Ketek

KETEK — telithromycin tablet, film coated
Physicians Total Care, Inc.

Ketek is contraindicated in patients with myasthenia gravis. There have been reports of fatal and life-threatening respiratory failure in patients with myasthenia gravis associated with the use of Ketek. (See CONTRAINDICATIONS.)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of KETEK and other antibacterial drugs, KETEK should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

KETEK® tablets contain telithromycin, a semisynthetic antibacterial in the ketolide class for oral administration. Chemically, telithromycin is designated as Erythromycin, 3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]imino]]-.

Telithromycin, a ketolide, differs chemically from the macrolide group of antibacterials by the lack of α-L-cladinose at position 3 of the erythronolide A ring, resulting in a 3-keto function. It is further characterized by a C11-12 carbamate substituted by an imidazolyl and pyridyl ring through a butyl chain. Its empirical formula is C43 H65 N5 O10 and its molecular weight is 812.03. Telithromycin is a white to off-white crystalline powder. The following represents the chemical structure of telithromycin.

Chemical Structure
(click image for full-size original)

KETEK tablets are available as light-orange, oval, film-coated tablets, each containing 400 mg or 300 mg of telithromycin, and the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, red ferric oxide, talc, titanium dioxide, and yellow ferric oxide.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption

Following oral administration, telithromycin reached maximal concentration at about 1 hour (0.5 – 4 hours).

It has an absolute bioavailability of 57% in both young and elderly subjects.

The rate and extent of absorption are unaffected by food intake, thus KETEK tablets can be given without regard to food.

In healthy adult subjects, peak plasma telithromycin concentrations of approximately 2 µg/mL are attained at a median of 1 hour after an 800-mg oral dose.

Steady-state plasma concentrations are reached within 2 to 3 days of once daily dosing with telithromycin 800 mg.

Following oral dosing, the mean terminal elimination half-life of telithromycin is 10 hours.

The pharmacokinetics of telithromycin after administration of single and multiple (7 days) once daily 800-mg doses to healthy adult subjects are shown in Table 1.

Table 1
Mean (SD)
Parameter Single dose (n=18) Multiple dose (n=18)
SD=Standard deviation
Cmax =Maximum plasma concentration
Tmax =Time to Cmax
AUC=Area under concentration vs. time curve
t1/2 =Terminal plasma half-life
C24h =Plasma concentration at 24 hours post-dose
*
Median (min–max) values
Cmax (µg/mL) 1.9 (0.80) 2.27 (0.71)
Tmax (h)* 1.0 (0.5–4.0) 1.0 (0.5–3.0)
AUC(0–24) (µg∙h/mL) 8.25 (2.6) 12.5 (5.4)
Terminal t1/2 (h) 7.16 (1.3) 9.81 (1.9)
C24h (µg/mL) 0.03 (0.013) 0.07 (0.051)

In a patient population, mean peak and trough plasma concentrations were 2.9 µg/mL (±1.55), (n=219) and 0.2 µg/mL (±0.22), (n=204), respectively, after 3 to 5 days of KETEK 800 mg once daily.

Distribution

Total in vitro protein binding is approximately 60% to 70% and is primarily due to human serum albumin.

Protein binding is not modified in elderly subjects and in patients with hepatic impairment.

The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg.

Telithromycin concentrations in bronchial mucosa, epithelial lining fluid, and alveolar macrophages after 800 mg once daily dosing for 5 days in patients are displayed in Table 2.

Table 2
Hourspost-dose Mean concentration (µg/mL) Tissue/Plasma Ratio
Tissue orfluid Plasma
*
Units in mg/kg
Bronchial mucosa 2 3.88* 1.86 2.11
12 1.41* 0.23 6.33
24 0.78* 0.08 12.11
Epithelial lining fluid 2 14.89 1.86 8.57
12 3.27 0.23 13.8
24 0.84 0.08 14.41
Alveolar macrophages 2 65 1.07 55
8 100 0.605 180
24 41 0.073 540

Telithromycin concentration in white blood cells exceeds the concentration in plasma and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 µg/mL at 6 hours, and remained at 14.1 µg/mL 24 hours after 5 days of repeated dosing of 600 mg once daily. After 10 days, repeated dosing of 600 mg once daily, white blood cell concentrations remained at 8.9 µg/mL 48 hours after the last dose.

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