Pharmacokinetics of cefetamet pivoxil and interaction with cisapride and N-acetylcysteine

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ORIGINAL ARTICLE

Pharmacokinetics of cefetamet pivoxil and interaction with cisapride and N-acetylcysteine Klaus-Jurgen Gutleben', Jorg Eller', Jessica Vockler', Margot Rau', Peter Koeppe", Jochen Kotwas2 and Hartmut Lode' 'City Hospital Berlin-ZehlendorflHeckeshorn, affil. Freie Universitat Berlin, and 2Klinikum Benjamin Franklin, Freie Universitat Berlin, Berlin, Germany

Objective: To evaluate the pharmacokinetics of cefetamet pivoxil and possible interaction with N-acetylcysteine and cisapride in healthy volunteers. Methods: In a double-blind, randomized three-way crossover study with 12 healthy male volunteers, serum and urine concentrations of cefetamet were determined over 12 h by a validated bioassay method after oral administration of 0.5 g cefetamet pivoxil and, randomly, placebo, 5x20 mg cisapride, or 0.6 g N-acetylcysteine. Results: The study medications were well tolerated, although there were 10 cases of altered bowel movements, two cases of mild, transient headache and one case of increased serum transferase levels (AST and ALT). The mean peak serum level of cefetamet pivoxil in the placebo group was 4.86 t1.35 mg/L. The urine recovery/24 h in the placebo group was 41.9 t3.8% of the oral dose. The elimination half-life was 3.5650.92 h. N-Acetylcysteine had no effect on the pharmacokinetics of cefetamet pivoxil. With concomitant administration of cisapride there was an accelerated absorption of cefetamet pivoxil and a slightly increased C ,, of cefetamet. The C , values differed significantly (pc0.05) only between the cisapride group (5.765 1.50 mg/L) and the N-acetylcysteine group (4.5351 .I8mg/L). Conclusion: None of the small pharmacokinetic differences between the three groups is expected to have any relevance in the treatment of infectious diseases with cefetamet pivoxil.

Key words: Cefetamet pivoxil, interaction, N-acetylcysteine, cisapride

Cefetamet pivoxil is an oral third-generation cephalosporin which is hydrolyzed to form the active agent, cefetamet. It is effective against many Gram-positive and Gram-negative pathogens, including Huemophifus influenme, streptococci and a broad spectrum of Enterobacteriaceae [l]. Cefetamet pivoxil has been investigated in the treatment of several infectious diseases, e.g. respiratory tract infections, pharyngotonsillitis, urinary tract infections, otitis media and pneumonia in

children [2-61. Especially in respiratory tract infections antibiotics are often combined with N-acetylcysteine, a well-described mucolytic agent, which has also been shown to influence several antibiotics [7,8]. Cisapride, chemically related to metoclopramide, is an orally administered agent which facilitates or restores motility throughout the length of the gastrointestinal tract. It is mainly used in gastroesophageal reflux disease, functional dyspepsia, gastroparesis and constipation [9]. Increased motility might alter the pharmacokinetic parameters of concomitantly administered drugs, such as antibiotics; our hypothesis was a possible reduction of bioavailability due to accelerated transport along the absorptive mucosa in the upper intestine. Therefore, the main objective of this study was to determine the pharmacokinetics of cefetamet pivoxil in male volunteers after oral administration with and without concomitant administration of cisapride and Nacetylcysteine.

Corresponding author and reprint requests: H. Lode, Department of Pulmonary and Infectious Diseases, City-Hospital Berlin-ZehlendorWHeckeshorn,affil. Freie Universitat Berlin, Zum Heckeshorn 33, 14 109 Berlin, Germany Tel: 49-30-8002-2222 Fax: 49-30-8002-2623 E-mail: [email protected] Revised version accepted 3 October 1996 170

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MATERIAL AND METHODS Volunteers

Twelve male volunteers with an age range from 23 to 41 years (mean 28k5.2 years), an average weight of 78.5k8.1 kg and an average body height of 183+6 cm were included in this study after physical examination and laboratory screening. All volunteers had normal hepatic and renal functions (mean creatinine clearance: l o o k 6 niL/min/1.73 m2) and a negative medical history for drug abuse and for any drug allergies, especially to b-lactam antibiotics. None of the study subjects took any other drug during the 2 weeks preceding the study or during the study. Informed written consent was obtained from all subjects. The study was approved by the ethical committee of the Klinikum Benjamin Franklin, Freie Universitat Berlin, according to German law. Study design and procedure In a three-way crossover design with a wash-out period

of 2 weeks, each volunteer received the study medication according to the following schedule in a random order: (1) 0.5 g cefetamet pivoxil + placebo; (2) 0.5 g cefetamet pivoxil + 0.6 g N-acetylcysteine; (3) 0.5 g cefetamet pivoxil + 5 x 20 mg cisapride. For Nacetylcysteine and cisapride, the study was double blind and placebo controlled. Order of drug administration

Five doses of cisapride or placebo were administered every 12 h, each dose 30 min before a meal (last dose before a standard breakfast on profiling day). NAcetylcysteine or placebo was administered 30 min after the standard breakfast, together with 200 mL of tap water, concomitantly with cefetamet pivoxil. Postprandial absorption of cefetamet pivoxil is known to be much better than in the fasting state [lo]. Consumption of caffeine and alcohol was prohibited during the profiling time. Cefetamet pivoxil (EXP96 M0083 MFD09 93) in the form of capsules was kindly supplied by Hoffmann-La Roche Grenzach-Wyhlen, Germany; Cisapride (Ch.B.: 93F22/3F039), N-acetylcysteine (Ch.B.: 326006) and placebo capsules containing lactose (Ch.B.: P 508326) were obtained from the Klinikum Benjamin Franklin Pharmacy department, Berlin.

Collection and processing of samples

Blood samples of 10 mL for bioassay of cefetamet were taken from a peripheral intravenous line prior to administering 0.5 g cefetamet pivoxil and 15, 30 and 45 min, and 1, li, 2, 2;, 3, 4, 6, 8 and 12 h afterwards on each profiling day. The blood samples were centrifuged for 10 min at 1300g. All samples were covered to protect cefetamet from light exposure. After the agar plates were inoculated with serum, the remains of the samples were frozen at -20 "C together with the standard solutions to be used for repeated determinations in case of poorly readable results. The blank value was recorded prior to ingestion of the antibiotic to detect possible intrinsic activity in the serum. No volunteer exhibited any such activity. Urine samples were collected before and 0-3, 3-6,6-12 and 12-24 h after oral application of cefetamet pivoxil. Specimens of the urine samples were put into sterile tubes and also stored at -20°C together with the standard solutions until further processing. None of the urine samples taken prior to cefetamet pivoxil administration showed any intrinsic antibacterial activity. Bioassay method

A bioassay method, described by Reeves and Bywater [ I l l , was used to determine levels of cefetamet in serum and urine. The test strain was Klebsiella AT 10031. The lower detection limit was determined to be 0.12 mg/L in both serum and urine. The coefficient of variation in our tests was found to be between 3.0% (urine at 10 mg/L) and 5.6% (serum at 1 mg/L). As a control, we established solutions with a concentration of 2 mg/L on each profiling day which were determined 10 times. Means and standard deviations of the control were calculated. Each plate containing samples was also used to once again determine the concentration of the control solution, which was supposed to be within the range of three standard deviations. Otherwise the samples had to be processed again. Pharmacokinetic analysis

The estimation of the parameters C,,, T,,,, and ti/Z, was based on an open one-compartment model. All other parameters were analyzed non-compartmentally [12-141. Dose-dependent parameters (C,,,,,, AUC& were calculated for each dose per 70 kg of body weight. Statistical analysis

Composition of the standard breakfast

The standard breakfast comprised two rolls (25 g, 8% protein, 1% fat, 55% carbohydrate), 20 g butter (1% protein, 83% fat, 1% carbohydrate), one slice of sausage (15 g, 12% protein, 52% fat), 20 g jam (64% carbohydrate) and liquid (300 mL caffeine-free coffee).

The pharmacokinetic parameters of all three groups were compared by analysis of variance. If the F value was significant, the Student-Newman-Keuls multiple comparison test was used to compare the means two by two. A p value <0.05 was considered significant [151.

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Pharmacokinetics

The main pharmacokinetic parameters are shown in Table 1. For all groups there was a mean lag time of approximately 21 min before absorption occurred. The mean peak concentrations of cefetamet in serum after administration of 0.5 g cefetamet pivoxd plus placebo, 0.5 g cefetamet pivoxil plus concomitant administration of cisapride in steady state (5 x20 mg), and 0.5 g cefetamet pivoxil plus concomitant administration of 0.6 g N-acetylcysteine, were 4.9 mg/L, 5.8 mg/L and 4.5 mg/L, respectively (Figure 1). A significant difference (p
Safety and tolerance

There were no side effects that required treatment. None of the volunteers had to be excluded during the study. We noticed 10 cases of altered bowel habit, two cases of mild, transient headache and one case (placebo group) of increased serum transferase levels (aspartate aminotransferase (AST) 131 U/L and alanine aminotransferase (ALT) 110 U/L without serologic evidence of hepatitis A, B or C, cytomegalovirus or Epstein-Barr virus infection. Thus we have to consider cefetamet pivoxil as a possible cause for the increase in these parameters.

Table 1 Pharmacolunetic parameters (mean? standard deviation) of cefetamet after oral administration of cefetamet pivoxd

(Cef. Piv.) according to the schedule mentioned above Parameters

Cef. Piv. +placebo

(h)

0.36f0.15 4.86k1.35 3.10f0.98 3.56 f0.92 32.8f5.2 41.923.8 48.8f12.4 252 f38 106+20

zag

Cmax (mg/L) Trnm (h) h (h) AUC,,, (mg h/L)

Urine-Rec. (% of dose)

KJf

kg) (d/min/1.73 m’) cl,, (d/rnin/t.73 m2) Cl,,/f

Cef. Piv. + NACC

Cef. Piv. + Cisapride

0.35 k0.12 *4.53f 1.18 3.34f0.73 3.24 f0.81 32.9f5.8 42.9f7.2 50.9f 16.1 253 f 46 106f12

0.35 f0.14 *5.76f1.50 2.76f0.52 2.86f0.53 32.5f5.9 44.6 k4.1 42.8f8.9 256 f40 108f11

z,,=lag time; C,,=peak concentration; Tm= time of peak concentration; Ti,,,=biological elimination half-life; AUC=area under the curve; Urine-Rec.=urine recovery/24 h; K,/f= volume of distribution at steady state; CltOt/f=totd clearance; CI,,=renal clearance; f = bioavailability; NACC =N-acetylcysteine; * p <0.05.

10

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t

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,

-

-CP + placebo

x mean +std. dev CP + Nacetylcysteine CP + cisapride

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0

.

I

2

*

I

4

I

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6

r

I

8

Figure 1 Serum concentrations of cefetamet (mean? standard deviation).

r-,-.

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14

G u t l e b e n e t al: P h a r m a c o k i n e t i c s of c e f e t a m e t p i v o x i l

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C P + N-acetyicysteine

1 CEFETAMET PlVOXlL 500 mg I

CP + cisapride

0-3

T T

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0-12

0 - 24

T T T

Total

Collection interval [hours] Figure 2 Cumulative renal recovery of cefetamet (mean k standard deviation).

of 2.8 h, compared to 3.1 h in the placebo group and 3.3 h in the N-acetylcysteine group. The corresponding 24-h urine recovery of cefetamet (Figure 2) after concomitant cisapride administration was higher (45%) compared with both other groups (42'36, 43%), although not significantly increased. The biological elimination half-life was 3.6 h in the placebo group and 2.9 h in the cisapride group (p>0.05). There was no change in the area under the curve (AUCto,) and the renal clearance by concomitant administration of N-acetylcysteine or cisapride, indicating that concomitant administration of neither Nacetylcysteine nor cisapride altered the bioavailability of cefetamet pivoxil.

DISCUSSION The results presented above show that absorption of orally administered cefetamet pivoxil (0.5 g) leads to a mean peak serum concentration of cefetamet of approximately 4.9 mg/L and a renal excretion of about 42% of the given dose. These values confirm previous investigations o n the pharmacokinetics of cefetamet pivoxil [I 61. The peak concentration of cefetamet pivoxil is similar to the peak concentrations of other cephalosporin esters, such as cefuroxime axetil (5.6 mg/L), cefpodoxime proxetil (2.5 mg/L after 0.2 g orally) and cefotiam hexetil (4.4 mg/L after 0.4 g orally), whereas the peak concentration of cefixime is

lower (1.9 mg/L after 0.2 g orally). Loracarbef (19.2 mg/L after 0.4 g orally), ceftibuten (11.6 mg/L after 0.2 g orally) and cefprozil (9.6 mg/L) have higher peak concentrations [17]. The mean elimination half-life ( t I,*,) of cefetamet pivoxil is approximately 3.6 h, which is up to threefold longer than the elimination half-lives of cefuroxime axetil, cefprozil and loracarbef 1171. Since the bioavailability of cefetamet pivoxil is approximately 50% [16], the urinary recovery of 41.9+3.8% (placebo group) indicates a primarily renal elimination. The mean renal clearance in the placebo group was 106 mL/min/l.73 m2. Mainly renal elimination has also been described for most other new oral cephalosporins. Only cefixime has a low urine recovery and a high concentration in the bile, indicating hepatic elimination [37-191. O u r comparison of the area under the curve (concentration x time), the most important parameter of bioavailability, led to the following results. After the administration of 0.5 g cefetamet pivoxil we observed mean AUC values of 32.8 k 5.2 mg h/L, similar to the values of cefprozil (26.1 k h . 7 rrig h/L after 0.5 g orally), cefixime (14.9k5.2 mg h/L after 0.2 g orally), loracarbef(33.0k 5.9 mg h/L after 0.4 g orally) and the new cephalosporin esters (cefuroxime axetil, 37.8f7.2 mg h/L after 0.5 g; cefpodoxime proxetil, 14.0k3.9 mg h/L after 0.2 g, except for cefotiam hexetil with an AUC value of only 9.1 ing h/L after oral application of

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0.4 g). The AUC value of ceftibuten has been shown to be 48.345.7 mg h/L, after oral application of only 0.2 g 1171. As previously reported for loracarbef 1201 and recently shown for sparfioxacin 1211, the results of this study indicate that concomitant administration of cisapride in the steady state accelerates the absorption of cefetamet pivoxil, thus increasing the peak serum level. However, this difference was only significant (p<0.05) when the N-acetylcysteine group was compared with the cisapride group; nevertheless, the area under the curve (concentration x time) of these groups remained constant. Since T,, in the cisapride group is decreased compared to both other groups (not significantly), the increase in Cmaxmay be due to the accelerated gastric emptying caused by cisapride. Concomitant administration of N-acetylcysteine was also investigated because the combination of cephalosporins and mucolytic drugs is widely used in the treatment of respiratory tract infections, although some investigators have reported negative in vitro effects of N-acetylcysteine on antibiotics, including cephalosporins [8,9]. In this study, concomitant administration of 0.6 g Nacetylcysteine had no effect on the essential pharmacokinetic parameters (peak serum level, area under the curve, urinary excretion) of cefetamet pivoxil. None of the changes in pharmacokinetics of cefetamet pivoxil caused by the concomitant administration of cisapride or N-acetylcysteine is expected to have any clinical relevance in treatment of infectious diseases with cefetamet pivoxil. Acknowledgment Presented in part at the 19th International Congress of Chemotherapy, Montreal, Canada, 16 July 1995. References 1. Brysen HM, Brogden R N . Cefetamet pivoxil-a review of its antibacterial activity, pharniacokinetic properties and therapeutic use. Drugs 1993; 45: 589-621. 2. Grassi GG. Clinical eficacy of cefetamet pivoxil in lower respiratory tract infection. Drugs 1994; 47(suppl 3): 35-42. 3. Kissling M. Cefetamet pivoxil in community-acquired pneumonia: an overview. Curr Med Res Opin 1992; 12: 631-9. 4. Kissling M, Chadbourne U. Literature survey on clinical efticacy and tolerability on cefetamet pivoxil: an analysis of 3,128 cases. Respiration 1993; 60(suppl 1): 45-54. 5. Toporovsh J, Steffens L, Kranz A, Noack M, Burdeska A, Kissling M. Effectiveness of cefetamet pivoxil in the treatment ofpyelonephritis in children. J Int Med Res 1992; 20: 87-93.

6. Quevedo A, Sossouhounto R, Kissling M. Cefetamet pivoxil in otitis media. O R L J Otorhinolaryngol Relat Spec 1993; 55: 93-6. 7. Gottschalk B, Wichmann G. Die Wirkung von N-acetyl-LCystein (Mucosolvin) auf verschiedene Antibiotika. Das Deutsche Gesundheitswesen 1970; 15: 700-2. 8. Lawson D, Saggers BA. Some observations on the penetration of antibiotics through mucus in vitro. J Clin Pathol 1966; 19: 313-17. 9. Wiseman LR, Faulds D. Cisapride-an updated review of its pharmacology and therapeutic eficacy as a prokmetic agent in gastrointestinal motility duorders. Drugs 1995; 47: 11652. 10. Tam YK, KneerJ, Dubach UC, StoeckelK. Effects oftiming of food and fluid volume on cefetamet pivoxil absorption in healthy normal volunteers. Antimicrob Agents Chemother 1990; 34: 1556-9. 11. Reeves DS, Bywater MJ. Assay of antimicrobial agents. In de Louvois J, ed. Selected topics in clinical bacteriology. London: Badhere Tyndall, 1976; 21-78. 12. Schwarz %. Estimating the dimension of a model. Ann Statistics 1978; 6: 461-4. 13. Gibaldi M. Biopharmaceutics and clinical pharmacokinetics, 4th edn. Philadelphia and London: Lea & Febiger, 1991. 14. Koeppe P, Harnann CM. REVOL-non-linear regression based on the strategy of evolution. EDV Med Biol 1978; 9: 112-17. 15. Sachs L. Angewandte statistik, vol. 6. Berlin Heidelberg New York: Springer-Verlag, 1984. 16. Tam YK, Kneer J, Dubach UC, Stoeckel K. Pharmacokmetics of cefetamet pivoxil with ascending oral doses in normal healthy volunteers. Antimicrob Agents Chemother 1989; 33: 957-9. 17. Lode H, Fassbender M , Schaberg T, Borner K, Koeppe P. Comparative pharmacokinetics of the new oral cephalosporins. Drugs 1994; 47(suppl 3): 10-20. 18. Fassbender M, Lode H, Schaberg T, Borner K, Koeppe P. Pharmacokinetics of new oral cephalosporins, including a new carbacephem. Clin Infect Dis 1993; 16: 646-53. 19. Tanirnura H, Kobayashi N, Saito T, et al. Chemotherapy of biliary tract infections: concentrations of cefixime in bile and gallblader tissue and clinical evaluation on biliary tract infections. Chemotherapy (Tokyo) 1985; 33(suppl 6): 499517. 20. Eller J, TolksdorffE, Rau M, Vockler J, Koeppe P, Lode H. Pharmacokinetics of loracarbef and interaction with a prokmetic agent of the gastrointestinal tract [abstract 40721. In: Program and Abstracts of the 19th International Congress of Chemotherapy. Can J Infect Dis 1995; 6(suppl C). 21. Zix JA, Geerdes-Fenge HF, Rau M, Koeppe P, Lode H. Sparfloxacin-Interaktionen mit Sucralfat und Cisaprid. In: Program and Abstracts of the 102nd German Congress of Internal Medicine, Wiesbaden, Germany. D M W 1996; suppl 1: 99.