Response of plasma fatty acid profiles to changes in dietary n-3 fatty acids and its correlation with erythrocyte fatty acid profiles in dogs.

An elevated level of long-chain n-3 fatty acids (FA) in tissue membranes has a positive influence on the progression and treatment of many diseases. Therefore, dietary supplementation of n-3 FA is recommended in some diseases. Even though n-3 FA are absorbed readily from the diet, their incorporation into tissues may be compromised in diseased animals. In a clinical setting, it is desirable to monitor the success of dietary intervention. Plasma FA as well as erythrocyte membrane (EM) FA can be used to monitor dietary FA intake. This study compares FA from EM and plasma with regard to their reaction time and reliability for monitoring dietary changes of tissue FA profiles in dogs. Thirty dogs were divided into three groups and fed for 12 weeks. The control group (CONT) was fed a commercial standard diet low in n-3 FA. One group received the standard diet and 85 mg/kg body weight of a docosahexaenoic acid (DHA) concentrate (ADD). The third group was fed a commercial dog food containing fish oil (FO), which is rich in eicosapentaenoic acid (EPA). EM and plasma FA profiles were analysed by GC separately. Data on EM FA were published recently. n-3 FA in plasma reached the new level after 2 weeks (8 weeks in EM). Dietary differences between DHA and EPA are obvious after 1 week already. The concomitant decrease in plasma n-6 FA differed between ADD and FO. In general, the correlation of n-6 FA between plasma and EM was low. We therefore conclude that analysis of plasma FA is sufficient for monitoring a diet-induced increase in tissue n-3 FA in dogs. However, EM FA should be analysed if the effect of dietary intervention on tissue n-6 FA is important.

Influence of food on the pharmacokinetics of oral alitretinoin (9-cis retinoic acid).

BACKGROUND: Previous studies have shown that concomitant administration of food may enhance the bioavailability of oral retinoids. AIM: To assess the influence of food on the pharmacokinetics (PK) of alitretinoin after a single oral dose. METHODS: This was a single-dose, open-label, randomized, crossover study, which enrolled 30 healthy men, aged 18-44 years. Subjects received sequential doses of alitretinoin 40 mg either after fasting (treatment A) or 5 min after completion of a standard breakfast (treatment B), with the dosing sequence randomized (A/B or B/A). The washout period between the two doses was 1 week. Plasma concentrations over time were plotted and standard PK variables [area under the curve (AUC) of plasma concentration vs. time, maximum plasma concentration (C(max)), time to maximum plasma concentration (t(max)) and elimination half-life (t(1/2)] were determined. RESULTS: Drug exposure was markedly increased when alitretinoin was taken with food compared with fasting, and there were significant increases in mean C(max) (82.8 vs.25.4 ng/mL, respectively) and AUC (220.2 vs. 55.7 ng · h/mL). The delaying effect of food on t(max) was less marked (median of 3.0 vs. 2.0 h). Administration with food also increased exposure to drug metabolites. Variability in exposure was markedly reduced if alitretinoin was taken with vs. without food (percentage coefficient of variation 40% vs. 74% for AUC; 49% vs. 85% for C(max)). Alitretinoin was generally well tolerated, with typical retinoid adverse reactions, mostly comprising headache. CONCLUSIONS: Intake of alitretinoin with food substantially increased the bioavailability of alitretinoin, but variability in exposure was reduced. Consequently, oral alitretinoin should be taken with food as outlined in the manufacturer's summary of product characteristics.

Pharmacokinetics, efficacy and safety of alitretinoin in moderate or severe chronic hand eczema.

BACKGROUND: Recent studies have found that alitretinoin can induce clinically significant responses in subjects with severe chronic hand eczema (CHE) unresponsive to topical corticosteroids. AIMS: To assess the pharmacokinetics (PK), efficacy and safety of alitretinoin 10 or 30 mg once daily. METHODS: This was a randomized, double-blind study, which enrolled 32 subjects aged 18-75 years with CHE unresponsive to potent topical corticosteroids. Subjects received alitretinoin 10 mg (n = 16) or 30 mg (n = 16) once daily for 12 or 24 weeks. Standard PK variables [area under the curve (AUC) of plasma concentration vs. time, maximum plasma concentration (C(max)), time to maximum plasma concentration (t(max)), elimination half-life (t(1/2)), total systemic clearance (CL/F) and volume of distribution (Vd/F)] were determined for alitretinoin and metabolites. Efficacy was assessed using the Physician's Global Assessment (PGA) scale. RESULTS: Chronic administration of alitretinoin for up to 24 weeks did not result in accumulation or time-dependent changes in the disposition of alitretinoin. Exposure was found to be proportional to dose. Systemic exposure (AUC) to alitretinoin was proportional to dose for 10 and 30 mg alitretinoin; 62.8% of subjects achieved clear/almost clear hands in the 30 mg group and 12.5% in the 10 mg group. Alitretinoin was well tolerated. CONCLUSIONS: Chronic administration of alitretinoin for 12-24 weeks did not lead to accumulation or time-dependent changes in drug exposure. Alitretinoin was effective and well tolerated in the treatment of subjects with moderate or severe CHE unresponsive to potent topical corticosteroids.

Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557.

Isavuconazole is a promising new antifungal drug with favorable pharmacokinetic properties and excellent activity against a number of fungi. It is administered as a water-soluble prodrug (BAL8557) that is cleaved by plasma esterases to isavuconazole, which is eliminated primarily by hepatic metabolism. The objective of this investigation was to assess the effect of alcohol-related liver disease on the pharmacokinetics of isavuconazole. Subjects were 16 healthy individuals, 16 with mild liver impairment, and 16 with moderate liver impairment who were randomized to receive a single oral or intravenous dose of BAL8557 equivalent to 100 mg isavuconazole. Blood samples were collected for 21 days following drug administration, and plasma concentrations of isavuconazole, BAL8557, and the cleavage product BAL8728 were measured using high-pressure liquid chromatography coupled with tandem mass spectrometry. Following intravenous administration, the half-life of isavuconazole increased from 123 h for healthy volunteers to 224 h and 302 h for subjects with mild and moderate liver impairment, respectively. The systemic clearance of isavuconazole following intravenous administration decreased from 2.73 liters/h for healthy subjects to 1.43 liters/h for subjects with moderate liver impairment (47.6% decrease [P < 0.05]). A similar decrease (23.5%) was observed after oral administration. These results suggest that a dose adjustment may be needed when isavuconazole is used to treat fungal infections in patients with liver disease.

[Relative bioavailability of an optimised galenical formulation of mefloquine]. / Relative Bioverfügbarkeit einer optimierten galenischen Formulierung von Mefloquin.

The bioequivalence of an optimised formulation of a generic mefloquine (Mephaquin Lactabs/Test) compared to the reference product under fed conditions was assessed in a GCP/ICH conformable study. A standard two-way randomised crossover design with a 9 week washout period between treatments was used. Blood samples for determination of mefloquine concentrations for calculation of Cmax and AUC were collected at pre-dose and at predefined intervals up to 2016 hours after administration of a single oral dose of 750 mg. A standard bioequivalence analysis was performed on the two one-sided t-test procedure for log-transformed Cmax and AUC. 90% confidence intervals were calculated for both parameters and evaluated against regulatory standards of 80-125% (T/R). Analysis of plasma for mefloquine concentration was performed using a validated LC/MS method with MS detection. The ratio of mean AUC and Cmax (T/R) was 1.015 and 1.044, respectively. The 90% confidence intervals were 95.8-109.3% for AUC and 98.2-110.5% for Cmax. Mephaquin produces plasma concentrations comparable to those after administration of the reference product. The 90% confidence intervals for AUC and Cmax are within the acceptable ranges for bioequivalence of 80-125%. Thus, the optimised galenical formulation of Mephaquin Lactabs is bioequivalent to the reference product.

High-dose omeprazole: use of a multiple-dose study design to assess bioequivalence and accuracy of CYP2C19 phenotyping.

The objectives of this multiple-dose study were to compare the performance of a new formulation of omeprazole (40 mg) with that of an established formulation and to assess the accuracy of CYP2C19 phenotyping during high-dose chronic administration. Twenty-eight healthy subjects were randomized (1:1) to receive 40 mg of either Gasec-40 Gastrocaps (Mepha) or Antra 40 (Astra) daily for 5 days. The pharmacokinetics of omeprazole and the omeprazole/5'-hydroxyomeprazole ratio 3 hours postdose were assessed on day 5. Subjects switched formulations starting on day 6, and all measurements were repeated on day 8. Subjects with metabolic ratios greater than 6 were genotyped for CYP2C19. Gasec-40 was found to be bioequivalent to Antra based on the 90% confidence interval for AUC (102.4-111.7) and Cmax (100.6-120.7). Formulation had no effect on the ratio of omeprazole to 5'-hydroxyomeprazole, which was higher than previously reported with single 20 mg doses of omeprazole. The mean ratio did not differ between day 5 and day 8 but was highly variable: 7 of 28 subjects had more than a 2-fold difference between assessments. In four individuals identified by genotype as extensive metabolizers (EMs), phenotype could not be clearly assigned. The relative bioavailability of omeprazole can be accurately assessed using this multiple-dose study design. Chronic administration of 40 mg doses of omeprazole shifts the metabolic ratio in EMs toward that in poor metabolizers (PMs), apparently because of the nonlinear metabolic clearance of the drug. The assignment of phenotype in patients receiving chronic high-dose omeprazole treatment should be interpreted with caution.

Stability of cephalosporin prodrug esters in human intestinal juice: implications for oral bioavailability.

The levels of degradation of cefetamet pivoxil (CAT), cefuroxime axetil (CAE), and cefpodoxime proxetil (CPD) in 0.6 M phosphate buffer (pH 7.4) and human intestinal juice (pH 7.4) at 37 degreesC over 24 h were compared. Significant differences in the time courses of degradation and in the patterns of degradation products were observed. (i) The relative proportions of the Delta2- and Delta3-cephalosporins were roughly reversed in the two incubation media. In phosphate buffer, the major degradation product was the Delta2-cephalosporin (CAT = 61%; CAE = 74%; CPD = 85%), while in intestinal juice it was the Delta3-cephalosporin (CAT = 86%; CAE = 75%; CPD = 87%). (ii) Generally, the degradation of the prodrug esters progressed faster in intestinal juice than in phosphate buffer (e.g., for CAT the half-lives [t1/2s] were 0.78 and 4.3 h, respectively). (iii) The two diastereoisomers of CAE and CPD were degraded at different rates in intestinal juice (for the CAE diasteroisomers, t1/2s = 0.37 and 0.93 h; for the CPD diastereoisomers, t1/2s = 0.18 and 0.98 h) but were degraded at similar rates in phosphate buffer (for the CAE diastereoisomers, t1/2 = 1.6 h; for the CPD t1/2 diastereoisomers, = 2.2 h). It is concluded that (i) the Delta2 isomerization does not significantly affect the bioavailability of prodrug esters since enzymatic hydrolysis in the intestinal fluid proceeds mainly to the active Delta3-cephalosporin and (ii) the high degree of stereoselectivity of the enzymatic ester hydrolysis should make it possible to increase the bioavailabilities of certain prodrug esters (CAE, CPD) by using the more stable diasterioisomer.

Prospective comparison of ceftriaxone and cefotaxime for the short-term treatment of bacterial meningitis in children.

The effectiveness and safety of ceftriaxone and cefotaxime in the short-term treatment of primary bacterial meningitis were compared using a prospective, randomized, multicenter study design. Children between the ages of 6 weeks and 16 years received either ceftriaxone as a single dose (100 mg/kg on the first day followed by 75 mg/kg/day) or cefotaxime as four divided doses (200 mg/kg/day) for 4-7 days. A total of 82 patients (44 ceftriaxone, 38 cefotaxime) with documented bacteria in the CSF were studied. In patients receiving ceftriaxone, full recovery occurred in 79.5% while a further 13.7% recovered with neurologic sequelae. Full recovery was observed in 71.1% of children treated with cefotaxime with sequelae in a further 23.6% (no statistically significant differences between drugs). The time to clinical improvement and resolution of fever (3-4 days) was also similar for both drugs. All but 1 of the 82 patients studied had negative CSF cultures within 24 h of the beginning of therapy consistent with the excellent penetration into the CSF (trough concentrations of 2.7 mg/l for both drugs at the end of therapy). No differences were observed in the incidence of clinically significant adverse events. Ceftriaxone and cefotaxime are both effective in the treatment of bacterial meningitis. Ceftriaxone offers an advantage in case of administration since it is administered as a single daily dose.

Pharmacokinetics of ceftriaxone in patients undergoing continuous veno-venous hemofiltration.

Continuous hemofiltration is used widely in the management of patients with acute renal failure, but administration guidelines for many drugs have yet to be established. In this study, the pharmacokinetics of ceftriaxone were compared in patients with normal renal function (n = 9), mild renal insufficiency (n = 5), and acute renal failure receiving continuous veno-venous hemofiltration (n = 6). Pharmacokinetic parameters were determined under steady state conditions. Patients with mild renal insufficiency had a significantly lower renal clearance and longer half-life of ceftriaxone; however, drug recovery in the ultrafiltrate with continuous veno-venous hemofiltration was similar to that in the urine of patients with normal renal function. Pharmacokinetic parameters for renal, nonrenal, and systemic clearance and for volume of distribution and half-life were also similar between patients receiving continuous veno-venous hemofiltration and those with normal renal function. The sieving coefficient (S) of ceftriaxone (0.69) significantly exceeded the expected free fraction in plasma, confirming previous reports that protein binding does not limit the sieving of this compound. The results suggest that a reduction in the usual daily dose of ceftriaxone is not required in patients with acute renal failure receiving continuous veno-venous hemofiltration.

Influence of maturation and growth on cefetamet pivoxil pharmacokinetics: rational dosing for infants.

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.

Penetration of cefetamet pivoxil and cefuroxime axetil into the maxillary sinus mucosa at steady state.

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).

Pharmacokinetics of ceftriaxone in patients with typhoid fever.

Ceftriaxone in short courses has emerged as an effective alternative to chloramphenicol for the treatment of typhoid fever. To study the pharmacokinetics of ceftriaxone in acute typhoid fever, 10 febrile Nepalese adolescents and young adults with blood culture-positive illness were treated with 3 g of ceftriaxone (intravenous infusion for 30 min) daily for 3 days. On the 1st and 3rd day of treatment, blood and urine samples were collected at defined intervals for measurements of drug concentrations. Kinetic parameters including concentrations at the end of infusion (Cmax) and 24 h after the end of infusion (Cmin), elimination half-life (t1/2), area under the plasma concentration-time curve (AUC), total plasma clearance, renal clearance, percentage excreted in urine, and volume of distribution were estimated. On day 1, mean values were as follows: Cmax, 291 micrograms/ml; Cmin, 21.7 micrograms/ml; plasma t1/2, 5.2 h; AUC, 1,428 micrograms.h/ml; total plasma clearance, 37 ml/min; renal clearance, 19 ml/min; percentage excreted in urine, 49.7%; and volume of distribution, 16.1 liters. Mean values on day 3 were not significantly different from those on day 1. Compared with published values for healthy volunteers who received the same dose, our mean t1/2s and AUCs were lower and our mean total plasma clearances, renal clearances, and volumes of distribution were higher. The good clinical responses of these patients to therapy and the adequate Cmins support the use of ceftriaxone once daily for the treatment of typhoid fever.

Accumulation kinetics of propranolol in the rat: comparison of Michaelis-Menten-mediated clearance and clearance changes consistent with the "altered enzyme hypothesis".

(+)-Propranolol was infused at two rates into the pyloric vein (a portal vein tributary) of 15 male Sprague Dawley rats until apparent steady-state conditions were established (i.e., 8 hr at each rate). One group (n = 7) received the high dose (40 micrograms/min/kg) first, and in the other group (n = 8) the low dose (20 micrograms/kg/min) was used to initiate treatment. Free and total serum concentrations of propranolol were measured. When the low dose was given first, the apparent steady-state concentrations achieved during low- and high-rate infusion steps were 166 +/- 37 and 774 +/- 235 ng/mL, respectively. These data are consistent with a simple Michaelis-Menten kinetic model and the key parameters of such a model (Vmax and Km) were estimated. However, a crucial test of such a model (and one which should give insight regarding the relevance of an "altered enzyme hypothesis") is to reverse the order of infusion steps since, in a system controlled by Michaelis-Menten kinetics, the same steady-state concentrations should be achieved regardless of the order in which infusion steps are given. When the sequence of infusion rates was reversed, steady-state concentrations were 492 +/- 142 and 298 +/- 79 ng/mL for the high and low infusion rates, respectively. Clearly, a history of high-dose exposure reduces the intrinsic clearance of total drug (CLss) during a subsequent low-dose exposure (i.e., the apparent steady-state levels during the low-dose pyloric vein infusions were significantly different; P < 0.001). When these data were corrected for plasma protein binding, the same trends emerged.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability of syrup and tablet formulations of cefetamet pivoxil.

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 clinical pharmacokinetics.

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)

Models for describing absorption rate and estimating extent of bioavailability: application to cefetamet pivoxil.

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.

Cefetamet pivoxil: a review of its microbiology, toxicology, pharmacokinetics and clinical efficacy.

Cefetamet pivoxil is an oral, third-generation cephalosporin whose broad spectrum of antibacterial activity and favorable pharmacokinetic profile make it particularly suitable for the treatment of a wide range of infectious diseases. Cefetamet has high in vitro activity against both gram-positive and gram-negative bacteria that cause a number of respiratory tract and urinary tract infections. These include penicillin-sensitive Streptococcus pneumoniae, Streptococcus spp, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Proteus spp., Klebsiella spp. and Neisseria gonorrhoeae. It is not active against staphylococci, enterococci, Pseudomonas spp. or Bacteroides fragilis but does inhibit most bile-sensitive (oral) Bacteroides spp. Animal toxicology studies indicate that neither cefetamet pivoxil nor the active compound cefetamet have significant teratogenic, mutagenic, photogenic or allergenic potential. Cefetamet is eliminated unchanged in the urine with a half-life of 2.2 h. Volume of distribution approximates the extracellular fluid space (0.3 1/kg), protein binding is minima (22%) and oral bioavailability of cefetamet pivoxil is approximately 50% when taken with food. No significant drug interactions have been noted to date. The efficacy and tolerability of cefetamet pivoxil have been evaluated in the treatment of gram-positive and gram-negative infections in almost 5,000 patients. In comparative studies, cefetamet pivoxil was at least as effective, and in many cases clinically superior, to most currently recommended antibiotics for the treatment of urinary tract infections including gonorrhea and complicated infections in high risk patients. Efficacy has also been demonstrated in acute exacerbations of chronic bronchitis, pneumonia and infections of the ear, nose and throat. Clinical trials have shown that a 7 day treatment period with cefetamet pivoxil is as effective as a 10 day course of phenoxymethylpenicillin in the treatment of pharyngotonsillitis. Cefetamet pivoxil has been well-tolerated in clinical trials with only 1.2% of patients on standard doses discontinuing therapy prematurely. The most common adverse effects are gastrointestinal (diarrhea, nausea, vomiting) which occur in less than 10% of patients. Many current antibiotic treatment regimens involve the administration of three or more daily doses. However, standard doses of cefetamet pivoxil 500 mg twice daily provide unbound plasma concentrations of cefetamet which generally exceed the MIC(90) for susceptible organisms throughout the dosing interval and have been demonstrated to be clinically effective. This should result in good compliance with therapy in out-patients. Dosing regimens for cefetamet pivoxil should be adjusted in patients with impaired renal function while standard doses can be given to elderly patients and those with liver disease. Standard doses in children are 10 mg/kg or alternatively, children may receive a dose reduced in proportion to the ratio of their body surface area to that of an adult.