CLINICAL PHARMACOLOGY
Pharmacokinetics
Following oral administration of a single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC0–72 = 4.3 (1.2) µg∙h/mL; Cmax = 0.5 (0.2) µg/mL; Tmax = 2.2 (0.9) hours.
With a regimen of 500 mg (two 250 mg capsulesAzithromycin 250 mg tablets are bioequivalent to 250 mg capsules in the fasted state.
Azithromycin 250 mg capsules are no longer commercially available.) on day 1, followed by 250 mg daily (one 250 mg capsule) on days 2 through 5, the pharmacokinetic parameters of azithromycin in plasma in healthy young adults (18–40 years of age) are portrayed in the chart below. Cmin and Cmax remained essentially unchanged from day 2 through day 5 of therapy.
| Pharmacokinetic Parameters (Mean) |
Total n=12
Day 1
|
Day 5
|
| Cmax (µg/mL) |
0.41 |
0.24 |
| Tmax (h) |
2.5 |
3.2 |
| AUC0–24 (µg∙h/mL) |
2.6 |
2.1 |
| Cmin (µg/mL) |
0.05 |
0.05 |
| Urinary Excret. (% dose) |
4.5 |
6.5 |
In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1,500 mg of azithromycin administered in single daily doses over either 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2–5) or 3 days (500 mg per day for days 1–3). Due to limited serum samples on day 2 (3-day regimen) and days 2–4 (5-day regimen), the serum concentration-time profile of each subject was fit to a 3-compartment model and the AUC0–
∞ for the fitted concentration profile was comparable between the 5-day and 3-day regimens.
|
3-Day Regimen |
5-Day Regimen |
Pharmacokinetic Parameter
[mean (SD)] |
Day 1 |
Day 3 |
Day 1 |
Day 5 |
| Cmax (serum, µg/mL) |
0.44 (0.22) |
0.54 (0.25) |
0.43 (0.20) |
0.24 (0.06) |
| Serum AUC0–
∞ (µg∙hr/mL) |
17.4 (6.2)
|
14.9 (3.1)
|
| Serum T1/2
|
71.8 hr |
68.9 hr |
Median azithromycin exposure (AUC0–288) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following either the 5-day or 3-day regimen was more than a 1000-fold and 800-fold greater than in serum, respectively. Administration of the same total dose with either the 5-day or 3-day regimen may be expected to provide comparable concentrations of azithromycin within MN and PMN leukocytes.
Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet.
Absorption
The absolute bioavailability of azithromycin 250 mg capsules is 38%.
In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC.
When azithromycin suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and 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 Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.
Distribution
The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL.
Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg. Greater azithromycin concentrations in tissues than in plasma or serum were observed. High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy. The antimicrobial activity of azithromycin is pH related and appears to be reduced with decreasing pH. However, the extensive distribution of drug to tissues may be relevant to clinical activity.
Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in the following table:
AZITHROMYCIN CONCENTRATIONS FOLLOWING A 500 mg DOSE (TWO 250 mg CAPSULES) IN ADULTSAzithromycin tissue concentrations were originally determined using 250 mg capsules.
| TISSUE OR FLUID |
TIME AFTER DOSE (h) |
TISSUE OR FLUID CONCENTRATION
(µg/g or µg/mL) |
CORRESPONDING
PLASMA OR SERUM
LEVEL (µg/mL) |
TISSUE (FLUID)
PLASMA (SERUM)
RATIO |
| SKIN |
72–96 |
0.4 |
0.012 |
35 |
| LUNG |
72–96 |
4.0 |
0.012 |
>100 |
| SPUTUMSample was obtained 2–4 hours after the first dose.
|
2–4 |
1.0 |
0.64 |
2 |
| SPUTUMSample was obtained 10–12 hours after the first dose.
|
10–12 |
2.9 |
0.1 |
30 |
| TONSIL
|
9–18 |
4.5 |
0.03 |
>100 |
| TONSIL
|
180 |
0.9 |
0.006 |
>100 |
| CERVIXSample was obtained 19 hours after a single 500 mg dose.
|
19 |
2.8 |
0.04 |
70 |
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 importance 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 µg/mL) in the presence of non-inflamed meninges.
Metabolism
In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.
Elimination
Plasma concentrations of azithromycin following single 500 mg oral and i.v. doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.
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.
Special Populations
Renal Insufficiency
Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, mean Cmax and AUC0–120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0–120 increased 61% and 35%, respectively in subjects with severe renal impairment (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). (See
DOSAGE AND ADMINISTRATION.)
Hepatic Insufficiency
The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established.
Gender
There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.
Geriatric Patients
When studied in healthy elderly subjects aged 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.
Pediatric Patients
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 pediatric patients (aged 1–5 years and 5–15 years, respectively). The mean pharmacokinetic parameters on day 5 were Cmax=0.216 µg/mL, Tmax=1.9 hours, and AUC0–24=1.822 µg∙hr/mL for the 1- to 5-year-old group and were Cmax=0.383 µg/mL, Tmax=2.4 hours, and AUC0–24=3.109 µg∙hr/mL for the 5- to 15-year-old group.
Two clinical studies were conducted in 68 pediatric patients aged 3–16 years to determine the pharmacokinetics and safety of azithromycin for oral suspension. Azithromycin was administered following a low-fat breakfast.
The first study consisted of 35 pediatric patients treated with 20 mg/kg/day (maximum daily dose 500 mg) for 3 days of whom 34 patients were evaluated for pharmacokinetics.
In the second study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for 5 days of whom 31 patients were evaluated for pharmacokinetics.
In both studies, azithromycin concentrations were determined over a 24 hour period following the last daily dose. Patients weighing above 25.0 kg in the 3-day study or 41.7 kg in the 5-day study received the maximum adult daily dose of 500 mg. Eleven patients (weighing 25.0 kg or less) in the first study and 17 patients (weighing 41.7 kg or less) in the second study received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg.
Pharmacokinetic Parameter
[mean (SD)] |
3-Day Regimen
(20 mg/kg × 3 days) |
5-Day Regimen
(12 mg/kg × 5 days) |
| n |
11 |
17 |
| Cmax (µg/mL) |
1.1 (0.4) |
0.5 (0.4) |
| Tmax (hr) |
2.7 (1.9) |
2.2 (0.8) |
| AUC0–24(µg∙hr/mL) |
7.9 (2.9) |
3.9 (1.9) |
The similarity of the overall exposure (AUC0–∞) between the 3-day and 5-day regimens in pediatric patients is unknown.
Single dose pharmacokinetics in pediatric patients given doses of 30 mg/kg have not been studied. (See
DOSAGE AND ADMINISTRATION.)
Drug-Drug Interactions
Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effect of other drugs on the pharmacokinetics of azithromycin are shown in Table 2.
Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-administered with azithromycin.
Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. (See
PRECAUTIONS - Drug Interactions.)
Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin
| Co-administered Drug |
Dose of Co-administered Drug |
Dose of Azithromycin |
n |
Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
|
|
|
|
Mean Cmax
|
Mean AUC |
| NA - Not Available |
| Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo. |
| Atorvastatin |
10 mg/day × 8 days |
500 mg/day PO on days 6–8 |
12 |
0.83
(0.63 to 1.08) |
1.01
(0.81 to 1.25) |
| Carbamazepine |
200 mg/day × 2 days, then 200 mg BID × 18 days |
500 mg/day PO for days 16–18 |
7 |
0.97
(0.88 to 1.06) |
0.96
(0.88 to 1.06) |
| Cetirizine |
20 mg/day × 11 days |
500 mg PO on day 7, then 250 mg/day on days 8–11 |
14 |
1.03
(0.93 to 1.14) |
1.02
(0.92 to 1.13) |
| Didanosine |
200 mg PO BID × 21 days |
1,200 mg/day PO on days 8–21 |
6 |
1.44
(0.85 to 2.43) |
1.14
(0.83 to 1.57) |
| Efavirenz |
400 mg/day × 7 days |
600 mg PO on day 7 |
14 |
1.04
|
0.95
|
| Fluconazole |
200 mg PO single dose |
1,200 mg PO single dose |
18 |
1.04
(0.98 to 1.11) |
1.01
(0.97 to 1.05) |
| Indinavir |
800 mg TID × 5 days |
1,200 mg PO on day 5 |
18 |
0.96
(0.86 to 1.08) |
0.90
(0.81 to 1.00) |
| Midazolam |
15 mg PO on day 3 |
500 mg/day PO × 3 days |
12 |
1.27
(0.89 to 1.81) |
1.26
(1.01 to 1.56) |
| Nelfinavir |
750 mg TID × 11 days |
1,200 mg PO on day 9 |
14 |
0.90
(0.81 to 1.01) |
0.85
(0.78 to 0.93) |
| Rifabutin |
300 mg/day × 10 days |
500 mg PO on day 1, then 250 mg/day on days 2–10 |
6 |
See footnote below |
NA |
| Sildenafil |
100 mg on days 1 and 4 |
500 mg/day PO × 3 days |
12 |
1.16
(0.86 to 1.57) |
0.92
(0.75 to 1.12) |
| Theophylline |
4 mg/kg IV on days 1, 11, 25 |
500 mg PO on day 7, 250 mg/day on days 8–11 |
10 |
1.19
(1.02 to 1.40) |
1.02
(0.86 to 1.22) |
| Theophylline |
300 mg PO BID ×
15 days |
500 mg PO on day 6, then 250 mg/day on days 7–10 |
8 |
1.09
(0.92 to 1.29) |
1.08
(0.89 to 1.31) |
| Triazolam |
0.125 mg on day 2 |
500 mg PO on day 1, then 250 mg/day on day 2 |
12 |
1.06
|
1.02
|
| Trimethoprim/Sulfamethoxazole |
160 mg/800 mg/day PO × 7 days |
1,200 mg PO on day 7 |
12 |
0.85
(0.75 to 0.97)/
0.90
(0.78 to 1.03) |
0.87
(0.80 to 0.95/
0.96
(0.88 to 1.03) |
| Zidovudine |
500 mg/day PO × 21 days |
600 mg/day PO × 14 days |
5 |
1.12
(0.42 to 3.02) |
0.94
(0.52 to 1.70) |
| Zidovudine |
500 mg/day PO × 21 days |
1,200 mg/day PO × 14 days |
4 |
1.31
(0.43 to 3.97) |
1.30
(0.69 to 2.43) |
Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs (See PRECAUTIONS - Drug Interactions.)
| Co-administered Drug |
Dose of Co-administered Drug |
Dose of Azithromycin |
n |
Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
|
|
|
|
Mean Cmax
|
Mean AUC |
| NA – Not available |
| Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo. |
| Efavirenz |
400 mg/day × 7 days |
600 mg PO on day 7 |
14 |
1.22
(1.04 to 1.42) |
0.92- 90% Confidence interval not reported
|
| Fluconazole |
200 mg PO single dose |
1,200 mg PO single dose |
18 |
0.82
(0.66 to 1.02) |
1.07
(0.94 to 1.22) |
| Nelfinavir |
750 mg TID × 11 days |
1,200 mg PO on day 9 |
14 |
2.36
(1.77 to 3.15) |
2.12
(1.80 to 2.50) |
| Rifabutin |
300 mg/day × 10 days |
500 mg PO on day 1, then 250 mg/day on days 2–10 |
6 |
See footnote below |
NA |
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.
Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the
INDICATIONS AND USAGE
section.
Aerobic and facultative gram-positive microorganisms
Staphylococcus aureus
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.
Aerobic and facultative gram-negative microorganisms
Haemophilus ducreyi
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
"Other" microorganisms
Chlamydia pneumoniae
Chlamydia trachomatis
Mycoplasma pneumoniae
Beta-lactamase production should have no effect on azithromycin activity.
The following in vitro data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for azithromycin. However, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
Aerobic and facultative gram-positive microorganisms
Streptococci (Groups C, F, G)
Viridans group streptococci
Aerobic and facultative gram-negative microorganisms
Bordetella pertussis
Legionella pneumophila
Anaerobic microorganisms
Peptostreptococcus species
Prevotella bivia
"Other" microorganisms
Ureaplasma urealyticum
Susceptibility Testing Methods
When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient use, but could aid the physician in selecting the most effective antimicrobial.
Dilution techniques
Quantitative methods are used to determine antimicrobial minimum 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 method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of azithromycin powder. The MIC values should be interpreted according to criteria provided in Table 3.
Diffusion techniques
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-µg azithromycin to test the susceptibility of microorganisms to azithromycin. The disk diffusion interpretive criteria are provided in Table 3.
Table 3. Susceptibility Interpretive Criteria for Azithromycin
| Susceptibility Test Result Interpretive Criteria |
|
Minimum Inhibitory Concentrations (µg/mL) |
Disk Diffusion
(zone diameters in mm) |
| Pathogen |
|
|
|
|
|
|
|
S |
I |
R
|
S |
I |
R
|
|
Haemophilus spp. |
≤ 4 |
-- |
-- |
≥ 12 |
-- |
-- |
|
Staphylococcus aureus
|
≤ 2 |
4 |
≥ 8 |
≥ 18 |
14–17 |
≤ 13 |
| Streptococci including S. pneumoniae
Susceptibility of streptococci including S. pneumoniae to azithromycin and other macrolides can be predicted by testing erythromycin.
|
≤ 0.5 |
1 |
≥ 2 |
≥ 18 |
14–17 |
≤ 13 |
No interpretive criteria have been established for testing Neisseria gonorrhoeae. This species is not usually tested.
A report of "susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of "intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.
Quality Control
Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard azithromycin powder should provide the following range of values noted in Table 4. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant.
Table 4. Acceptable Quality Control Ranges for Azithromycin
| QC Strain |
Minimum Inhibitory Concentrations (µg/mL) |
Disk Diffusion
(zone diameters in mm) |
Haemophilus influenzae
ATCC 49247 |
1.0–4.0 |
13–21 |
Staphylococcus aureus
ATCC 29213 |
0.5–2.0 |
|
Staphylococcus aureus
ATCC 25923 |
| 21–26 |
Streptococcus pneumoniae
ATCC 49619 |
0.06–0.25 |
19–25 |
ANIMAL TOXICOLOGY
Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs treated with azithromycin at doses which, expressed on the basis of mg/m2, are approximately equal to the recommended adult human dose, and in rats treated at doses approximately one-sixth of the recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs given daily doses of azithromycin ranging from 10 days to 30 days. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (30 mg/kg dose) at observed Cmax value of 1.3 µg/mL (six times greater than the observed Cmax of 0.216 µg/mL at the pediatric dose of 10 mg/kg). Similarly, it has been shown in the dog (10 mg/kg dose) at observed Cmax value of 1.5 µg/mL (seven times greater than the observed same Cmax and drug dose in the studied pediatric population). On a mg/m2 basis, 30 mg/kg dose in the neonatal rat (135 mg/m2) and 10 mg/kg dose in the neonatal dog (79 mg/m2) are approximately 0.5 and 0.3 times, respectively, the recommended dose in the pediatric patients with an average body weight of 25 kg. Phospholipidosis, similar to that seen in the adult animals, is reversible after cessation of azithromycin treatment. The significance of these findings for animals and for humans is unknown.
REFERENCES
- National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2 (ISBN 1-56238-394-9). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2000.
- National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1 (ISBN 1-56238-393-0). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2000.
- National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing – Eleventh Informational Supplement. NCCLS Document M100-S11, Vol. 21, No. 1 (ISBN 1-56238-426-0). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2001.
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