CEDAX Capsule / Oral suspension Ref.[50729] Active ingredients: Ceftibuten

Pharmacokinetics

Absorption

CEDAX CAPSULES

Ceftibuten is rapidly absorbed after oral administration of CEDAX Capsules. The plasma concentrations and pharmacokinetic parameters of ceftibuten after a single 400-mg dose of CEDAX Capsules to 12 healthy adult male volunteers (20 to 39 years of age) are displayed in the table below. When CEDAX Capsules were administered once daily for 7 days, the average C_max was 17.9 µg/mL on day 7. Therefore, ceftibuten accumulation in plasma is about 20% at steady state.

CEDAX ORAL SUSPENSION

Ceftibuten is rapidly absorbed after oral administration of CEDAX Oral Suspension. The plasma concentrations and pharmacokinetic parameters of ceftibuten after a single 9-mg/kg dose of CEDAX Oral Suspension to 32 fasting pediatric patients (6 months to 12 years of age) are displayed in the following table:

The absolute bioavailability of CEDAX Oral Suspension has not been determined. The plasma concentrations of ceftibuten in pediatric patients are dose proportional following single doses of CEDAX Capsules of 200 mg and 400 mg and of CEDAX Oral Suspension between 4.5 mg/kg and 9 mg/kg.

Distribution

CEDAX CAPSULES

The average apparent volume of distribution (V/F) of ceftibuten in 6 adult subjects is 0.21 L/kg (± 1 SD = 0.03 L/kg).

CEDAX ORAL SUSPENSION

The average apparent volume of distribution (V/F) of ceftibuten in 32 fasting pediatric patients is 0.5 L/kg (± 1 SD = 0.2 L/kg).

Protein Binding

Ceftibuten is 65% bound to plasma proteins. The protein binding is independent of plasma ceftibuten concentration.

Tissue Penetration

Bronchial secretions

In a study of 15 adults administered a single 400-mg dose of ceftibuten and scheduled to undergo bronchoscopy, the mean concentrations in epithelial lining fluid and bronchial mucosa were 15% and 37%, respectively, of the plasma concentrations.

Sputum

Ceftibuten sputum levels average approximately 7% of the concomitant plasma ceftibuten level. In a study of 24 adults administered ceftibuten 200 mg bid or 400 mg qd, the average C_max in sputum (1.5 µg/mL) occurred at 2 hours postdose and the average C_max in plasma (17 µg/mL) occurred at 2 hours postdose.

Middle-ear fluid (MEF)

In a study of 12 pediatric patients administered 9 mg/kg, ceftibuten MEF area under the curve (AUC) averaged approximately 70% of the plasma AUC. In the same study, C_max values were 14.3 ± 2.7 µg/mL in MEF at 4 hours postdose and 14.5 ± 3.7 µg/mL in plasma at 2 hours postdose.

Tonsillar tissue

Data on ceftibuten penetration into tonsillar tissue are not available.

Cerebrospinal fluid

Data on ceftibuten penetration into cerebrospinal fluid are not available.

Metabolism and Excretion

A study with radiolabeled ceftibuten administered to 6 healthy adult male volunteers demonstrated that cis-ceftibuten is the predominant component in both plasma and urine. About 10% of ceftibuten is converted to the trans-isomer. The trans-isomer is approximately ⅛ as antimicrobially potent as the cis-isomer.

Ceftibuten is excreted in the urine; 95% of the administered radioactivity was recovered either in urine or feces. In 6 healthy adult male volunteers, approximately 56% of the administered dose of ceftibuten was recovered from urine and 39% from the feces within 24 hours. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment (see DOSAGE AND ADMINISTRATION).

Food Effect on Absorption

Food affects the bioavailability of ceftibuten from CEDAX Capsules and CEDAX Oral Suspension.

The effect of food on the bioavailability of CEDAX Capsules was evaluated in 26 healthy adult male volunteers who ingested 400 mg of CEDAX Capsules after an overnight fast or immediately after a standardized breakfast. Results showed that food delays the time of C_max by 1.75 hours, decreases the C_max by 18%, and decreases the extent of absorption (AUC) by 8%.

The effect of food on the bioavailability of CEDAX Oral Suspension was evaluated in 18 healthy adult male volunteers who ingested 400 mg of CEDAX Oral Suspension after an overnight fast or immediately after a standardized breakfast. Results obtained demonstrated a decrease in C_max of 26% and an AUC of 17% when CEDAX Oral Suspension was administered with a high-fat breakfast, and a decrease in C_max of 17% and an AUC of 12% when CEDAX Oral Suspension was administered with a low-calorie nonfat breakfast (see PRECAUTIONS).

Bioequivalence of Dosage Formulations

A study in 18 healthy adult male volunteers demonstrated that a 400-mg dose of CEDAX Capsules produced equivalent concentrations to a 400-mg dose of CEDAX Oral Suspension. Average C_max values were 15.6 (3.1) µg/mL for the capsule and 17.0 (3.2) µg/mL for the suspension. Average AUC values were 80.1 (14.4) µg∙hr/mL for the capsule and 87.0 (12.2) µg∙hr/mL for the suspension.

Special Populations

Geriatric patients

Ceftibuten pharmacokinetics have been investigated in elderly (65 years of age and older) men (n = 8) and women (n = 4). Each volunteer received ceftibuten 200-mg capsules twice daily for 3½ days. The average C_max was 17.5 (3.7) µg/mL after 3½ days of dosing compared to 12.9 (2.1) µg/mL after the first dose; ceftibuten accumulation in plasma was 40% at steady state. Information regarding the renal function of these volunteers was not available; therefore, the significance of this finding for clinical use of CEDAX Capsules in elderly patients is not clear. Ceftibuten dosage adjustment in elderly patients may be necessary (see DOSAGE AND ADMINISTRATION).

Patients with renal insufficiency

Ceftibuten pharmacokinetics have been investigated in adult patients with renal dysfunction. The ceftibuten plasma half-life increased and apparent total clearance (CI/F) decreased proportionately with increasing degree of renal dysfunction. In 6 patients with moderate renal dysfunction (creatinine clearance 30 to 49 mL/min), the plasma half-life of ceftibuten increased to 7.1 hours and CI/F decreased to 30 mL/min. In 6 patients with severe renal dysfunction (creatinine clearance 5 to 29 mL/min), the half-life increased to 13.4 hours and CI/F decreased to 16 mL/min. In 6 functionally anephric patients (creatinine clearance <5 mL/min), the half-life increased to 22.3 hours and CI/F decreased to 11 mL/min (a 7- to 8-fold change compared to healthy volunteers). Hemodialysis removed 65% of the drug from the blood in 2 to 4 hours. These changes serve as the basis for dosage adjustment recommendations in adult patients with mild to severe renal dysfunction (see DOSAGE AND ADMINISTRATION).

Microbiology

Ceftibuten exerts its bactericidal action by binding to essential target proteins of the bacterial cell wall. This binding leads to inhibition of cell-wall synthesis.

Ceftibuten is stable in the presence of most plasmid-mediated beta-lactamases, but it is not stable in the presence of chromosomally-mediated cephalosporinases produced in organisms such as Bacteroides, Citrobacter, Enterobacter, Morganella, and Serratia. Like other beta-lactam agents, ceftibuten should not be used against strains resistant to beta-lactams due to general mechanisms such as permeability or penicillin-binding protein changes like penicillin-resistant S. pneumoniae.

Ceftibuten has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE):

Gram-positive aerobes:

Streptococcus pneumoniae (penicillin-susceptible strains only)
Streptococcus pyogenes

Gram-negative aerobes:

Haemophilus influenzae (including β-lactamase-producing strains)
Moraxella catarrhalis (including β-lactamase-producing strains)

There are no known organisms which are potential pathogens in the indications approved for ceftibuten for which ceftibuten exhibits in vitro activity but for which the safety and efficacy of ceftibuten in treating clinical infections due to these organisms, have not been established in adequate and well-controlled trials.

NOTE: Ceftibuten is INACTIVE in vitro against Acinetobacter, Bordetella, Campylobacter, Enterobacter, Enterococcus, Flavobacterium, Hafnia, Listeria, Pseudomonas, Staphylococcus, and Streptococcus (except pneumoniae and pyogenes) species. In addition, it shows little in vitro activity against most anaerobes, including most species of Bacteroides.

Susceptibility Testing

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized concentrations of ceftibuten powder. The MIC values should be interpreted according to the following criteria when testing Haemophilus species using Haemophilus Test Media (HTM):

The current absence of resistant strains precludes defining any categories other than “Susceptible”. Strains yielding results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing.

A report of “Susceptible” implies that an infection due to the strain may be appropriately treated with the dosage of antimicrobial agent recommended for that type of infection and infecting species, unless otherwise contraindicated.

Ceftibuten is indicated for penicillin-susceptible only strains of Streptococcus pneumoniae. A pneumococcal isolate that is susceptible to penicillin (MIC ≤0.06 µg/mL) can be considered susceptible to ceftibuten for approved indications. Testing of ceftibuten against penicillin-intermediate or penicillin resistant isolates is not recommended. Reliable interpretive criteria for ceftibuten are not currently available. Physicians should be informed that clinical response rates with ceftibuten may be lower in strains that are not penicillin-susceptible.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspect of laboratory procedures. Standard ceftibuten powder should provide the following MIC values:

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 µg of ceftibuten to test the susceptibility of microorganisms to ceftibuten.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-µg ceftibuten disk should be interpreted according to the following criteria when testing Haemophilus species using Haemophilus Test Media (HTM):

The current absence of resistant strains precludes defining any categories other than “Susceptible”. Strains yielding results suggestive of a “Nonsusceptible” category should be submitted to a reference laboratory for further testing.

Interpretation should be as stated above for results using dilution techniques.

Ceftibuten is indicated for penicillin-susceptible only strains of Streptococcus pneumoniae. Pneumococcal isolates with oxacillin zone sizes of ≥20 mm are susceptible to penicillin and can be considered susceptible for approved indications. Reliable disk diffusion tests for ceftibuten do not yet exist.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-µg ceftibuten disk should provide the following zone diameters in these laboratory test quality control strains:

Cephalosporin-class disks should not be used to test for susceptibility to ceftibuten.