ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 1990, p. 1556-1559 0066-4804/90/081556-04$02.00/0 Copyright © 1990, American Society for Microbiology

Vol. 34, No. 8

Effects of Timing of Food and Fluid Volume on Cefetamet Pivoxil Absorption in Healthy Normal Volunteers YUN K. TAM,' JOHANNES KNEER,2 ULRICH C. DUBACH,3 AND KLAUS STOECKEL2* Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8,' and Pharmacokinetics, Department of Clinical Research, F. Hoffmann-La Roche Ltd., 4002 Basel,2 and Therapeutic Investigation Station, University Medical Outpatient Department, Cantonal Hospital, 4031 Basel,3 Switzerland Received 28 September 1989/Accepted 24 May 1990

Cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 16 male subjects (age, 23.4 + 1.7 years; weight, 73.9 + 7.0 kg) 1 h before (BE), with (WI), and 1 h after (AF) a standard breakfast. The time to peak concentration of cefetamet in plasma (T..,) was increased from 3.25 + 1.44 h in the BE group to 4.31 ± 1.54 and 4.13 ± 1.54 h in the WI and AF groups, respectively (P < 0.05). The maximum cefetamet concentration in plasma (C..) and the area under the plasma cefetamet concentration-time profiles (AUC) in the BE, WI, and AF groups were 5.50 ± 1.06, 5.47 ± 1.4, and 6.57 ± 0.93 gIg/ml and 38.2 ± 10.1, 35.7 ± 11.9, and 42.8 ± 6.8 ugi h/ml, respectively. The Cm. and AUC values were not different between the BE and WI groups (P > 0.05). However, differences in these values were found between the WI and AF groups (P < 0.05). The effect of fluid volume intake on cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 12 male subjects (age, 23.8 + 2.3 years; weight, 74.9 + 9.0 kg) under fasted and WI conditions. Increasing fluid volume intake from 250 to 450 ml under the fasted condition had no effect on the absorption of the prodrug (Tm.., 2.50 ± 0.52 versus 2.83 ± 0.94 h; C.., 4.89 ± 1.04 versus 4.84 ± 0.89 gig/ml; AUC, 29.6 ± 5.1 versus 30.7 ± 7.1 gig . h/ml; P > 0.05). Similar results were obtained under the fed state (Tm.., 4.75 ± 0.62 versus 4.67 ± 0.78 h; C.., 6.00 ± 1.37 versus 6.36 ± 1.14 gig/ml; AUC, 38.6 ± 8.8 versus 39.6 + 6.1 ,ugg h/ml; P > 0.05). Thus, independent of fluid volume intake, cefetamet pivoxil absorption is enhanced when it is given within 1 h of a meal, and it is recommended that the prodrug should be taken during this period of increased bioavailability.

Cefetamet (Ro 15-8074) is a new broad-spectrum cephalosporin. This agent possesses a broad spectrum of activity against many aerobic gram-positive and -negative organisms, including members of the family Enterobacteriaceae and Proteus mirabilis (8). Cefetamet is not effective when administered orally because this drug is not absorbed from the gastrointestinal tract. The development of the prodrug cefetamet pivoxil (Ro 15-8075) circumvents this problem. This pivaloyloxymethyl ester is readily absorbed from the gut and is converted to its active metabolite, cefetamet, presystemically (3). Similar to another oral cephalosporin, cefuroxime axetil (7), the absorption of cefetamet pivoxil is incomplete. The mean absolute bioavailabilities of cefuroxime axetil and cefetamet pivoxil under fasted condition are 32 to 35% and 41%, respectively (1, 7). The mechanisms responsible for this phenomenon are not known; however, significant hydrolysis by esterases in the gut lumen and a pH-dependent solubility of cefetamet pivoxil (>20 mg/ml at pH 1, 0.18 mg/ml at pH 4) could affect the extent of absorption of this prodrug. Earlier studies showed that the absolute bioavailabilities (F) of both cefuroxime axetil (7) and cefetamet pivoxil (1, 3) were enhanced when they were taken shortly after the ingestion of food. The causes of this increase may be related to inhibition of gut esterase activities, delayed gastric emptying, and increased gastric secretions. These transient effects of food could alter the enzymatic stability and the dissolution profile of this drug. Therefore, it is hypothesized that the timing of food ingestion and the volume of fluid intake could significantly alter the bioavailability of cefetamet pivoxil. *

MATERIALS AND METHODS Timing of food ingestion study. An open-label, randomized (4 by 4) Latin square design was used in the timing of food ingestion study. Sixteen healthy young male volunteers (age, 23.4 ± 1.7 years; weight, 73.9 ± 7.0 kg) were randomly given a 20-min intravenous (i.v.) infusion of 567 mg of cefetamet sodium, equivalent to 538 mg of cefetamet free acid, and 1,000 mg of cefetamet pivoxil hydrochloride (two 500-mg tablets), equivalent to 693 mg of cefetamet free acid, 1 h before, with, and 1 h after a standard breakfast. The drug was taken with 200 ml of water when administered 1 h before and after the meal. When the drug was administered concomitantly with a meal, it was taken with a cup of tea or coffee. Fluid volume study. An open-label, randomized crossover design was used in the fluid volume study. Twelve healthy male subjects (age, 23.8 + 2.3 years; weight, 74.9 + 9.0 kg) were recruited. Each subject received 1,000 mg of cefetamet pivoxil hydrochloride (two 500-mg tablets) on four occasions. Under the fasted condition, the prodrug was taken with either 250 or 450 ml of water. Under the fed condition, the prodrug was taken concomitantly with a standard breakfast, with or without 200 ml of water. The standard breakfast for these two studies contained two rolls with a small amount of butter (5 g) and jam (20 g), one cup of black coffee or tea (100 ml), one cup of milk (150 ml), one orange or banana, and 50 g of Swiss cheese (Emmentaler). The total volume of fluid in the standard meal was 250 ml. These two studies were approved by the local institutional ethics committee. Written consents were obtained from all subjects. The inclusion and exclusion criteria from our previous studies were adopted (1, 3). All subjects were required to fast overnight and refrain from alcohol for at

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FACTORS DETERMINING CEFETAMET PIVOXIL ABSORPTION

least 12 h prior to dosing. Four hours subsequent to drug administration, a standard light lunch was given. Each drug treatment was separated by a 1-week washout period. Blood samples (5 ml) were collected into VACUTAINERS (Becton Dickinson Vacutainer Systems, Rutherford, N.J.) containing potassium oxalate and sodium fluoride as anticoagulants at the following times: after cefetamet pivoxil, predose, 10, 20, and 30 min and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h postdose; after cefetamet, preinfusion, 5, 10, 15, and 20 min during the infusion and 25, 30, 40, and 50 min and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h after start of the infusion. Urine was collected for each of the treatments predose and at 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 10, 10 to 12, and 12 to 24 h after drug administration. Additional details concerning sample handling and storage have been described in previous reports (1, 3). Cefetamet in plasma and urine was quantified by the high-performance liquid chromatographic method reported by Wyss and Bucheli (9). All samples were analyzed in duplicate. The quantification limits for the assay were 0.5 and 20 pug/ml in plasma and urine, respectively. The linearity of the multilevel calibration (six points) was controlled for each assay batch (r2 was always >0.999). Quality-control plasma specimens containing drug concentrations of 1, 20, and 40 ,ug/ml and urine specimens containing drug concentrations of 30, 300, and 500 ,ug/ml were analyzed in duplicate with each assay batch. The resulting coefficients of variation at high and low concentrations were 3.9 and 7.3% for plasma and 8.3 and 5.2% for urine, respectively. Pharmacokinetic analysis. Plasma concentration-time data were analyzed by standard noncompartmental pharmacokinetic techniques (2). The terminal elimination rate constant, P, was estimated by using unweighted linear regression. When the log-linear segments were fitted by nonlinear least squares and with weighting functions of 1, y-1, and y-2 similar values were obtained. The greatest difference (6.2%) was found between the mean values calculated from the weighting function 1 and y-2 after i.v. administration. The area under the plasma concentration-time curve (AUC) was calculated by using a combination of the linear and log trapezoidal rule methods. The log trapezoidal rule method was applied to the log-linear decline phase of the concentration-time curve, whereas the remainder was estimated by the linear trapezoidal rule method. The AUC from the last point to infinity was estimated by dividing the last concentration by P. The extrapolated areas were between 1 and 2% of the total area after the i.v. treatment and between 3 and 17% after the oral treatment. After oral administration, the maximum concentration (Cmax) and the time to achieve this concentration (Tmax) were read directly from the concentration-time curve. In the timing of food study, F was calculated as the ratio of the dose-corrected AUC after oral and i.v. administration, according to the equation F = [AUC}. (oral) x dose (i.v.)]/ (i.v.) x dose (oral)], where AUC>. is the AUC from time zero to infinity and where doses and AUCs were expressed in equivalents of cefetamet free acid. Statistical analysis. Analysis of variance for the Latin square design was used to evaluate the effect of timing of food onCmax, Tmax, AUC, F, half-life at,B phase (t4/2x), renal clearance (CLR), and the fraction of dose excreted into urine in 24 h (f,). It was shown that there was an insignificant period effect in these analyses. Therefore, a randomized crossover design was adopted in the fluid volume study. Repeated-measure anaylsis of variance was used to evaluate the same kinetic parameters. When a statistical difference

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FIG. 1. Mean ± SD plasma cefetamet concentration-time curve after a 20-min infusion of 567 mg of cefetamet sodium. was detected in these tests, the Fisher least-squares difference test was used to evaluate paired means. The unpaired t test was used to compare kinetic parameters between the two studies. The criterion for statistical significance was set at P < 0.05. All data were recorded as means + standard

deviations. RESULTS Timing of food ingestion study. (i) i.v. infusion. Figure 1 shows the mean ± standard deviation cefetamet plasma concentration-time curve obtained from the i.v. infusion study. The pharmacokinetic parameters AUC, t1/21, total body clearance (CL), CLR, and volume of distribution at steady state (Vss) were 69.0 + 8.7 ,ug * h/ml, 2.22 + 0.21 h, 132 ± 17 ml/min, 119 ± 19 ml/min, and 21.8 ± 3.5 liters, respectively. The percentage of dose recovered in the urine after 24 h (fu x 102) was 90.2 ± 9.2%. These data confirm previous results (1, 3) indicating that cefetamet is mainly eliminated via the renal route. The t1/2, and Vss values were also in close agreement with our previously reported results (1, 3). (ii) Oral treatments. The mean cefetamet plasma concentration-time curves obtained after the three oral treatments (1 h before, with, and 1 h after a breakfast) are shown in Fig. 2. The corresponding pharmacokinetic data are reported in Table 1. t1/2, and CLR were not significantly different among those in the oral treatment groups (P > 0.05). Values for these parameters were also consistent with the results obtained from the i.v. infusion study, suggesting that the elimination kinetics of cefetamet are not altered when cefetamet pivoxil is administered. The Tmax values were significantly higher in the volunteers in the treatment groups that received cefetamet pivoxil simultaneously with or 1 h after the standard breakfast than in those in the group that received drug 1 h before a standard breakfast (P < 0.05; Table 1). When the drug was given 1 h after food, Cmax values were significantly higher than those in the other two oral treatment groups (P < 0.05). The values of F and AUC were also highest in the group that was given the drug 1 h after a standard breakfast. The difference achieved statistical significance when data were compared with those for the group that received cefetamet pivoxil concomitantly with food (P < 0.05).

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ANTIMICROB. AGENTS CHEMOTHER.

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FIG. 2. Mean plasma cefetamet concentration-time data obtained from healthy normal subjects after oral administration of 1,000 mg of cefetamet pivoxil (two tablets) 1 h before food (0), with food (O), and 1 h after food (A).

The cumulative urinary excretion data were consistent with the plasma data (Table 1). Administration of cefetamet pivoxil 1 h after food ingestion resulted in the highest recovery of cefetamet in urine. Similar to the AUC data, recoveries of cefetamet in urine after the other two oral treatments were not significantly different from each other (P > 0.05). Fluid volume study. The mean plasma cefetamet concentration-time profiles after the four treatments are presented in Fig. 3. The corresponding pharmacokinetic data are presented in Table 2. The elimination of cefetamet was not affected by the volume of fluid or food intake because t2,, and CLR were not different between the treatment groups (P > 0.05; Table 2). When cefetamet pivoxil was administered under fasted conditions, absorption was delayed by less than 0.5 h. There was an increase in the lag time to approximately 1 h when cefetamet pivoxil was given concomitantly with food (Fig. 3). No differences in the absorption parameters, Tmax and Cm., were evident between the two fasted treatments (P > 0.05). Similarly, the AUCs were not altered after these treatments (P > 0.05), suggesting that an increase in the volume of fluid intake from 250 to 450 ml has no effect on the bioavailability of cefetamet pivoxil. Similar observations were made for the fed conditions. Tmn, Cmax, and AUC values were insignificantly different between the two treatments (P > 0.05). Although the range of fluid volumes used in this study did not alter the absorption of cefetamet pivoxil, the bioavailability of the prodrug was again shown to be enhanced by food. The AUC and f,, values were increased by approxi-

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FIG. 3. Mean plasma cefetamet concentration-time data obtained from healthy normal subjects under fasted (-) and fed (- -) conditions with 250 (0) and 450 (0) ml of fluid.

mately 30%, and Tmn was significantly delayed (P < 0.05; Table 2). These results are consistent with our previous observations (1, 3).

DISCUSSION Recent observations of the effects of food on cefetamet pivoxil absorption suggest that changes in a number of physiological factors such as gastric emptying, gastric pH, intestinal transit time, and esterase activities in the gastrointestinal tract could have a significant influence on the rate and extent of absorption of this prodrug (1, 3). Since a standard meal could transiently alter these parameters, it was postulated that the timing of food intake in relation to dosing could have a significant impact on the absorption profile of this prodrug. Our hypothesis was that the maximum effects of food occurred when cefetamet pivoxil was administered with food. Delayed gastric emptying has been attributed to the slower absorption rate of cefetamet pivoxil (1, 3). It was not surprising to find that the absorption rate of cefetamet pivoxil was highest when it was given 1 h before a standard breakfast (Table 1), because food did not exert its effects until 1 h into prodrug absorption. The most interesting observation in this study, however, was related to the timing of the effect of food on the extent of cefetamet pivoxil absorption. We have shown in previous studies (1, 3) that, compared with the fasted condition, the absolute bioavailability of cefetamet pivoxil is approximately 25% higher when it is administered 10 min after a standard breakfast. In the present study, it was somewhat surprising to find that the F, AUC, andf0 values were lowest in the group that received drug with food (Table 1), because

TABLE 1. Effects of timing of food ingestion on the pharmacokinetic parameters of cefetamet after oral administration of 1,000 mg of cefetamet pivoxila Time of food x 102 F x 102 AUC CLR (h) C ( (tWml) ingestion ( (%) t112, (h) (gLg * h/ml) (ml/min) 1 h before 3.3 1.4b 5.50 ± 1.06 2.46 ± 0.49 38.1 ± 10.1 43.2 ± 10.6 42.0 ± 9.3 132 ± 28 With a meal 4.3 ± 1.5 5.47 ± 1.40 2.41 ± 0.37 35.6 ± 11.9c 39.7 ± 10.6c 39.1 ± 10.4c 131 ± 23 1 h after 4.1 ± 1.5 6.57 ± 0.93b 2.33 ± 0.43 42.8 ± 6.8 48.4 ± 6.4 49.2 + 5.0 135 ± 23

T.n

a Values are means ± standard deviations. b Significantly different from the other two treatment groups. c Significantly different from the group given drug 1 h after food.

FACTORS DETERMINING CEFETAMET PIVOXIL ABSORPTION

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TABLE 2. Effects of fluid volume on the pharmacokinetic parameters of cefetamet after oral administration of 1,000 mg of cefetamet pivoxila Treatment

Fasted 250 ml 450 ml Fed 250 ml 450 ml

102

CLR (mi/min)

Tmax (h)

Cmax (p.g/ml)

2.5 ± 0.5 2.8 ± 0.9

4.89 ± 1.04 4.84 ± 0.89

2.34 ± 0.34 2.31 ± 0.31

29.6 ± 5.1 30.7 ± 7.1

33.2 ± 5.6 35.5 ± 6.8

130 ± 16 135 ± 17

4.8 ± 0.6b 4.7 ± 0.8b

6.00 ± 1.37b 6.36 ± 1.14b

2.34 ± 0.30 2.25 ± 0.26

38.6 ± 8.8b 39.6 ± 6.1b

43.9 ± 4.8b 46.6 ± 5.1b

135 ± 21 138 ± 17

AUC (h) t1/2P 1/ ()(jig.h/mI)

X

(%

a Values are means ± standard deviations. bSignificantly different from the fasted groups.

the effect of food was postulated to be at its maximum when the drug was given together with food. It should be pointed out that the F, AUC, andf, values of the group that received drug with food were not different from those of the group that received drug 1 h before food ingestion (P > 0.05). The question is whether food effects are present. There is not enough information in the data presented here to answer this question, because the absorption of the prodrug was under the influence of food, even though the prodrug was taken 1 h before a standard breakfast (Tmax, >3 h). Although F, AUC, andf, values were highest in the group that received drug 1 h after a standard breakfast, they were not statistically different from those for the group that received drug 1 h before a standard breakfast (P > 0.05). Differences were significant, however, when the values of the groups that received drug with and 1 h after a standard breakfast were compared (P < 0.05). It was postulated that other mechanisms might be operating in controlling cefetamet pivoxil absorption. A careful review of the protocol showed that, besides the difference in the timing of food intake, there was a variance in the fluid volume consumption. The tablets were taken with 200 ml of water in the oral treatment groups given drug 1 h before and 1 h after a standard breakfast, whereas in the group that received food with drug, cefetamet was taken only with the coffee or tea provided with the breakfast. Because of the limited solubility of cefetamet pivoxil under acidic conditions (0.16 mg/ml at pH 1), it was therefore postulated that fluid volume could significantly alter the dissolution rate of the tablets and, subsequently, the extent of the prodrug absorption. A number of well-documented studies have shown that the bioavailabilities of several penicillins are increased when they are taken with a large volume of fluid (6). Presumably, this is due to an improvement in the dissolution of the drugs, an increase in the gastric emptying rate, or both. Since these studies were performed under fasted conditions, it is not clear whether similar effects could be observed under fed conditions. The fluid volume study was designed to evaluate these aspects of cefetamet pivoxil absorption. The results of this study show that by increasing the fluid volume intake from 250 to 450 ml, there is no effect on the rate or extent of prodrug absorption, regardless of the fasted and fed conditions (Table 2). In the fluid volume effect study, the characteristic effect of food on cefetamet pivoxil absorption was once again confirmed. Although the AUCs in the timing of food study were the lowest in the group that received drug with food the presence of a food effect was demonstrated in the fluid volume study. It should also be pointed out that when the

Cmax and AUC values in the fluid volume study, under the fed conditions, were compared with those of the group that received drug with food in the timing of food study (Tables 1 and 2), the values were higher, although not statistically different (P > 0.05). Interestingly, when these results from the fluid volume study were compared with those of the group that received drug 1 h after a standard breakfast, a statistical difference could not be found (P > 0.05; Tables 1 and 2). The combined results of these two studies lead to the conclusions that (i) the absorption of cefetamet pivoxil is enhanced from 1 h before to 1 h after food ingestion and (ii) an increase in the fluid volume from 250 to 450 ml has no effect on cefetamet pivoxil absorption. Based on the results of the previous (1, 3) and the present two studies, it is recomnmended that cefetamet pivoxil be taken within 1 h of a meal such that enhanced bioavailability can be obtained. The small delay in absorption with food (lag time, -1 h) is of no significance, particularly during multiple dosings. LITERATURE CITED 1. Blouin, R. A., J. Kneer, and K. Stoeckel. 1989. Pharmacokinetics of intravenous cefetamet (Ro 15-8074) and oral cefetamet pivoxil (Ro 15-8075) in young and elderly subjects. Antimicrob. Agents Chemother. 33:291-296. 2. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed., p. 445-449. Marcel Dekker, Inc., New York. 3. Koup, J. R., U. C. Dubach, R. Brandt, R. Wyss, and K. Stoeckel. 1988. Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans. Antimicrob. Agents Chemother. 32:573-579. 4. Sommers, D. E. K., M. Van Wyk, J. Moncrieff, and H. S. Schoeman. 1984. Influence of food and reduced gastric acidity on the bioavailability of bacampicillin and cefuroxime axetil. Br. J. Clin. Pharmacol. 18:535-539. 5. Thomson, A. B. R., B. Pinchbeck, J. Kirdeikis, P. Kirdeikis, L. Zuk, and K. Brunet. 1988. Evaluation of antacid tablets and liquid in fasting and fed men and women. Clin. Ther. 10:158-168. 6. Welling, P. G. 1977. How food and fluid affect drug absorption. Postgrad. Med. 62:73-82. 7. Williams, P. E. O., and S. M. Harding. 1984. The absolute bioavailability of oral cefuroxime axetil in male and female volunteers after fasting and after food. J. Antimicrob. Chemother. 13:191-196. 8. Wise, R., J. M. Andrews, and L. J. V. Piddock. 1986. In vitro activity of Ro 15-8074 and Ro 19-5247, two orally administered cephalosporin metabolites. Antimicrob. Agents Chemother. 29: 1067-1072. 9. Wyss, R., and F. Bucheli. 1988. Determination of cefetamet and its orally active ester, cefetamet pivoxil, in biological fluids by high-performance liquid chromatography. J. Chromatogr. Biomed. Appl. 430:81-92.

Effects of timing of food and fluid volume on cefetamet pivoxil absorption in healthy normal volunteers.

Cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 16 male subjects (age, 23.4 +/- 1.7 years; weight, 73.9 +/- 7.0 kg) 1 h before (BE), w...
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