the cerebrospinal fluid (CSF) was shown to be a function of their lipid to water partition coefficient. The penetration of pefloxacin into the CSF has been studied in humans in the presence and absence of meningeal inflammation.!84-86.115] In individuals with hydrocephalus and external ventricular drains, but with no meningeal inflammation, mean C max values of 8.54 mg/L in plasma and 2.97 mg/L in CSF, occurred after administration of a single 400mg intravenous dose.!86] The ratio of the concentration of pefloxacin in CSF to that in plasma was relatively stable between 6 and 24 hours postdose, ranging from 0.57 to 0.64.!85.86] The apparent half-time of pefloxacin transfer from plasma to ventricular CSF was 1.26 hours, while the tl/2 from ventricular CSF was similar to the tl/2 of pefloxacin from plasma, i.e. 13.4 hours. The rate of transfer of N-demethyl-pefloxacin across the blood-CSF barrier is low as its C max in the CSF does not exceed 0.2 mg/L.[86] In patients with meningitis the ratio of AVC for CSF : AVC for serum was 0.53 after the first 400mg dose and 0.66 at steady-state.!85] Analogous data were reported by Wolff et al.[84] in patients with meningitis or ventriculitis. After repeated intraClin. Pharmacokinet. 27 (6) 1994

432

Bressolle et al.

Table V. Penetration of pefloxacin into fluids Fluids

Saliva Saliva

Saliva

Saliva

Oose (mg) [route No. of patients and dosage regimen)"

400 [PO SO)

400 [PO M07)

400 [IV SO)

12

10

10

400 [PO SO) Otolaryngological fluids Sinus aspirate fluid 400 [PO M01)

Sinus fluid, cystic fluid, nasal secretions

400 [PO M01)

39

39

Bronchial secretions and sputum 400 [IV M03) Bronchial secretions

12

Sputum

35

Sputum Sputum Sputum

800+400 [PO M010)

Sampling time postdose (h)

Concentration (mg/L)

9 24

Fluid: S or P ratio

References

fluid

0.97·2.71

0.69·1.44

0.61

76

0.31·0.95

0.15·0.61

0.65

32

0.17·0.69

0.12·0.33

0.70

1 (01)

3.89

3.46

0.89

3

3.19

2.03

0.64

SorP

25(02)

5.5

5.3

0.96

73(04)

6.71

5.94

0.89

145(07)

8.02

7.54

0.94

169(08)

4.90

5.02

1.02

217 (010)

0.46

0.26

0.57

0.5

4.6

3.6

0.64

tmax

3.7

2.7

0.61

before 2nd dose

1.5

2.2

1.5

3

5.0

7.37

1.5

6

3.1

3.82

1.2

9

2.7

3.5

1.3

3.31 2.3 b·2.3c·1.9d

1.4 1.5b·1.5c· 1.3d

6.9b·7.1 c·9.1 d 3.7b·4.0c·3.~ 3.5b·4.2c·3.0d 2.8b.4.1c.2.8d

1.4b·1.4c·1.8d 1.2b·1.3c· 1.2d

12

2.4

before 2nd dose

1.5

3

5.0

6

3.1

9 12

2.7 2.2

0.5

11.1

15.3

1.4

6

8.35

13.7

1.6

12

6.5

7.6

1.2

1 (01); 1 (03)

8.6e ·9.81

9".11.81

1.05".1 .21

2 (01) ; 2 (03)

10e ·11 .i

11".11 .21

1.1".0.961

3 (01); 3 (03)

12.7".9.11

8.1 e ·8.61

0.64".0.951

4 (01) ; 4 (03)

13.7"·18.i

14.1e ·22.61

1.01".1.21 1

20

4.6

3.8

0.83

400 [PO SO)

20

5.14

4.6

0.89

400 [IV SO)

8

0.68

400 [PO SO)

8

0.77

800 + 400 [IV]

17

6

CSF

5

400 [IV SO)

© Adis Inlernationallimiled. All rights reserved.

77

78

79

1.3b·1.6c·1.1 d 1.3b·1.9c·1.3d

400 [IV SO)

Cerebrospinal fluid (CSF) CSF 400[IVx 2; 8 hourly)

48

3

5.7

13.6

2.4

6

7.2

13.3

1.8

12

3.7

10.2

2.7

0.5

7.3

3.3

0.46

2

4.5

3.8

0.84

7.5

1.8

2.0

1.1

0.5

8.4

3.2

0.38

2

7.7

4.4

0.57

7.5

6.3

4.1

0.65

80

81

82 71 83

85

85

Clin. Pharmacokinet. 27 (6) 1994

Pefloxacin Clinical Pharmacokinetics

433

Table V. Contd Fluids

CSF

Concentration (mg/L)

Dose (mg) [route No. of and dosage patients regimen)a

Sampling time postdose (h)

fluid

Fluid : S or P ratio

References

SorP

7,5 mg/kg

9

2

10,3

4,8

0,58

84

15 mg/kg [IV M01,5)

8

2

20.2

8,3

0,52

7.5 mg/kg

12

4

9,1

3.4

0,373

15 mglkg [PO M01,5)

3

4

9,1

0,607

400 [IV SO]

9

6-24

(IV M01,5]

[PO M01.5]

CSF

1 (tmax)

15

0,57-0.64

86

8,54

4 (tmax)

2.97

Cervical secretions Cervical secretions 400 [PO M020]

7

020

14.4

24.4

1.7

87

Prostate and ejaculate fluids Seminal fluid 400 [PO M020]

15

020

7,4

9,1 (1st F)

1.2 (1st F)

87

10.4 (2nd F)

1.4 (2nd F)

Split ejaculates

400 [PO M021-28)

12

021-028

Ocular fluids Aqueous humor

400 [PO SO]

35

tmax

6,4

1,36

0.21

89

Aqueous humor

400 [IV SO]

20

tmax

5,75

1.48

0.26

90

Aqueous humor

800 [PO] + 400 [PO M03]

91-94

800 [PO] + 400 [PO M07] Aqueous humor Aqueous humor Aqueous humor

Vitreous fluid

400 [IV SO]

88

6

2

11 ,2

5,77

0,5

6

6

12,3

7,69

0,62

6

12

9.8

6,76

0,73

8

24

5,2

4,21

0,89

6

36

4.4

2,3

0,5

6

48

1,5

1.2

0,81

6

6

17,1

8,74

0,51

5

4.2

4,5

1

0,22

13,7

10,3

0,75

400 [IV M08]

13

400 [IV x 2 q8h]

24

1,04-4,31

800 [IV x 2 q8h]

6

3.81-7,80

400 [IV x 2 q8h)

24

9-12

4.8-6

2,0-2,76

0,44

800 [IV x 2 q8h]

6

9-12

12,9-15

4,16-7.15

0,32-0.48

5

4,2

4,5

1.6

0.35

13,7

11.9

0,87

9-22

0,5-30

1-13

0,8-10

400 [IV SO] 400 [IV M08]

Vitreous fluid

8,7 (1st F) 9,8 (2nd F)

13

800 [IV SO]

5

800 [IV SO]

6

24

95 96 97

95 98

5

24

3-32

1.7-12

Vitreous fluid

400 [PO SO]

20

6

3,03

1.37

0.45

99

Bile fluids Sileg

800 [IV SO)

12

100

400 [PO M04)

Gallbladder bile

400 [PO SO]

NO

4

16,8

47,6

2,8

24

5,6

8,6

1,5

48

3,8

3,5

0,92

12

2

83

41,5

101

Continued next page

© Adis International Limited, All rights reserved,

Clin, Pharmacokinet, 27 (6) 1994

434

Bressolle et a/.

Table V. Contd Fluids

Dose (mg) [route No. of patients and dosage regimen]a

Sampling time postdose (h)

Concentration (mg/L) SorP

fluid

Fluid : S or P ratio

References

Duct bile

800 [IV SD]

12

1-2

7.8

14.4

1.85

102, 103

Gallbladder bile

800 [IV SD]

12

1-2

7.8

12.0

1.54

103

Bile

400 [IVx 3]

8

104

Other fluids Amniotic fluid

Breast milk

Pancreatic juice

400 [IV x 2]

400 [POx3]

400 [PO SD]

1

19

22

1.16

4

17.2

18.9

1.1

24

10.2

10.0

0.98

8

3-6

4.3

2.06

0.48

5

6.5-8

3.9

2.74

0.7

7

9.5-12.5

2.5

1.97

0.8

2

4.75

3.54

0.75

4 6 9

3.63

3.43

0.94

2.82

2.93

1.04

2.24

2.24

1.0

20

5

12

1.82

1.79

0.98

24

0.88

0.88

1.0

1.7 2.5

4.2

105,106

105

107 4.6

Peritoneal fluid

400 [IV SD]

38

1.58

0.88

108. 109

Peritoneal secretion

800 [IV SD]

12

4

16.8

17.1

1.02

100

48

3.8

5.3

1.4

Wound secretion

800 [IV SD]

4 8

16.8

18.2

1.08

3.8

5.0

1.3

12

100

Dosage interval of 12 hours. Determinations in sinus fluid. c Determinations in cystc fluid. d Determinations in nasal secretions. e Determined on day 1. f Determined on day 3. g Bile concentration measured via a T-drain implanted in the common bile duct. Abbreviations: 0 =day; F =fraction (1st =ejaculate fraction by the prostate; 2nd =ejaculate fraction by seminal vesicles); IV = intravenous administration; MDn = multiple dose administration for n days; NR = not reported; P = Plasma; PO = oral administration; S = Serum ; SD = single dose; tmax = time taken to achieve maximum plasma concentration. a b

venous and oral administration, pefloxacin concentrations in CSF ranged from 4.8 to 8.3 mglL after administration of 7.5 mg/kg and from 10.3 to 20.2 mg/L after administration of 15 mg/kg. The CSF : plasma ratio was 0.58 in patients receiving the low dose, and 0.52 in those receiving the high dose. Interestingly, 50% of the dose penetrated into the CSF even after these patients were considered to be cured of meningitis)84] The diffusion of pefloxacin into the CSF is equivalent to that of ofloxacin, but greater than ciprof1oxacin, presumably because of pefloxacin has greater Jipophilicity than ciprofloxacin)9] © Adis Internatio nal Limited. All rights rese rved.

6.7 Cervica[ Secretions

Pefloxacin concentrations in cervical secretions were higher than serum pefloxacin concentrations, the corresponding mean concentration ratio (secretions : serum) was 1.7.£87) 6.8 Prostatic and Ejaculate Fluids

Penetration into prostatic fluid is difficult to assess since urine might contaminate the specimens. Naber et al. l 116) and Sorgel et al.£ 117] attempted to quantitate urine contamination of prostatic fluid by elin. Pharmacokinet. 27 (6) 1994

Pefloxacin Clinical Pharmacokinetics

the determination of ioxitalamic acid as an indicator. Diffusion of drugs into prostatic fluid is dependent on the pH gradient across the prostatic epitheliumJ 118) The pH of prostatic fluid of healthy volunteers is slightly acidic (mean value 6.7), whereas its pH in patients is slightly basic (mean value 8.1)J 119) The degree of ionisation in plasma and prostatic fluid plays an important role in passage of quinolones into prostatic fluid.(120) Pefloxacin concentrations in seminal fluid from total ejaculate or from ejaculate fractions produced mainly by the prostate or seminal vesicles were higher than serum pefloxacin concentrationsJ87) The concentration of pefloxacin in the secretory fluids of the prostate and seminal vesicles were 30- to 100-fold higher than the MIC90 of susceptible pathogens, without causing modifications of sperm. Indeed, after pefloxacin therapy, no change in motility, vitality, or morphology of spermatozoids was observed. The concentration of pefloxacin and its N-demeth y1ated derivative was measured in split ejaculates after 3 to 4 weeks of continuous administration of pefloxacin 400mg twice daily. The concentrations in ejaculate fractions produced by the prostate or seminal vesicles averaged 8.7 and 9.8 mg/L, respectively. Corresponding concentrations were 4.2 and 4.3 mg/L for the metabolite.l 88 ] Similar results were found by Grizard et al.£87] 6.9 Ocular Fluids

After a single intravenous administration of pefloxacin 400mg to healthy volunteers, the mean tears: plasma concentration ratio averaged 0.73.(77) In contrast with ciprofloxacin, enoxacin and norfloxacin; pefloxacin has a high penetration into tears. The structural feature responsible for this difference may be the methylation of the piperazine ring in the 4-positionJ 110) Intraocular diffusion of pefloxacin was studied in patients during elective cataract extraction and during lens extracapsular extraction. After repeated oral administration of 400mg twice daily for 3 to 7 days, C max in aqueous humor was reached © Adis International Limited. All rights reserved.

435

6 hours postdose. The aqueous humor: plasma concentration ratio ranged from 0.5 to 0.9.£91-94) In patients treated with 400mg intravenously twice daily for 8 days, the aqueous humor: plasma concentration ratio averaged 0.75, 4.2 hours postdoseJ95) After administration of 2 intravenous doses at 8 hourly intervals, pefloxacin aqueous humor reached a C max, 6 to 12 hours postdose, of approximately 1 to 4 mg/L after administration of 400mg, and 4 to 8 mg/L after 800mg. The corresponding aqueous humor: plasma concentration ratio ranged from 0.32 to 0.48J96,97) Following a single intravenous or oral 400mg dose, this ratio ranged from 0.21 to 0.26.[89,90,95) The apparent tl/2 of pefloxacin from plasma and aqueous humor was 16 and 15.5 hours, respectively.(94) After administration of single and multiple intravenous doses of pefloxacin, the concentrations of the drug in vitreous fluid were higher than the concentrations in aqueous humor; vitreous fluid: plasma concentration ratio was 0.35 after a single dose and 0.87 after repeated dosesJ95,99) Large interindividual variability in the pefloxacin concentrations in vitreous fluid were reported.(98) 6.10 Bile

After intravenous administration of pefloxacin 800mg, high drug concentrations were obtained in bile duct and gallbladder bile, exceeding the serum concentrations by 2- to 3_fold.[100,102.103) In bile, C max was attained 4 hours postdose. Between 2 to 18 hours after drug administration, bile: serum concentration ratios ranged from 2.5 to 4.(100) After intravenous administration of 3 doses of 400mg 12 hourly, Galanakis et al.f 104 ) reported bile concentrations of drug to be very similar to those in the serum; the tl/2 from bile was more than 24 hours. After administration of a single oral dose of 400mg to patients undergoing elective cholecystectomy, concentrations of 83 mg/L of pefloxacin was measured 12 hours after administration, in gallbladder bileJIOl) When gallbladder obstruction occurred, concentrations were low (0.7 mg/L, 6 hours postdose) and concentrations of drug in the choledocal bile were higher (7.6 mg/L). High Clin. Pharmacokinet. 27 (6) 1994

Bressolle et al.

436

concentrations of norfloxacin in bile were also found.!101,121] The concentration of pefloxacin achieved in bile exceeded the MIC for most organisms encountered in the biliary tree. These high concentrations of drug in the bile were excellent for prevention of septic complications after biliary surgery. In fact, a single dose of pefloxacin 800mg gave an excellent clinical outcome.!103] The study was conducted in 12 male patients undergoing elective biliary surgery. The results showed a satisfactory clinical response and there was only 1 patient who had secretion from the wound. 6. 11 Other Fluids Pefloxacin penetrates the placenta and is found in amniotic fluid at low concentrations; much lower than those in the serum. Much higher concentrations of pefloxacin are reported in breast milk. From 4 to 24 hours after the third oral dose (400mg twice daily), pefloxacin concentrations in breast milk were similar to the corresponding serum concentrations.[IOs] Therefore, because of the potential for quinolones to cause arthropathy injuvenile animals, their use should be avoided in pregnant and lactating women.! I05] Pefloxacin penetrates into the pancreas very well. The average concentration of drug in pancreatic juice was the same as that in serum. The mean C max in pancreatic juice was 4.6 mg/L and occurred 2.5 hours after drug intake. The decrease in pancreatic concentrations with time was parallel to the decrease in serum concentrations.[107) Intraperitoneal penetration was determined in patients undergoing elective gastrointestinal surgery or bile surgery. Individual peritoneal fluid concentrations varied widely, but generally exceeded 2 mg/L for at least 4 hours following a 400mg intravenous infusion. The peritoneal fluid: serum concentration ratio averaged 1.0)100,108,109] In wound secretions, 1 hour after infusion of a 800mg dose, a C max value higher than 20 mg/L was reached; 48 hours postdose, mean concentrations of 5 mg/L (n = 10) were still measured. The wound © Adis International Limited. All rights reseNed.

secretions: serum concentration ratios were equal or higher than I during the 48 hours postdose. [100]

7. Penetration into Tissues Table VI summarises the distribution of pefloxacin into tissues following oral or intravenous administration. 7.1 Heart

Penetration of pefloxacin into cardiac muscle and heart valves was studied in patients undergoing open heart surgery after a administration of a 800mg intravenous dose. In the myocardium, pefloxacin exceeds plasma concentrations by 3fold. The mean concentration ratio between the myocardium and plasma was 2.72.[122,123) No time dependence of the myocardium: plasma concentration ratio was observed by these investigators, suggesting a rapid transfer of pefloxacin into myocardial tissue and from the myocardium back into blood. The concentrations of pefloxacin in heart valves were significantly lower than those in the myocardium, which might have been caused by a lower blood supply to this area. Mean concentration ratios between valves and plasma averaged 0.86 (aortic valve) and 1.0 (mitral valve).!122,123] In patients who underwent cardiac surgery with cardiovascular-bypass, pefloxacin tissue: serum concentration ratios, determined I and 3 hours after oral administration of 800mg, averaged 2.!124] 7.2 Lung

Penetration of pefloxacin into lung tissue was studied in male patients undergoing a selective thoracotomy for bronchial carcinoma. Pefloxacin concentrations in plasma and tissues (normal and carcinomatous) were determined 1 hour after a single intravenous infusion and at steady-state. After a single dose of pefloxacin 400mg, the mean concentration ratios between the lung tissues (normal and pathological) and plasma were 2.7 and 3, respectively. At steady-state these ratios were 1.9 and 2.4, respectively.! 125] Clin. Pharmocokinet. 27 (6) 1994

437

Pefloxacin Clinical Pharmacokinetics

At steady-state, the mean bronchus: plasma concentration ratio was 1.9)125] Similar results were reported by Lrebours-Pigeonnierre et al)126] I hour after a single intravenous 400mg dose the ratio lung: serum concentrations was 1.9. At steady-state, in patients receiving 400mg twice daily, pefloxacin concentrations in bronchial mucosa were 11 mg/kg between 1 and 4 hours postdose, generating a tissue: serum ratio of 1.1.[127] Penetration of pefloxacin into the bronchial mucosa and the lung parenchyma was studied in patients undergoing lung resection after intravenous administration of 2 doses of the drug (800mg as a first dose and 400mg 12 hours later). The lung tissue: serum ratios averaged 4.6, 3.7 and 5.4, respectively, 3, 6 and 12 hours after the 2nd injection. In bronchial mucosa, these ratios were 5.9,3.2 and 3.9, respectively)83] In this study, contamination of lung tissue with blood from the systemic circulation was 2.8% (range 0.8 to 5.8%). Lung and bronchial tissue concentrations of pefloxacin exceeded the MIC90 of most of the respiratory pathogens. The rapid equilibration between these tissues and plasma is in accordance with the rich blood supply of the lung. 7.3 Muscle, Fat and Skin

Pefloxacin concentrations in muscle, fat and skin were recorded following 6 oral doses of 400mg administered at 12-hourly intervals. Twelve hours after administration of the last dose, tissues concentrations were 5.6 mg/kg for muscle, 7.6 mg/kg for skin and 2.2 mg/kg for fat;[J28] the corresponding serum concentrations were 1.9, 1.8 and 3.8 mg/L, respectively. Pefloxacin concentrations in fat were lower than that in other tissues, and were between 30 and 60% of serum concentrations) 122, 123, 128, 129] Because of its poor blood perfusion, fat concentrations did not reach plasma concentrations, the fat: serum concentration ratio slowly increased with time after drug administration. After repeated oral administration of pefloxacin, the skin: plasma concentration ratios were 2.65 and 4.65, 2.3 and 5 hours after drug administra© Adis International limited. All rights reserved.

tion)24, 129, 130] Twelve hours later, this ratio averaged 4.2.[128] 7.4 Bone

The penetration of pefloxacin into bone and cartilage is good; the concentration in these tissues sometimes exceeding serum concentrations. Following repeated intravenous administration of pefloxacin (400mg twice daily for 48 hours, followed by oral treatment with 400mg twice daily for at least 7 days), concentrations in bone ranged from 3.0 to 10.2 mg/kg and serum concentrations ranged from 3.7 to 21 mglL.[138) Lower tissue concentrations were found by Pangon et al.[128] and Gehanno et al. [129] after repeated oral administration (400mg twice daily for 3 days); a bone: plasma concentration ratio of 0.3 was reported. In bone biopsies of the iliac crest, tissue pefloxacin concentrations ranged from 2 to 9 mg/kg in 15 patients with chronic osteomyelitis receiving 400mg twice daily, initially by intravenous injection and then orally) 131,132] Concentrations of pefloxacin in bone range from half to several times the simultaneous serum concentrations, reaching mean bone: plasma ratios between 0.27 to 0.5) 131,132] In patients requiring hip surgery, after repeated oral and intravenous administration of pefioxacin, concentrations of the drug in bone, 2 to 6 hours postdose, ranged from 1.2 to 1.9 mglkg.ll37) Following a single infusion of pefloxacin 400mg, pefioxacin bone concentrations were higher than serum concentrations between the second and fourth hour after administration.[148] Similar results were found by Etesse-Carsenti et al.[I34] in patients who underwent orthopaedic surgery. Up to 24 hours postdose, the bone concentrations were greater than 2 mg/L in cortical as well as in spongy bone, and were higher than the corresponding plasma concentrations. However, following a single 400 and 800mg intravenous dose of pefloxacin, Becq-Giraudon et al)135] and Desbordes et aUI36) reported a mean ratio bone: plasma concentrations of 0.4 in cerebral bone, 2 hours postdose. Bone concentrations were 1.16 and 2.53 mg/kg after the 400 and 800mg doses, respectively, and were doseClin. Pharmacoklnet. 27 (6) 1994

438

Bressolle et al.

Table VI. Penetration of pefloxacin into tissues Tissues

Heart Heart valve:

Dose (mg) [route and dosage regimen]"

mitral Cardiac muscle

800 [IV SO]

Endocardiac tissue

800 [PO SO]

Lung. diseased

Lung

Concentration (mg/L) SorP

tissue

Tissue: S or P ratio

8

4-8

7.07-8.52

6.08-7.29

0.86

800 [IV SO]

aortic

Lung Lung. healthy

Sampling time postdose (h)

No. of patients

122.123 5

8

8.5

8.5

1.0

3

4

7.07

20.1

2.8

122

34

1

5.4

10.9

2.01

124

3

2.8

5.8

2.0

400 [IV SO]

13

5.1

13.6

2.7

400 [PO M03] + 400 [IV]

16

11.2

20.9

1.9

400 [IV SO]

13

5.1

15.4

3.0

400 [PO M03] + 400 [IV]

16

11.2

26.7

2.4

800 + 400 [IV]

References

6

3

5.7

24.7

4.6

6

7.2

22.8

3.7

12 Lung

400 [IV SO]

Bronchial mucosa

400 [MO]

Bronchial mucosa

400 [PO M03] + 400 [IV]

6

Bronchial mucosa

800 + 400 [IV]

6

3

6

6

5

12

12

1-4

Muscle, fat and skin Muscle

400 [PO M03]

25

Fat

400 [PO M03]

27

Fat

400 [PO M03]

12

125

83

3.7

19.5

5.4

7.28

13.8

1.9

10

11

1.1

127

8.74

16.6

1.9

125

5.7

33.6

5.9

83

7.2

22.8

3.2

3.7

14.4

3.9

126

1.9

5.6

3

2.8

1.7

0.6

129

12

3.3

2.2

0.8

128

128

Subcutaneous tissue

800 [IV SO]

4

8

8.52

5.65

0.7

122

Skin

400 [PO M03]

9

12

1.8

7.6

4.2

128

Skin

400 [PO M03]

11

1.9

6.9

3.7

129

Skin

400 [PO M03] + 400 [IV]

12

2.3b

7.8

20.8

2.65

130

5c

5.1

23.7

4.65

2.3

0.7

0.3

129

3.5-21

2.08-9

0.27-0.5

131.132

2.54

0.74

0.29

Bone Bone

400 [PO M03]

5

Bone (iliac crest)

400 [IV M03]

15

2

Bone (cortical):

400 [IV SO]

23

6

healthy infected Bone (cortical)

Bone (medulla)

800 [PO SO]

800 [PO SO]

© Adis International limited. All rights reseNed.

26

26

0.5

133 2.54

1.1

0.43

9.6

5

0.52

10.0

48

4.8 3.3

24

1.6

5.2

0.5

9.6

12.2

1.3

1

10.0

32.0

3.2

6

5.8

8.0

1.4

12

5.7

17.8

3.1

24

1.6

6.6

4.1

134

134

Clin. Pharmocokinet. 27

(6)

1994

439

Pefloxacin Clinical Pharmacokinetics

Table VI. Contd Tissues

Bone (spongious):

Dose (mg) [route and dosage regimen]"

No. of patients

Sampling time postdose (h)

400 [IV SD]

23

6

healthy infected Bone (cranial) Bone (hip)

SorP

Concentration (mg/L) tissue

Tissue: S or P ratio

2.54

1.24

0.49 0.57

133 2.54

1.44

800 [IV SD]

11

2

6.49

2.53

0.39

400 [IV SD]

10

2

3.03

1.12

0.37

400 [IV MD2]

13

0-2

1.4

2-4

1.6

400[POMD2)

10

4-6

1.7

0-2

1.9

2-4

1.5

4-6 Bone (sternum)

800 [PO]

Bone

400 [IV MD2] + 400 [PO MD7]

34

References

135,136 137

1.2 5.4

5.5

3.7-21

3-10.2

1.02

124 138

Gynaecological tissues Myometrium

400 [IV SD]

400 [PO MD3] +400 [IV]

25

12

0.5-1

7.6

8.2

1.08

1-2

8.5

7.3

0.86 0.96

2-3

7.4

7.1

3-4

7.5

8.9

1.2

4-5

3.4

6.7

2.0

5-6

5.3

3.1

0.58

3.55

8.3

38.7

4.96

139

130,140

Endometrium

400 [IV SD]

4

Fallopian tubes

400 [IV SD]

4

139

Fallopian tubes

400 [PO MD3] + 400 (IV)

12

3.4

8.3

31.9

4.02

130,140

Ovary

400 (PO MD3) + 400 (IV)

12

3.33

7.9

44.9

6.03

130,140

800 [PO] + 400 [POMD3]

6

2

11.2

1.65

0.15

91,92

139

Ocular tissues Lens

Lens

6

6

12.4

3.17

0.26

6

12

9.84

4.59

0.47

8

24

5.24

2.48

0.47

6

36

4.42

1.53

0.35

6

48

1.45

1.68

1.16

800 [PO] + 400 [POMD7]

6

6

17.1

4.47

0.26

800 [PO] + 400 [POMD3-7]

38

6to 12

12.3

4.6

0.37

12

2.14

6.0

2.8

128

2.3

5.5

2.4

129

93,94

Otolaryngological tissues Tonsil

400 [PO MD3]

3

Oropharyngeal mucosa

400 [PO MD3]

14

Otopharyngeal mucosa

400 [PO MD3]

19

128,129

9

Continued next page

© Adis International limited. All rights reserved,

elin, Pharmacokinet. 27 (6) 1994

440

Bressolle et al.

Table VI. Contd Tissues

Dose (mg) [route and dosage regimenJ a

Prostate tissue and epididymis Prostate: 800 [IV SDJ

No. of patients

Sampling time postdose (h)

65

0.33

central

Concentration (mg/L) S or P tissue

Tissue: S or P ratio

9.9

3.8

0.38 0.48

References

141,142 9.9

4.8

Prostate

400 [PO MD7J

14

5-7

7.69

10.4

1.35

143

Epididymis

400 [PO MD3J + 400 [IVJ

10

2.5-11 .5

2.66-11.3

8.15-21.8

1.23-4.48

144

peripheral

Other tissues Liver

1

10.6-11.6

9 8

8

35-40

3

10.8

101.5

10

146

1-2

7.8

10.2

1.3

103

5.05-10.22

3.28-4.5

0.44 0.96

400 [PO SO]

Renal parenchyma

800 [IV SO]

6

Gallbladder wall

800 [IV SO]

12

Brain:

400 [IV SDJ

9

147 5.05-10.22

9.8

2. 71 b

9.2

9.2

1

4.1'

6.2

9.3

1.5

tumoral

a

400 [PO MD3J + 400 [IVJ

12

29.5-31.3

12

healthy Peritoneum

145

130

Dosage interval of 12 hours.

b

Sample taken at the beginning of the surgical procedure.

c

Sample taken at the end of the surgical procedure.

Abbreviations: IV = intravenous administration; MDn = multiple dose administration during n days; P = plasma; PO = oral administration; S = serum; SO = single dose.

proportional. In patients who underwent cardiac surgery with cardiovascular-bypass, pefloxacin concentrations in serum and breast-bone were determined 1 hour after oral administration of 800mg. Bone: serum concentration ratio averaged 1.02.f 124J The degree of homogenisation and extraction significantly affects the recovery of the drug from bone; moreover, many bone samples contain a high amount of blood. Some investigators considered blood contamination and corrected their results by the haemoglobin content and the respective plasma concentration. [135,136] Consequently, this may explain why results are contradictory.

significant difference in pefloxacin tissue concentrations between myometrium, endometrium and fallopian tubes. Norfloxacin, a metabolite of pefloxacin, contributed 10 to 20% of the total tissue concentrations. After repeated administration (400mg twice daily for 3 days followed by a 400mg intravenous infusion preoperatively), pefloxacin concentrations in myometrium, ovary and fallopian tubes exceeded 4- to 6-fold the corresponding plasma concentrations 3.5 hours after the last drug intake. Higher pefloxacin concentrations were detected in the ovary than in the myometrium and fallopian tubes,l130, 1401

7.5 Gynaecological Tissues 7.6 Ocular Tissues

Pefloxacin concentrations in gynaecological tissues were in the same range as corresponding serum concentrations up to 4 hours after a single intravenous dose of 400mg,l139] There was no © Adis International Limited. All rights reserved.

Data on the penetration into ocular tissues are scarce. Intraocular diffusion of pefloxacin in lens tissues was studied 2, 6, 12, 24, 36 and 48 hours Clin. Pharmacokinel. 27 (6) 1994

441

Pefloxacin Clinical Pharmacokinetics

after repeated oral administration of the drug (a loading dose of 800mg, then 400mg twice daily for 3 to 7 days). C max (4.6 mg/kg) was reached 6 to 12 hours postdose; the mean tissue: plasma ratio averaged 0.37.[91-94]

7.7 Otolaryngological Tissues

Pefloxacin attains concentrations in tonsillar tissues or sinus mucosa equal to or 3-fold higher than the corresponding serum concentrations.l 128 ] After repeated oral administration (400mg twice daily for 3 days), otopharyngeal mucosa: plasma concentration ratio averaged 2.8.[128,129]

7.8 Prostatic Tissue and Epididymis

To date, few data are available on the diffusion of pefloxacin into prostate tissue and epididymis. The central and peripheral prostatic tissue concentrations were determined in 65 patients undergoing abdominal prostatectomy due to prostatic hypertrophy. Prostatic (central 3.8 mg/kg; periphery 4.8 mg/kg) and serum (9.9 mg/L) concentrations were determined 20 minutes after intravenous infusion of 800mg of pefloxacin. The tissue : serum ratio averaged 0.43.1 141 ,142] At steady-state (400mg twice daily orally), tissue: plasma concentration ratios averaged 1.35,5 to 7 hours postdose.! 143] Following repeated administration of pefloxacin (400mg twice daily for 3 days followed by a 1 hour infusion of 400mg on the day of surgery), epidi dymal samples were obtained between 2.5 and 11.5 hours following the intravenous administration in patients hospitalised for surgery as part of their treatment for prostatic adenoma or prostatic cancer. The epididymal drug concentration ranged from 8.15 to 21.8 mg/kg. The tissue: plasma ratios averaged 2.35 (1.23 to 4.48).1 144] Pefloxacin achieves tissue concentrations to justify its use as an antimicrobial agent to treat acute or chronic prostatitis or epididimitis, since tissue concentrations exceed the MIC90 of most susceptible pathogens. © Adis International limited . All rights reserved.

7.9 Other Tissues

Pefloxacin achieved and maintained, for at least 12 hours, concentrations effective against susceptible strains, in hepatic tissue after administration of a single oral dose of 400mg to patients suffering from chronic hepatitis or undergoing cholecystectomy.l145] In patients undergoing renal surgery, the penetration of pefloxacin into the renal parenchyma was investigated after administration of a single intravenous dose of 800mg. The concentrations of pefloxacin in the renal parenchyma averaged 101.5 mg/kg, the corresponding renal parenchyma: plasma concentration ratio was 10.1 146 ] The diffusion of pefloxacin into renal tissue was similar to that observed after ciprofloxacin. One to two hours after administration of pefloxacin 800mg by slow intravenous infusion, the concentration of the parent drug in gallbladder wall averaged 10.2 mg/kg. The corresponding mean tissue: serum concentration ratio was 1.3.[103] Following repeated oral administration, the peritoneum: plasma concentration ratios ranged from 1 to 1.5 between 2.7 and 4.7 hours after the last dose.[130] In patients receiving various regimens of pefloxacin before removal of a brain tumour, pefloxacin appears to reach potentially therapeutic concentrations in brain tissue. The concentrations of pefloxacin in brain tissue ranged from 3.28 to 4.5 mg/L compared with concentrations in plasma of 5.05 to 10.2 mg/Lat the time of tumour removal. Pefloxacin concentrations were 2- to 3-fold higher in the tumour tissue than in samples obtained simultaneously from the surrounding unaffected brain tissue.[147]

8. Therapeutic Considerations Pefloxacin is a fluoroquinolone characterised by a wide spectrum of action, with pharmacokinetic characteristics that include essentially 100% bioavailability, a prolonged tl/2 and good diffusion in body fluids and tissues. In addition to tissue penetration activities, the ability of pefClin . Pharmacokinet. 27 (6) 1994

Bressolle et a/.

442

loxacin to enter phagocytic cells is an important factor affecting therapy for infections caused by organisms that survive and multiply intracellularly after phagocytosis. Pefloxacin rapidly achieves high plasma and dialysate concentrations in patients with CAPD peritonitis. The only other oral antibiotics that achieve therapeutic concentrations in dialysis fluid are cefalexin, cefradine and ciprofloxacin.l 61 ) Pefloxacin appeared to achieve CSF concentrations necessary for the treatment of meningitis caused by Gram-negative bacteria, allowing optimal CSF bactericidal activity and bacterial eradication from the CSF. The high penetration into CSF is influenced by its high lipid solubility, its low degree of ionisation and its low protein binding.[149) In patients with severe hepatic insufficiency or reduced hepatic blood flow, dosage adjustments are necessary and in some cases, it is necessary to increase the interval between doses. Although studies have shown that the pharmacokinetics of pefloxacin are unaltered in patients with renal failure, other studies reported that the AVC and tl/2 are significantly higher in patients with renal failure than in heathy volunteers. These results were attributed to a decrease in extrarenal clearance; so, therapeutic drug monitoring may be necessary if nonrenal elimination is also impaired. Pefloxacin is not currently indicated for the treatment of pregnant or nursing women. Because quinolones have the potential to produce arthralgias, the use of pefloxacin in children and adolescents in the growing phase is contraindicated. [I 6) Pefloxacin may be a useful antibacterial drug for the management of serious treatment-resistant and nosocomially acquired infections. However, in the treatment of respiratory tract infections, pefloxacin is not drug of first choice due to the resistance of some S. pneumoniae strains.[16) Pefloxacin may be of value for both culture-guided and empirical antibacterial treatment in patients with various forms of immune depression.l l50 ) Pefloxacin has been shown to be generally well tolerated during short and long term administration. The oral and the intravenous routes of admin© Adis International Limited. All rights reserved.

istration have similar pharmacokinetic profiles allowing easy interchange of routes of administration and flexibility.

Acknowledgements The authors gratefully acknowledge support of this work by Bellon Laboratories, Paris, France.

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Correspondence and reprints: Professeur F. Bressolle, Laboratoire de Pharmacocinetique, Faculte de Pharmacie, Avenue Ch. Flahault, 34060 Montpeliier Cedex 01, France.

Clin. Phormacokinet. 27 (6) 1994