CLINICAL PHARMACOLOGY
Pharmacokinetics
In patients hospitalized with community-acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean Cmax± S.D. achieved was 3.63 ± 1.60 µg/mL, while the 24-hour trough level was 0.20 ± 0.15 µg/mL, and the AUC24 was 9.60 ± 4.80 µg·h/mL.
The mean Cmax, 24-hour trough and AUC24 values were 1.14 ± 0.14 µg/mL, 0.18 ± 0.02 µg/mL, and 8.03 ±0.86 µg· h/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia that received the same 3-hour dosage regimen for 2-5 days.
Plasma concentrations (µg/mL ± S.D.) after the last daily intravenous infusion of 500 mg azithromycin
|
Infusion Concentration,
Duration
|
Time after starting the infusion (hr)
|
|
|
0.5
|
1
|
2
|
3
|
4
|
6
|
8
|
12
|
24
|
|
2 mg/mL, 1 hr a |
2.98
|
3.63
|
0.60
|
0.40
|
0.33
|
0.26
|
0.27
|
0.20
|
0.20
|
|
±1.12
|
±1.73
|
±0.31
|
±0.23
|
±0.16
|
±0.14
|
±0.15
|
±0.12
|
±0.15
|
|
1 mg/mL, 3 hr b |
0.91
|
1.02
|
1.14
|
1.13
|
0.32
|
0.28
|
0.27
|
0.22
|
0.18
|
|
±0.13
|
±0.11
|
±0.13
|
±0.16
|
±0.05
|
±0.04
|
±0.03
|
±0.02
|
±0.02
|
|
a = 500 mg (2 mg/mL) for 2-5 days in Community-acquired pneumonia patients.
b = 500 mg (1 mg/mL) for 5 days in healthy subjects.
|
|
The average CLt and Vd values were 10.18 mL/min/kg and 33.3 L/kg, respectively, in 18 normal volunteers receiving 1000 to 4000-mg doses given as 1 mg/mL over 2 hours.
Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin showed only an 8% increase in Cmax but a 61% increase in AUC24 reflecting a threefold rise in C24 trough levels.
Following single oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, Cmax, trough level, and AUC24 were reported to be 0.41 µg/mL, 0.05 µg/mL, and 2.6 µg·h/mL, respectively. These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500-mg I.V. 3-hour infusion (Cmax: 1.08 µg/mL, trough: 0.06 µg/mL, and AUC24: 5.0 µg·h/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval. The pharmacokinetic parameters on day 5 of azithromycin 250-mg capsules following a 500-mg oral loading dose to healthy young adults (age 18-40 years old) were as follows: Cmax: 0.24 µg/mL, AUC24: 2.1 µg·h/mL. Azithromycin 250 mg capsules are no longer commercially available. Azithromycin 250 mg tablets are bioequivalent to 250 mg capsules in the fasting state.
Median azithromycin exposure (AUC0-288) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following 1,500 mg of oral 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) to 12 healthy volunteers, was more than a 1000-fold and 800-fold greater than in serum, respectively.
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.
Tissue concentrations have not been obtained following intravenous infusions of azithromycin. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios following oral administration of azithromycin are shown in the following table:
AZITHROMYCIN CONCENTRATIONS FOLLOWING
A 500 mg DOSE (TWO 250 mg CAPSULES) IN ADULTS
|
TISSUE OR FLUID
|
TIME AFTER DOSE
(h)
|
TISSUE OR FLUID
CONCENTRATION
(µg/g or µg/mL) 1 |
CORRESPONDING
PLASMA OR SERUM
LEVEL (µg/mL) |
TISSUE (FLUID)
PLASMA (SERUM)
RATIO 1 |
|
SKIN
|
72-96
|
0.4
|
0.012
|
35
|
|
LUNG
|
72-96
|
4.0
|
0.012
|
>100
|
|
SPUTUM *
|
2-4
|
1.0
|
0.64
|
2
|
|
SPUTUM **
|
10-12
|
2.9
|
0.1
|
30
|
|
TONSIL ***
|
9-18
|
4.5
|
0.03
|
>100
|
|
TONSIL ***
|
180
|
0.9
|
0.006
|
>100
|
|
CERVIX ****
|
19
|
2.8
|
0.04
|
70
|
| 1 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.
* Sample was obtained 2-4 hours after the first dose.
** Sample was obtained 10-12 hours after the first dose.
*** Dosing regimen of 2 doses of 250 mg each, separated by 12 hours.
**** Sample was obtained 19 hours after a single 500 mg dose.
|
|
Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients. Approximately 17 hours after dosing, azithromycin concentrations were 2.7 µg/g in ovarian tissue, 3.5 µg/g in uterine tissue, and 3.3 µg/g in salpinx. Following a regimen of 500 mg on the first day followed by 250 mg daily for 4 days, concentrations in the cerebrospinal fluid were 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.
In a multiple-dose study in 12 normal volunteers utilizing a 500-mg (1 mg/mL) one-hour intravenous-dosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hours was about 11% after the 1st dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration.
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
Pharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration in older volunteers (65-85 years old) were similar to those in younger volunteers (18-40 years old) for the 5-day therapeutic regimen.
Pediatric Patients
Pharmacokinetic studies with intravenous azithromycin have not been performed in children.
Drug-Drug Interactions
Drug interaction studies were performed with oral 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
|
|
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) |
NA - Not Available
* - 90% Confidence interval not reported
|
|
Mean rifabutin concentrations one-half day after the last dose rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo.
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
|
|
Efavirenz
|
400 mg/day × 7 days
|
600 mg PO on day 7
|
14
|
1.22
(1.04 to 1.42) |
0.92 * |
|
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 |
NA - Not available
* - 90% Confidence interval not reported
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.
|
|
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 of the package insert for ZITHROMAX (azithromycin for injection).
Aerobic and facultative gram-positive microorganisms Staphylococcus aureus Streptococcus pneumoniae
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 influenzae Moraxella catarrhalis Neisseria gonorrhoeae "Other" microorganisms Chlamydia pneumoniae Chlamydia trachomatis Legionella pneumophila Mycoplasma hominis Mycoplasma pneumoniae
Beta-lactamase production should have no effect on azithromycin activity.
Azithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for ZITHROMAX (azithromycin tablets) and ZITHROMAX (azithromycin for oral suspension).
Aerobic and facultative gram-positive microorganisms Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes 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 clinical trials. Aerobic and facultative gram-positive microorganisms
Streptococci (Groups C, F, G)
Viridans group streptococci
Aerobic and facultative gram-negative microorganisms Bordetella pertussis Anaerobic microorganisms Peptostreptococcus species
Prevotella bivia "Other" microorganisms Ureaplasma urealyticum
Beta-lactamase production should have no effect on azithromycin activity.
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 1.
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 1.
Table 1. Susceptibility Interpretive Criteria for Azithromycin Susceptibility Test Result Interpretive Criteria
| Pathogen |
Minimum Inhibitory Concentrations (µg/mL)
|
Disk Diffusion
(zone diameters in mm) |
S </= 4
</= 2
</= 0.5
|
I
--
4
1
|
R a --
>/= 8
>/= 2
|
S >/= 12
>/= 18
>/= 18
|
I --
14-17
14-17
|
R a --
</= 13
</= 13
|
Haemophilus spp.
Staphylococcus aureus
Streptococci including
S. pneumoniae b |
a The current absence of data on resistant strains precludes defining any category other than "susceptible". If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
b Susceptibility of streptococci including S. pneumoniae to azithromycin and other macrolides can be predicted by testing erythromycin.
|
|
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 2. 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 2. 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
|
|
|
