Clarithromycin pharmacokinetics and molecular data

Pharmacokinetics
Absorption Peak plasma concentration Excretion HIV infected patients Patients with impaired hepatic/renal function Distribution Administration with Omeprazole Microbiology In vitro activity against Mycobacteria Susceptibility testing

Absorption
Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg Clarithromycin tablets was approximately 50%. For a single 500 mg dose of Clarithromycin, food slightly delays the onset of Clarithromycin absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the Clarithromycin peak plasma concentration by about 24%, but does not affect the extent of Clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH Clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, Clarithromycin tablets may be given without regard to food. Return to top

Peak plasma concentration
In nonfasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma Clarithromycin concentrations were attained within 3 days and were approximately 1 to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3 to 4 mcg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of Clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of Clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH Clarithromycin, attains a peak steady-state concentration of about 0.6 mcg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH Clarithromycin is slightly higher (up to 1 mcg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days. Return to top

Excretion
After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as Clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of Clarithromycin is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hours, approximately 40% is excreted in urine as Clarithromycin. The renal clearance of Clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH Clarithromycin, which accounts for an additional 10% to 15% of the dose with either a 250 mg or a 500 mg tablet administered every 12 hours. Return to top

HIV infected patients
Steady-state concentrations of Clarithromycin and 14-OH Clarithromycin observed following administration of 500 mg doses of Clarithromycin every 12 hours to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500 mg or 1000 mg doses of Clarithromycin every 12 hours, steady-state Clarithromycin Cmax values ranged from 2 to 4 mcg/mL and 5 to 10 mcg/mL, respectively. Return to top

Patients with impaired hepatic/renal function
The steady-state concentrations of Clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH Clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH Clarithromycin was at least partially offset by an increase in renal clearance of Clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects. The pharmacokinetics of Clarithromycin was also altered in subjects with impaired renal function. Return to top

Distribution
Clarithromycin and the 14-OH Clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular concentrations, tissue concentrations are higher than serum concentrations. Examples of tissue and serum concentrations are presented below. Return to top

Administration with Omeprazole
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult males. The plasma levels of Clarithromycin and 14-hydroxy-Clarithromycin were increased by the concomitant administration of omeprazole. For Clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when Clarithromycin was administered with omeprazole than when Clarithromycin was administered alone. Similar results were seen for 14-hydroxy-Clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole. Return to top

Microbiology
Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.

Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms as well as most Mycobacterium avium complex (MAC) microorganisms.

Additionally, the 14-OH Clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH Clarithromycin is twice as active against Haemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than Clarithromycin. The clinical significance of this activity against Mycobacterium avium complex is unknown.

Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections: Aerobic Gram-positive Microorganisms Aerobic Gram-negative Microorganisms Other Microorganisms Mycobacterium avium complex (MAC) consisting of:' NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to Clarithromycin. Omeprazole/Clarithromycin dual therapy; ranitidine bismuth citrate/Clarithromycin dual therapy; omeprazole/Clarithromycin/amoxicillin triple therapy; and lansoprazole/Clarithromycin/amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections. Helicobacter Return to top
 * Staphylococcus aureus
 * Streptococcus pneumoniae
 * Streptococcus pyogenes
 * Haemophilus influenzae
 * Haemophilus parainfluenzae
 * Moraxella catarrhalis
 * Mycoplasma pneumoniae
 * Chlamydia pneumoniae (TWAR)*
 * Mycobacteria
 * Mycobacterium avium
 * Mycobacterium intracellulare
 * Beta-lactamase production should have no effect on Clarithromycin activity.
 * Helicobacter pylori

In vitro activity against Mycobacteria
Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) microorganisms isolated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium species from M. intracellulare, many studies only reported results on M. avium complex (MAC) isolates. Various in vitro methodologies employing broth or solid media at different pH’s, with and without oleic acid-albumin-dextrose-catalase (OADC), have been used to determine Clarithromycin MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth media increases from 5 to 7.4. At pH 7.4, MIC values determined with Mueller-Hinton agar were 4- to 8-fold higher than those observed with Middlebrook 7H12 media. Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values. Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS patients was evaluated using a micro-dilution method with Middlebrook 7H9 broth. Results showed an MIC value of ≤4 mcg/mL in 81% and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of the non-AIDS isolates had an MIC value ≤0.5 mcg/mL. Clarithromycin was also shown to be active against phagocytized M. avium complex (MAC) in mouse and human macrophage cell cultures as well as in the beige mouse infection model. Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms. In one study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 mcg/mL. Clarithromycin inhibited all isolates at >10 mcg/mL. Return to top

Susceptibility testing
For information on susceptibility testing see the FDA label. Return to top