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The pharmacokinetics of intravenous (i.v.) cefetamet and the bioavailability of oral cefetamet pivoxil in infants aged 3.5 to 17.3 months who were hospitalized for urological surgery were characterized. The absorption of cefetamet pivoxil administered in a syrup formulation was 38 +/- 19% (n = 5) for infants, which was comparable to values observed for children and adults. The plasma half-life of i.v. cefetamet was 3.03 +/- 0.96 h (mean +/- standard deviation; n = 20) in the infants. This was not different from the value observed for normal adult subjects but was longer than that reported for children aged 3 to 12 years. Urinary recovery of cefetamet after i.v. administration to infants was 63.4 +/- 17.7% (n = 16), which was less than the 80% recovery found in older children and adults. The steady-state volume of distribution was 399 +/- 116 ml/kg of body weight. It was comparable in size and showed the same dependence on body weight as it did in children and adults. The mean systemic clearance per kilogram of body weight in the infants was lower than that in children and adults, apparently because of immaturity of clearance processes. A model that accounted for maturation and growth with increasing age was developed for the clearance. On the basis of this model, the clearance capacity increased from birth to 5 years by a factor of 4.5 because of maturation. Maturation progressed exponentially, with a half-life of 14 months. This model was used to develop dosing regimen guidelines for pediatric patients aged 3.5 months and older.

The penetration of cefetamet and cefuroxime into the maxillary sinus mucosa after the administration of cefetamet pivoxil and cefuroxime axetil was investigated in patients undergoing elective surgery of the maxillary sinus. A total of 27 patients, 13 for cefetamet pivoxil and 14 for cefuroxime axetil, ranging from 15 to 70 years of age participated in this study. Each patient received three oral doses of either one tablet of cefetamet pivoxil (500 mg of GLOBOCEF) or two film tablets of cefuroxime axetil (125 and 250 mg of ZINAT) every 12 h. Sinus mucosa tissue samples were removed during surgery at times ranging from 2 to 4.5 h after the last oral administration. Blood samples were collected before drug administration, 2 h after the first and third doses, and concomitantly with tissue sample collection during surgery. All samples were analyzed by high-performance liquid chromatography. The concentrations of cefetamet and cefuroxime in plasma samples measured concomitantly with those in tissue samples ranged between 0.83 and 4.5 micrograms/ml for cefetamet and 0.59 and 3 micrograms/ml for cefuroxime. The mean tissue-to-plasma ratios calculated with reference to total (bound plus unbound) plasma drug concentrations were 0.60 (range, 0.52 to 0.77) for cefetamet (n = 4) and 0.38 (range, 0.28 to 0.44) for cefuroxime (n = 6). Both drugs seem to penetrate freely and easily into the sinus mucosa. The antibacterial activities of cefetamet pivoxil and cefuroxime axetil in cases of sinusitis therefore depend mainly on their achieved active plasma drug concentrations and their intrinsic activities in inhibiting the causative organism(s).

Two studies examining the bioavailability of cefetamet pivoxil in healthy male subjects were conducted. In the first, the bioavailabilities of the 250-mg (M250) and M500 tablet formulations of cefetamet pivoxil to be marketed were compared with that of a tablet used in clinical trials. All products were given with food at a dose of 500 mg. In the second study, the bioavailability of the syrup formulation was evaluated under both fasting and nonfasting conditions and compared with that of the M500 tablet formulation given with food. The absolute bioavailabilities of the M500 and M250 tablets (55.0% +/- 8.0% and 55.7% +/- 7.0%, respectively) were not significantly different from that of the clinical-trial formulation (49.8% +/- 8.5%). The newer tablet formulations exhibited faster absorption as evidenced by higher peak concentrations (3.8 [M500] and 3.9 [M250] mg/liter compared with 3.2 mg/liter for the clinical-trial formulation), a shorter time to peak concentration, and a shorter mean absorption time. The syrup formulation was found to have significantly lower absolute bioavailability (37.9% +/- 6.0%) compared with that of the M500 tablet (58.4% +/- 9.0%) when both were given with food. Food had no significant effect on the bioavailability of the syrup, which averaged 34.0% +/- 8.6% under fasting conditions, although absorption was delayed by food (mean absorption time increased from 2.2 to 3.9 h). This contrasts with the results of previous studies documenting significant increases in tablet bioavailability with food. Despite the lower bioavailability of the syrup, unbound-cefetamet concentrations are expected to remain above the MICs for 90% of the strains tested for susceptible organisms for approximately 10 h of the usual 12-h dosing interval with both syrup and tablet formulations of cefetamet pivoxil given with food.

Cefetamet pivoxil is an orally absorbed prodrug ester of the microbiologically active cephalosporin, cefetamet. The prodrug ester is completely hydrolysed to the active compound cefetamet on its first pass through the gut wall, the liver or both. Cefetamet is classified as a third generation cephalosporin with excellent activity against streptococci, Enterobacteriaceae, Neisseria and Haemophilus species. It has enhanced stability against beta-lactamases compared with penicillins and first and second generation cephalosporins. The antibacterial spectrum is comparable with that of cefotaxime except for its poor activity against staphylococci. Following a 20-minute zero-order intravenous infusion, cefetamet had a rapid distribution phase followed by a monoexponential decline. The average pharmacokinetic parameters from 152 healthy volunteers were: total body clearance 136 ml/min (8.16 L/h); renal clearance 119 ml/min (7.14 L/h); nonrenal clearance 17 ml/min (1.02 L/h); volume of distribution at steady-state 0.29 L/kg; terminal elimination half-life 2.2 hours; 88% of the dose recovered in the urine. Cefetamet is not extensively bound to plasma proteins. Consequently, these data indicate that cefetamet is predominantly eliminated unchanged by the kidney via glomerular filtration with possibly a minor component of tubular secretion. Cefetamet has a relatively small apparent volume of distribution consistent with that of other beta-lactam antibiotics. Results following ascending intravenous doses of cefetamet in healthy young male volunteers demonstrated that the pharmacokinetics of intravenous cefetamet are independent of the dose. The absolute bioavailability of cefetamet tablets following oral cefetamet pivoxil administration is enhanced by the presence of food. Under fed conditions, 50 to 60% of the final oral dose is absorbed into the systemic circulation. This food effect is observed when cefetamet pivoxil is administered within 1 hour of a meal. Food also produces a slight delay in the time to reach peak plasma concentrations of this drug. Changes in fluid volume intake with cefetamet pivoxil administration have no effect on the bioavailability of this drug. Similar absorption characteristics have been observed for all of the tablet dosage formulations studied during clinical development. The absolute bioavailability of the final syrup dosage formulation was between 38 and 47%. Little improvement in the bioavailability of this preparation has been observed with food. The absorption and disposition of cefetamet in human subpopulations [i.e. children, elderly (< 75 years of age), renal impairment, liver disease and patients taking concomitant drugs] have been studied extensively. Only impaired renal function appears to significantly alter the elimination of this drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Five absorption rate models have been compared for describing cefetamet data in 34 adults after oral administration of cefetamet pivoxil with food alone or in combination with either an antacid or an H2 antagonist. A sequential zero- then first-order input process provided the most flexible description of the absorption rate of cefetamet. If the first-order rate constant is linked to the zero-order input parameters the model can be interpreted as the consequence of solubility-limited absorption. While a sequential input is theoretically reasonable to assume, the first-order process appeared to be independent of the zero-order input. A population-based approach was applied to estimate the effect of dose and gastric pH increase on absorption and disposition. There appeared to be a dose-associated change in several parameters. The most marked change was an increase in volume of distribution of cefetamet. Treatments expected to increase gastric pH slowed the first-order component of the absorption process. Three models for estimating the extent of bioavailability have been compared using observations from 18 adults and 13 children receiving iv cefetamet and oral cefetamet pivoxil on two separate occasions. The most consistent estimates of the disposition parameters and the extent of bioavailability were achieved with the sequential zero- and first-order model under the assumption that steady state volume of distribution and nonrenal clearance were the same after iv and oral treatment.

The pharmacokinetics of cefetamet were determined after intravenous (i.v.) administration of cefetamet and oral administration of cefetamet pivoxil syrup to patients between the ages of 3 and 12 years. The patients were hospitalized for reconstructive urological surgery; to prevent infection, prophylactic i.v. cefetamet was administered on the day of surgery and oral cefetamet pivoxil was administered 2 days later. After i.v. administration, the mean (+/- standard deviation) half-life of cefetamet was 1.97 +/- 0.60 h (n = 18), which was different from the 2.46 +/- 0.33 h reported for nine adults (22 to 68 years old) in a previous study. The average values for the mean residence times were 2.35 +/- 0.94 and 2.83 +/- 0.34 h and the average values for the fraction of the dose eliminated unchanged in the urine were 79.9% +/- 8.99% and 80% +/- 11% in children and adults, respectively. Plots of mean systemic clearance and steady-state volume of distribution versus body weight for the children and comparative adults were linear on log-log coordinates, and the slopes of the plots were 0.661 and 0.880, respectively. These slope values suggested that mean systemic clearance values per unit of body surface area were similar in children and adults and that maintenance doses for children should be the adult maintenance dose multiplied by the child's surface area divided by 1.73 m2. The mean (+/- standard deviation) oral bioavailabilities of cefetamet pivoxil were 49.3% +/- 15.7% in 3- to 7-year-old children who received a 500-mg dose and 37.9% +/- 10.0% in 8- to 12-year-old children who received a 1,000-mg dose. These values were not different from that observed in the adult group after two 500-mg tablets. Likewise, the peak concentration of cefetamet in plasma and its time of occurrence in children were in line with the values which have been observed for adults.

The purpose of this investigation was to assess the influence that treatment with antacid and ranitidine had on the pharmacokinetics of oral cefetamet pivoxil in 18 healthy male volunteers. Each subject received, in an open-labeled, randomized, three-way crossover design, a single oral dose of 1,000 mg (two tablets) of cefetamet pivoxil 10 min after a standard breakfast during each of the following treatments: treatment A, control period; treatment B, antacid (80 ml of suspension; Maalox 70) administered on the evening before cefetamet pivoxil dosing (-12.5 h) and again 2 h before and 2 h after a standard breakfast; treatment C, ranitidine (150 mg) administered twice a day for 4 days and again 1 h and 10 min prior to cefetamet pivoxil dosing. Plasma and urine samples were collected over a 24-h period following cefetamet pivoxil administration. Cefetamet was analyzed by high-performance liquid chromatography. Oral bioavailability parameters (area under the concentration-time curve from 0 to 12 h, area under the concentration-time curve from 0 h to infinity, time to maximum concentration of drug in plasma, and maximum concentration of drug in plasma) were obtained by noncompartmental techniques. The results showed that none of these bioavailability parameters was significantly (P greater than 0.05) affected by antacid or rantidine coadministration. A compartmental analysis showed no significant differences. In addition, the terminal elimination half-life and the fraction of cefetamet excreted unchanged in the urine was also not significantly (P greater than 0.05) affected by antacid or ranitidine exposure. Relatively wide intrasubject variability was observed for time to maximum concentration of drug in plasma and terminal elimination half-life in several of the 18 subjects studied. Although these irregularities did not appear to be strongly associated with a particular treatment, they increased in subjects in both the antacid and H2-receptor antagonist treatment groups compared with those in subjects in the control treatment group. We conclude that antacid and ranitidine treatment likely does not alter the bioavailability of oral cefetamet pivoxil.

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 (Tmax) 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 less than 0.05). The maximum cefetamet concentration in plasma (Cmax) 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 micrograms/ml and 38.2 +/- 10.1, 35.7 +/- 11.9, and 42.8 +/- 6.8 micrograms.h/ml, respectively. The Cmax and AUC values were not different between the BE and WI groups (P greater than 0.05). However, differences in these values were found between the WI and AF groups (P less than 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 (Tmax, 2.50 +/- 0.52 versus 2.83 +/- 0.94 h; Cmax, 4.89 +/- 1.04 versus 4.84 +/- 0.89 micrograms/ml; AUC, 29.6 +/- 5.1 versus 30.7 +/- 7.1 micrograms.h/ml; P greater than 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.

The pharmacokinetics of orally administered cefetamet pivoxil and intravenously administered cefetamet were studied in 12 healthy subjects and 12 patients with hepatic cirrhosis without ascites. Cirrhosis had no detectable effect on the pharmacokinetics of cefetamet and on the bioavailability of cefetamet pivoxil. After intravenous cefetamet in control versus cirrhotic subjects, respectively, the following mean +/- standard deviation values were observed: total body clearance, 128 +/- 10.2 versus 123 +/- 28.8 ml/min; steady-state volume of distribution, 23.2 +/- 2.2 versus 22.7 +/- 4.6 liters; half-life, 2.42 +/- 0.21 versus 2.35 +/- 0.41 h. Renal and nonrenal clearances of cefetamet were similar in both groups, as were the mean residence times and areas under the plasma concentration-time curve. For oral cefetamet pivoxil, no differences were detected in the mean values of the percentage of dose absorbed: 44.6 +/- 9.1 versus 50.1 +/- 12.9. The rate of appearance of cefetamet in the plasma also was not affected by cirrhosis: similar mean values were found for the mean residence time and the maximum concentration in plasma and its time of occurrence.

The pharmacokinetics of cefetamet pivoxil during administration of ascending oral doses were studied in 16 male normal healthy volunteers (age, 24.5 +/- 2.1 years; weight, 73.5 +/- 8.5 kg). The subjects were randomly assigned to four oral treatments of 500, 1,000, 1,500, and 2,000 mg of cefetamet pivoxil according to a four-by-four Latin square design. After an overnight fast, the drug was administered 10 min after a standard breakfast. It was found that both the rate and extent of prodrug absorption, measured as cefetamet adsorption, were reduced with increasing doses. The time to maximum concentration of cefetamet in serum was delayed from 4.00 +/- 0.81 to 4.88 +/- 0.96 h (P less than 0.05) when the dose of cefetamet pivoxil was increased from 500 to 2,000 mg. The dose-normalized values of area under the curve from 0 h to infinity for cefetamet and fraction of dose excreted as cefetamet were reduced by averages of 10.3 and 12.5%, respectively, over the dose range studied (P less than 0.05). The changes in rate and extent of prodrug absorption are thought to be the main factors contributing to the nonlinear relationship between maximum concentration in serum and dose. The change in absorption characteristics of cefetamet pivoxil with dose is, however, expected to have few clinical consequences because the magnitudes of these changes are comparable with their respective intragroup variations.

The purpose of this investigation was to evaluate the effect of advanced age on the pharmacokinetics of cefetamet and its prodrug, cefetamet pivoxil. A secondary objective of this study was to assess the effect of food on the absorption of cefetamet pivoxil in the elderly. Twenty-four healthy subjects (twelve young and twelve elderly) received (in a Latin square design) a single-dose, 515-mg infusion of cefetamet, a single 1,000-mg oral dose of cefetamet pivoxil during fasted conditions, and a single 1,000-mg oral dose of cefetamet pivoxil 10 min after a standardized low-fat breakfast. Serial blood and urine samples were collected over a 36-h period and analyzed by high-performance liquid chromatography. Intravenous and oral pharmacokinetic parameters were obtained by using model-independent techniques. The systemic clearance and renal clearance of cefetamet were significantly lower (P less than 0.05) in elderly subjects compared with in young controls after intravenous administration. No significant difference was observed in the apparent volumes of distribution at steady state between the two groups. Consequently, half-life and mean residence time were prolonged. A trend toward a lower renal clearance/creatinine clearance ratio was observed in our elderly population. Oral clearance of cefetamet was only slightly reduced in our elderly subjects, consistent with an increase in plasma half-life. Otherwise, oral pharmacokinetic parameters were comparable between elderly and young subjects. Additionally, the same effects of food were observed on the absorption characteristics of cefetamet (no change in maximum concentration of drug in plasma and an increase in both time to maximum concentration of drug in plasma and bioavailability) in our elderly subjects as in our young volunteers. Age did not appear to alter the deesterification and bioavailability of cefetamet pivoxil. We conclude that the small reduction in the elimination of cefetamet in the elderly would not require dose adjustment for this population.

Cefetamet pivoxil belongs to the class of orally absorbed pro-drug esters which are hydrolyzed to the active compound (cefetamet) on their first pass through the gut wall and/or the liver. The intravenously administered cefetamet is eliminated predominantly unchanged in the urine by glomerular filtration. Systemic and renal clearance values for cefetamet were 140 and 130 ml/min, respectively. The plasma protein binding is 22%, whereby the only binding protein is albumin. The steady state volume of distribution (0.29 l/kg) corresponds roughly to the extracellular water space which is consistent with other low protein-bound cephalosporins. In general, after intravenous doses, cefetamet follows the kinetic behaviour of a cephalosporin with low protein binding, limited non-renal clearance, and renal clearance that is predominantly due to glomerular filtration, e.g. ceftizoxime, ceftazidime. After oral administration, cefetamet pivoxil shows a significant food effect (F = 41% vs 51%). Hence, cefetamet pivoxil is recommended to be taken after food. The food effect, however, is not of such a magnitude that it will be of clinical consequence when this recommendation is not followed. The food effect is not related to a change in gastric pH because antacids and ranitidine do not affect the absorption of cefetamet pivoxil, although in approximately 20% of the subjects absorption of the drug is delayed. The elimination of cefetamet is directly proportional to renal function. In patients with varying degrees of renal insufficiencies, dosage should be decreased accordingly. Age has no effect on the bioavailability of cefetamet pivoxil. However, the clearance of cefetamet is higher in children and lower in the elderly.

This report summarizes the results of three pharmacokinetic studies of cefetamet and cefetamet pivoxil conducted in normal adult male volunteers. In the first study the pharmacokinetics of cefetamet were evaluated after intravenous infusion of doses ranging from 133 to 2,650 mg. Over this dose range, the pharmacokinetics were linear. A dose-proportional increase in the area under the curve from zero to infinity was observed, whereas total clearance (140.3 +/- 23.6 ml/min), renal clearance (130.3 +/- 18.2 ml/min), volume of distribution at steady state (0.288 +/- 0.023 liter/kg), fraction excreted unchanged in the urine (94 +/- 11%), and elimination half-life (2.07 +/- 0.18 h) were independent of dose. In a second study the absolute bioavailability of single 1,500-mg doses of a tablet formulation of the pivaloyloxymethylester of cefetamet was evaluated under conditions of fasting and after a standard breakfast. Administration with food increased the extent of absorption (from 31 +/- 7 to 44 +/- 4%) while decreasing the rate of absorption (time to maximum concentration of drug in plasma increased from 3.0 +/- 0.6 to 4.8 +/- 0.4 h). The third study consisted of multiple oral administration of 1,000 mg of a similar oral tablet formulation twice daily for 10 days. This regimen was preceded and followed by intravenous administration of a 500-mg bolus dose of cefetamet. Oral doses were administered with breakfast and dinner. The absolute bioavailability of the tablet formulation was assessed after the first dose and after both the morning and the evening doses on day 10 of oral therapy. The compound was consistently absorbed to the extent of approximately 50% with no significant differences observed between the morning and evening doses on day 10.

The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLS), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t1/2 beta) was prolonged from 2.46 +/- 0.33 h in normal subjects to 29.1 +/- 13.9 h in patients with CLCR of less than 10 ml/min per 1.73 m2. Correspondingly, CLS and CLR decreased from 1.77 +/- 0.27 and 1.42 +/- 0.25 ml/min per kg to 0.14 +/- 0.04 and 0.04 +/- 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 +/- 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P greater than 0.05). After oral administration, the elimination parameters, t1/2 beta and CLR, were insignificantly different from the intravenous data (P greater than 0.05). Furthermore, the bioavailability (F) of cefetamet pivoxil (45 +/- 13%) was not altered by renal failure (P greater than 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 +/- 0.74 versus 14.8 +/- 6.14 micrograms/ml and 3.9 +/- 1.1 versus 8.4 +/- 1.7 h, respectively; P less than 0.05). Based on these observations, it is recommended that patients with CLcr of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily. Patients with CLcr between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLcr of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.