Clinical Pharmacology

Pharmacokinetics

Adults

Following oral administration, azithromycin is rapidly absorbed and widely distributed throughout the body. Rapid distribution of azithromycin into tissues and high concentration within cells result in significantly higher azithromycin concentrations in tissues than in plasma or serum.

The pharmacokinetic parameters of azithromycin capsules in plasma after a loading dose of 500 mg (2 ¾ 250 mg capsules) on day one followed by 250 mg (1-250 mg capsule) q.d. on days two through five in healthy young adults (age 18-40 years old).

In this study conducted there was no significant difference in the disposition of azithromycin between male and female subjects. Plasma concentrations of azithromycin following single 500 mg oral and i.v. doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. With a regimen of 500 mg on day 1 and 250 mg/day on days 2-5, C min and C max remained essentially unchanged from day 2 through day 5 of therapy. However, without a loading dose, azithromycin C min levels required 5 to 7 days to reach steady-state.

In an open, randomized, two-way crossover study, pharmacokinetic parameters (AUC 0-72, C max, T max) determined from 36 fasted healthy male volunteers who received two 250 mg commercial capsules and two 250 mg tablets.

When azithromycin capsules were administered with food to 11 adult healthy male subjects, the rate of absorption (C max) of azithromycin from the capsule formulation was reduced by 52% and the extent of absorption (AUC) by 43%.

In an open label, randomized, two-way crossover study in 12 healthy subjects to assess the effect of a high fat standard meal on the serum concentrations of azithromycin resulting from the oral administration of two 250 mg film-coated tablets, it was shown that food increased C max by 23% while there was no change in AUC.

When azithromycin suspension was administered with food to 28 adult healthy male subjects, the rate of absorption (C max) was increased by 56% while the extent of absorption (AUC) was unchanged.

The AUC of azithromycin was unaffected by co-administration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules; however, the C max was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.

When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.

The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 ml/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/ml to 7% at 2 mcg/ml.

Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

There are no pharmacokinetic data available from studies in hepatically ¾ or renally ¾ impaired individuals.

The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses adequate to reach therapeutic steady-state plasma levels is not known.

The extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical significance of these tissue concentration data is unknown.

Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/ml) in the presence of non-inflamed meninges.

Pediatric

In two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by 5 mg/kg on days 2 through 5 to two groups of children (aged 1-5 years and 5-15 years, respectively). The mean pharmacokinetic parameters at day 5 were C max=0.216 mcg/ml, T max=1.9 hours, and AUC 0-24=1.822 mcg ´ hr/ml for the 1- to 5-year-old group and were C max=0.383 mcg/ml, T max=2.4 hours, and AUC 0-24=3.109 mcg ´ hr/ml for the 5- to 15- year-old group.

There are no pharmacokinetic data on azithromycin suspension when administered at a dose of 12 mg/kg/day in the presence or absence of food.

MICROBIOLOGY

Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was >30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.