Vol. 35, No. 7

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 1991, p. 1492-1494

0066-4804/91/071492-03$02.00/0 Copyright © 1991, American Society for Microbiology

Pharmacokinetics of Single-Dose Intravenous, Oral, and Intraperitoneal Pefloxacin in Patients on Chronic Ambulatory Peritoneal Dialysis JEAN LUC SCHMIT,1* LIONEL HARY,2 PIERRE BOU,3 HENRI RENAUD,' PIERRE MICHEL ANDREJAK,2 AND ALBERT FOURNIER'

FRANCOIS WESTEEL,1

Department of Nephrology,l Department of Pharmacology,2 and Department of Pharmaceutics,3 University Hospital, Amiens 80030, France Received 26 March 1990/Accepted 4 April 1991

Comparison of plasma and dialysate concentrations of pefloxacin after intravenous, oral, or intraperitoneal administration shows excellent bidirectional diffusion of the quinolone through the peritoneal membrane, demonstrating that therapeutical concentrations can be achieved in the dialysate after intravenous or oral administration. In this study, the half-life of the drug was 18.8 + 1.4 h, i.e., apparently longer than that reported for normal controls or uremic patients on hemodialysis.

end of each 6-h dialysis period. Plasma and dialysate samples were stored at -20°C until the assay was performed. Concentrations of pefloxacin and its demethylated metabolite (norfloxacin) were determined by a high-performance liquid chromatography method which was derived from the technique of Montay and Tassel (14). Chromatography was done on a Novapak column C18 (15 by 0.39 cm; Waters Laboratories, Saint Quentin en Yvelynes, France). The mobile phase was acetonitrile (150 ml), citric acid, H20 (2 g), sodium acetate, 3H20 (2 g), triethylamine (1 ml), and water (850 ml), and the flow rate was 2 ml min-1. Sample specimens were precipitated with acetonitrile containing internal standard; the volume of injection was 5 to 10 ,ul, and fluorimetric detection (excitation wavelength, 330 nm; emission wavelength, 418 nm) had a limit of detection of 0.03 ,ug/ml for each compound. All samples from a single patient were assayed together the same day and concentrations were calculated by interpolation from a new calibration curve. Standard curves were linear from 0.63 to 10 ,ug/ml. The intraassay coefficients of variation at pefloxacin concentrations of 10, 2.5, and 0.625 ,ug/ml were 1.2, 2.1, and 3.4%, respectively (n = 6); for norfloxacin, coefficients were 2.4, 3.2, and 6.6% for concentrations of 5, 1.25, and 0.3125 1xg/ml, respectively. No analytical interference with other drug given to the patient was observed. Pharmacokinetic parameters of pefloxacin were calculated by noncompartmental methods. The elimination rate constant (XA) of pefloxacin was obtained by least-squares linear regression of the terminal part of logarithmic plasma concentration versus time curve. The elimination half-life was calculated as t1/2 = 0.693/XZ. The area under the pefloxacin plasma concentration-time curve (AUC) was calculated by linear trapezoidal approximation from the beginning of administration to the last datum point. The remaining area was calculated from this last datum point to infinity as C48/Xz, where C48 is the concentration at 48 h. Total body clearance (CL) was calculated as dose/AUC. The volume of distribution was calculated as Vz = dose/Xz. AUC. Peritoneal clearance (CLper) was determined in the 6- to 12-, 12- to 18-, and 18- to 24-h periods of dialysis after pefloxacin administration. It was calculated as the mean ratio of the amount of the drug recovered in the bag to the AUC of the corresponding period. For groups B and C, the absorption constant (Ka)

Peritonitis is a major source of morbidity in continuous ambulatory peritoneal dialysis (CAPD). It is usually due to Staphylococcus sp. or to gram-negative bacilli (5, 21). The commonly accepted therapeutic approach is the use of cephalosporin with or without aminoglycoside, administered intraperitoneally or intravenously (5, 18). Pefloxacin is the first new fluorinated quinolone to be licensed in France with oral and intravenous forms; it possesses an extended antibacterial spectrum, and its main pharmacokinetic characteristics are as follows: almost complete bioavailability after oral administration, large apparent volume of distribution (1.7 liters/kg), long half-life (11 h), and predominant hepatic route of elimination, with moderate variation of kinetic parameters in renal insufficiency (12, 13). The aim of this study was to compare plasma and dialysate concentrations of pefloxacin after intravenous, oral, or intraperitoneal administration in three groups of five patients undergoing CAPD, in order to propose guidelines for clinical use in peritonitis. Fifteen adult patients undergoing CAPD for at least 2 months and with creatinine clearance of less than 5 ml/min were enrolled; the study was approved by the Ethical Committee of our hospital and patients gave informed consent. In each group, mean age (years) and weight (kilograms) were as follows: group A, 65 and 71; group B, 67 and 65; and group C, 62 and 57, respectively. The patients had no history of hepatic disease or allergy to quinolones. Each patient had one exchange every 6 h for 48 h using low-osmolar (1.36 g of dextrose per liter) dialysis fluid bag (Dianeal; Travenol Laboratories, Plaisir, France). Five patients (group A) received 400 mg of pefloxacin intravenously over 30 min (mean dose, 5.87 + 0.54 mg/kg of body weight), five patients (group B) received 400 mg orally (mean dose, 6.35 ± 0.66 mg/kg), and five patients (group C) received 400 mg intraperitoneally (mean dose, 7.42 + 0.87 mg/kg) in the first bag. The stability of pefloxacin in the dialysis fluid was established in a preliminary study showing no variation in pefloxacin concentrations over 6 h. Plasma samples were obtained 0, 0.25, 0.5, 1, 1.5, 2, 3, 6, 12, 18, 24, and 48 h after the end of the administration; dialysis fluid samples were obtained at the *

Corresponding author. 1492

NOTES

VOL. 35, 1991

TABLE 2. Phamacokinetic parameters of pefloxacina

TABLE 1. Mean concentrations and range of pefloxacin in plasma and dialysis fluid after 400-mg dose samplea

Group A (i.v.)

Group B (p.o.)

Group C (i.p.)

3.1 (1.9-4.5) 2.8 (1.6-3.78)

4.1 (2.8-6.2) 1.8 (0.5-3.1)

3.5 (1.8-5.6) 13.6 (5.0-19.5)

6

P DF

Group A (i.v.)

Parameter

Pefloxacin concn (mg/liter)'

Time (h) and

12 P DF

2.4 (1.8-3.3) 1.6 (0.8-3.5)

3.0 (1.9-5.0) 1.7 (1.4-2.1)

2.5 (1.0-4.3) 2.9 (1.3-4.4)

P DF

1.8 (1.3-2.4) 1.2 (1.0-3.0)

2.6 (1.7-4.2) 2.4 (2.1-3.0)

1.9 (0.8-3.4)

P DF

1.5 (0.8-2.04) 1.1 (0.6-2.6)

2.0 (1.3-3.5) 1.5 (1.0-2.5)

1.4 (0.6-2.4) 1.3 (0.6-2.4)

P DF

0.6 (0.3-1.1) 0.64 (0.2-1.0)

0.7 (0.3-1.7) 0.9 (0.2-1.4)

0.7 (0.3-1.2) 0.6 (0.4-0.9)

18 1.9 (0.8-4.0)

24

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17.4 ± 2.3 t1/2 (h) 113.3 ± 18.7 AUC (mg Mhiter) per 65 kg of body wt 1.0 + 0.2 CL (ml/min) per kg 1.5 ± 0.5 V (liter/kg) CLper (ml/min) per kg 0.06 ± 0.01 6.4 ± 0.4 Cmax (mg/liter) per 65 kg of body wt Tmax (h)

Ka

Group B (p.o.)

Group C (i.p.)

19.2 ± 3.3 131.4 ± 30.8

19.7 ± 2.7 96.9 ± 21.2*

1.0 1.3 0.06 5.0

± 0.2 ± 0.1 ± 0.01 ± 0.6

3.2 ± 0.8 3.0 ± 1.1

1.3 1.9 0.09 3.5

± ± ± ±

0.3 0.5 0.02 0.8

4 ± 0.8 0.9 ± 0.1

a Values are the means + standard errors of the means. i.v., intravenous; p.o., oral; i.p., intraperitoneal. *, P = not significant (Kruskal-Wallis test).

48 a

P, plasma; DF, dialysis fluid. i.v., intravenous; p.o., oral; i.p., intraperitoneal.

was determined by the method of residuals applied to the log concentration-time relations, corresponding to a decomposition of the concentration-time equation in a sum of exponentials (19, 22). Results are presented as the means ± standard errors of the means. Nonparametric statistical tests were used: Wilcoxon signed rank for two groups and Kruskal-Wallis test for three or more. Concentrations of pefloxacin in plasma and dialysis fluid at 6, 12, 18, 24, and 48 h in each group are shown in Table 1, and pharmacokinetic parameters are listed in Table 2. Mean terminal half-life was 18.8 + 1.41 h; calculated percentage of the AUC from the last datum point to infinity was 13.4% ± 3.9% for group A, 15.2% + 10.2% for group B, and 11.7% ± 5% for group C. Plots of pefloxacin and norfloxacin plasma levels versus time in each group and mean pefloxacin dialysate levels at the end of each 6-h exchange are shown in Fig. 1. Comparability of the mean AUC per 65 kg observed for plasma concentrations in the three groups indicates good absorption of oral and intraperitoneal pefloxacin. Relatively large individual variations were seen in absorption of pefloxacin in group B (oral dose) in respect to Ka and Tmax: this was not due to concomitant therapy with aluminum antacids

as phosphate binders, since no patients in group B were given such therapy, but was possibly due to CaCO3 intake in two cases. Recent publications have reported the reduction of absorption of ciprofloxacin and norfloxacin by drug interaction with calcium carbonate in the intestinal lumen (15, 17), but this has not been investigated with pefloxacin. Six hours after administration, pefloxacin concentrations in peritoneal fluid reached 90% of the plasma value of the intravenous group, but only 43% of that of the oral group, in relation to the delay of absorption, and this should be kept in mind in establishing guidelines for peritonitis therapy. Mean overall dialysis fluid/plasma concentration ratios in groups A and B above 0.80 reflect high diffusion from blood to the peritoneal cavity as expected on the basis of physicochemical properties of the drug, i.e., relatively low molecular weight (319), low protein binding (25%), liposolubility, and high volume of distribution (8, 16). Total plasma clearance is affected very little by CAPD in relation to the small volume of exchange during each cycle. Intraperitoneal administration yields high levels of pefloxacin in the dialysis fluid up to 12 h, and this can ensure effective treatment of peritonitis at the early phase. Furthermore, intraperitoneal administration might be suitable for systemic infection therapy since plasma levels are comparable to those obtained after oral or intravenous administration after the sixth hour.

7

GROUP A

GROUP C 10

_E

C

E

C 0

a

4.

a

a. _. 3.

4

C3

C 3 r. c

c

ri; 0

CROUPB

74.

S.

2.a

0

6

2

1

3

lime (h)

3D

X

42

48

,1 0

1*3uX

time (h)

Z3

4

time (h)

FIG. 1. Plasma concentrations of pefloxacin (l) and norfloxacin (A) and dialysate concentration of pefloxacin (A) after intravenous (group A), oral (group B), or intraperitoneal (group C) administration of 400 mg of pefloxacin.

a

single

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ANTIMICROB. AGENTS CHEMOTHER.

NOTES

The mean elimination half-life of 18.8 h in uremic patients seems to be longer than that reported in the literature for healthy subjects who still demonstrate negligible renal clearance of the drug (12). This suggests alteration of nonrenal clearance of the drug and is apparently in opposition to previous data of Montay et al. (13), who found a mean half-life of 12 h in patients with end-stage renal failure. However, five of eight of Montay's patients were on regular hemodialysis, and this procedure can possibly increase hepatic metabolism (1, 11). In nonhemodialyzed patients, accumulation of N oxide metabolite of metabolized quinolones, pefloxacin and fleroxacin, has been described previously (9, 20), but no accumulation of the parent drug was demonstrated, at least in young patients (9). On the contrary, lower metabolic clearance of pefloxacin in older patients with normal (3) or impaired (7) renal function has been found. Indeed, the kinetics alterations could be explained in our study by the fact that most of our patients were elderly people and had underlying illnesses, such as cardiac insufficiency, that favored the choice of CAPD instead of hemodialysis as end-stage renal failure treatment in our institution. Insufficient data on the kinetics of the main metabolites of the drug in our study and lack of control groups prevent us from checking this hypothesis. According to these findings of prolonged half-life after a single dose and arguing that accumulation of the drug occurs in healthy subjects after repeated administration, in relation to a possible saturable process in the metabolic pathway (4), it is reasonable to propose that pefloxacin be given only once a day to CAPD patients, especially if they are elderly or polymorbid, provided that serum levels are monitored. This proposition is confirmed by data of Denis et al. (2), who treated 15 cases of peritonitis with an initial dose of 800 mg of pefloxacin intravenously the first day, followed by 400 mg intravenously or orally once a day for 3 days; mean plasma peak level at day 3 was 9.96 ± 2.28 mg/liter, close to values obtained after repeated 400-mg doses twice a day in normal

subjects. Ninety-percent MICs of pefloxacin for staphylococci and gram-negative bacilli range from 0.25 to 2 mg/liter, except for Pseudomonas sp. and some Proteus spp. (10), most streptococci and enterococci being resistant. Therapeutic dialysate concentrations may be achieved at the sixth hour after systemic administration of a single dose of 400 mg of pefloxacin, but it seems advisable to initiate peritonitis therapy with intraperitoneal injection. Dosage adjustment cannot be established from our data, but the prolonged half-life of pefloxacin observed in the populations we studied supports the need for comparative study with younger patients and suggests that plasma level monitoring would be useful in these settings. We are very grateful to C. Bilhaut for technical assistance. Support for this work was provided by Roger Bellon, Paris, France. REFERENCES 1. Balan, T. 1983. Consequences of renal insufficiency on hepatic clearance. Int. J. Clin. Pharmacol. Res. 6:459-474. 2. Denis, F., M. Mounier, C. Lagarde, and D. Benevent. 1987. Treatment of peritonitis in kidney failure patients under continuous ambulatory peritoneal dialysis by pefloxacin. Results and

pharmacokinetics. Pathol. Biol. 35:652-655. 3. Dow, J., A. M. Frydman, F. Djebbar, and J. Gaillot. 1988. Simple and multiple dose pharmacokinetics of pefloxacin in elderly patients. Rev. Infect. Dis. 10(Suppl. 1):S107. 4. Frydman, A. M., Y. le Roux, M. A. Lefebvre, F. Djebbar, J. B. Fourtillan, and J. Gaillot. 1986. Pharmacokinetics of pefloxacin after repeated intravenous and oral administration (400 mg bid.) in young healthy volunteers. J. Antimicrob. Chemother. 17(Suppl. B):65-79.

5. Gokal, R., D. M. A. Francis, T. H. J. Goodship, A. J. Blint, J. M. Ramos, R. E. Ferner, G. Proud, M. K. Ward, and D. N. S. Kerr. 1982. Peritonitis in continuous ambulatory peritoneal dialysis. Lancet ii:1388-1391. 6. Hoffken, G., K. Borner, P. D. Glateel, P. Koeppe, and H. Lode. 1985. Reduced enteral absorption of ciprofloxacin in the presence of antacids. Eur. J. Clin. Microbiol. 4:345. 7. Hoffler, D., I. Schafer, P. Koeppe, and F. Sorgel. 1988. Pharmacokinetics of pefloxacin in normal and impaired renal function. Arzneim. Forsch. 38:739-743. 8. Janknegt, R., and J. H. T. M. Koelman. 1987. Drug therapy in continuous ambulatory peritoneal dialysis patients. Pharm. Weekbl. 9:104-109. 9. Jungers, P., D. Ganeval, T. Hannedouche, B. Prieur, and G. Montay. 1987. Steady state levels of pefloxacin and its metabolites in patients with severe renal impairment. Eur. J. Clin. Pharmacol. 33:463-467. 10. King, A., and I. Phillips. 1986. The comparative in vitro activity of pefloxacin. J. Antimicrob. Chemother. 17(Suppl. B):1-10. 11. Matzke, G. R., P. A. Abraham, C. E. Halstenson, and W. F. Keane. 1985. Cefotaxime and desacetyl cefotaxime kinetics in renal impairment. Clin. Pharmacol. Ther. 38:31-37. 12. Montay, G., Y. Goueffon, and F. Roquet. 1984. Absorption, distribution, metabolic fate, and elimination of pefloxacin mesylate in mice, rats, dogs, monkeys, and humans. Antimicrob. Agents Chemother. 25:463-472. 13. Montay, G., C. Jacquot, J. Bariety, and R. Cunci. 1985. Pharmacokinetics of pefloxacin in renal insufficiency. Eur. J. Clin. Pharmacol. 29:345-349. 14. Montay, G., and J. P. Tassel. 1985. Improved high performance liquid chromatography determination of pefloxacin and its metabolite norfloxacin in human plasma and tissue. J. Chromatogr. 339:214-218. 15. Nix, D. E., J. H. Wilton, B. Ronald, L. Distlerath, V. C. Williams, and A. Norman. 1990. Inhibition of norfloxacin absorption by antacids. Antimicrob. Agents Chemother. 34:432435. 16. Paton, T. W., W. R. Cornish, M. A. Manuel, and B. G. Hardy. 1985. Drug therapy in patients undergoing peritoneal dialysis. Clinical pharmacokinetic considerations. Clin. Pharmacokinet. 10:404-426. 17. Polk, R. E. 1989. Drug-drug interactions with ciprofloxacin and other fluoroquinolones. Am. J. Med. 87(Suppl. 5A):S76-S81. 18. Prowant, B., K. Nolph, L. Ryan, Z. Twardowski, and R. Khanna. 1986. Peritonitis in continuous ambulatory peritoneal dialysis: analysis of an 8 year experience. Nephron 43:105-109. 19. Rowland, M., and T. N. Tozer. 1980. Estimation of the absorption half life from plasma concentration data, p. 293-295. In M. Rowland and T. N. Tozer (ed.), Clinical pharmacokinetics, 1st ed. Lea & Febiger, Philadelphia. 20. Singlas, E., A. Leroy, E. Sultan, M. Eddin, B. Moulin, A. M. Taburet, M. Dhib, and J. P. Fillastre. 1990. Disposition of fleroxacine. Clin. Pharmacokinet. 19:67-79. 21. Vas, S. I. 1983. Microbiologic aspects of chronic ambulatory peritoneal dialysis. Kidney Int. 23:83-92. 22. Wagner, J. G. 1975. Linear compartments models, p. 103-104. In J. G. Wagner (ed.), Fundamentals of clinical pharmacokinetics. Drug Intelligence Publications Inc., Hamilton, Ill.

Pharmacokinetics of single-dose intravenous, oral, and intraperitoneal pefloxacin in patients on chronic ambulatory peritoneal dialysis.

Comparison of plasma and dialysate concentrations of pefloxacin after intravenous, oral, or intraperitoneal administration shows excellent bidirection...
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