Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin.

Cardiac Electrophysiology
QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co- administration of azithromycin increased the QTc interval in a dose- and concentration- dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

Since the mean Cmax of azithromycin following a 500 mg IV dose given over 1 hr is higher than the mean C max of azithromycin following the administration of a 1500 mg oral dose, it is possible that QTc may be prolonged to a greater extent with IV azithromycin at close proximity to a one hour infusion of 500 mg.

Pharmacokinetic Properties

12.3 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 mcg/mL, while the 24-hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC24 was 9.60 ± 4.80 mcg·hr/mL.


The mean Cmax, 24-hour trough and AUC24 values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03 ±0.86 mcg·hr/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 who received the same 3-hour dosage regimen for 2-5 days.

Infusion                                           Time after starting the infusion (hr) Concentration,       0.5         1           2           3            4           6            8          12         24 Duration
2 mg/mL, 1 hra   2.98        3.63        0.60        0.40         0.33       0.26          0.27±0.15   0.20       0.20
±1.12       ±1.73       ±0.31       ±0.23        ±0.16      ±0.14                     ±0.12      ±0.15 1 mg/mL, 3 hrb   0.91        1.02        1.14        1.13         0.32       0.28          0.27±0.03   0.22       0.18 ±0.13       ±0.11       ±0.13       ±0.16        ±0.05      ±0.04                     ±0.02      ±0.02 a500   mg (2 mg/mL) for 2-5 days in community-acquired pneumonia patients.
b500   mg (1 mg/mL) for 5 days in healthy subjects.

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 mcg/mL, 0.05 mcg/mL, and 2.6 mcg·hr/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 mcg/mL, trough: 0.06 mcg/mL, and AUC24: 5.0 mcg·hr/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval.

Distribution
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.

Tissue concentrations have not been obtained following intravenous infusions of azithromycin, but following oral administration in humans azithromycin has been shown to penetrate into tissues, including skin, lung, tonsil, and cervix.
Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients.
Approximately 17 hr after dosing, azithromycin concentrations were 2.7 mcg/g in ovarian tissue, 3.5 mcg/g in uterine tissue, and 3.3 mcg/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 mcg/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 IV doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hr. 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 hr was about 11% after the 1st dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration.

Specific Populations
Patients with Renal Impairment
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).

Patients with Hepatic Impairment
The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.

Male and Female Patients
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. [see Geriatric Use 8.4 )].

Pediatric Patients
Pharmacokinetic studies with intravenous azithromycin have not been performed in children.

Drug Interaction Studies
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 effects 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 Drug Interactions (7.3)].

Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin
Co-           Dose of Co-administered      Dose of Azithromycin        n           Ratio (with/without administered                Drug                                                       azithromycin) of Co- Drug                                                                                administered Drug Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
Mean Cmax        Mean AUC
Atorvastatin        10 mg/day for 8 days        500 mg/day orally on days 6-8       12          0.83             1.01 (0.63 to 1.08)   (0.81 to 1.25)
Carbamazepine         200 mg/day for 2 days,      500 mg/day orally for days 16-       7          0.97             0.96 then 200 mg twice a day                  18                             (0.88 to 1.06)   (0.88 to 1.06) for 18 days
Cetirizine         20 mg/day for 11 days        500 mg orally on day 7, then       14          1.03             1.02 250 mg/day on days 8-11                 (0.93 to 1.14)   (0.92 to 1.13) Didanosine        200 mg orally twice a day     1,200 mg/day orally on days 8-       6          1.44             1.14 for 21 days                           21                           (0.85 to 2.43)   (0.83 to 1.57) Efavirenz         400 mg/day for 7 days            600 mg orally on day 7          14         1.04*            0.95* Fluconazole       200 mg orally single dose       1,200 mg orally single dose       18          1.04             1.01 (0.98 to 1.11)   (0.97 to 1.05)
Indinavir       800 mg three times a day         1,200 mg orally on day 5         18          0.96             0.90 for 5 days                                                        (0.86 to 1.08)   (0.81 to 1.00) Midazolam          15 mg orally on day 3        500 mg/day orally for 3 days       12          1.27             1.26 (0.89 to 1.81)   (1.01 to 1.56)
Nelfinavir       750 mg three times a day         1,200 mg orally on day 9         14          0.90             0.85 for 11 days                                                        (0.81 to 1.01)   (0.78 to 0.93) 

Sildenafil         100 mg on days 1 and 4            500 mg/day orally for 3 days      12          1.16                0.92 (0.86 to 1.57)      (0.75 to 1.12)
Theophylline        4 mg/kg IV on days 1, 11,          500 mg orally on day 7, 250       10          1.19                1.02 25                          mg/day on days 8-11                  (1.02 to 1.40)      (0.86 to 1.22) Theophylline          300 mg orally BID ×15            500 mg orally on day 6, then      8           1.09                1.08 days                      250 mg/day on days 7-10                 (0.92 to 1.29)      (0.89 to 1.31) Triazolam            0.125 mg on day 2               500 mg orally on day 1, then      12         1.06*               1.02* 250 mg/day on day 2
Trimethoprim/        160 mg/800 mg/day orally             1,200 mg orally on day 7        12          0.85                0.87 Sulfamethoxazol              for 7 days                                                           (0.75 to 0.97)/     (0.80 to 0.95/ e                                                                                               0.90                0.96 (0.78 to 1.03)      (0.88 to 1.03)
Zidovudine       500 mg/day orally for 21            600 mg/day orally for 14 days      5           1.12                0.94 days                                                                (0.42 to 3.02)      (0.52 to 1.70) Zidovudine      500 mg/day orally for 21           1,200 mg/day orally for 14 days     4           1.31                1.30 days                                                                (0.43 to 3.97)      (0.69 to 2.43) * - 90% Confidence interval not reported

Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs [see Drug Interactions (7.3)].
Co-administered              Dose of Co-                Dose of            n      Ratio (with/without co-administered drug) of Drug                  administered Drug          Azithromycin                Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax                Mean AUC

Efavirenz                   400 mg/day for 7 days   600 mg orally on day     14              1.22                       0.92* 7                                    (1.04 to 1.42)
Fluconazole                 200 mg orally single    1,200 mg orally single   18              0.82                       1.07 dose                    dose                                 (0.66 to 1.02)             (0.94 to 1.22) Nelfinavir                  750 mg three times a    1,200 mg orally on       14              2.36                       2.12 day for 11 days         day 9                                (1.77 to 3.15)             (1.80 to 2.50) * - 90% Confidence interval not reported

12.4         Microbiology
Mechanism of Action
Azithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.

Resistance
Azithromycin demonstrates cross-resistance with erythromycin. The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can determine cross resistance to other macrolides, lincosamides and streptogramin B (MLSB phenotype).

Antimicrobial Activity
Azithromycin has been shown to be active against the following microorganisms, both in vitro and in clinical infections.
[see Indications and Usage (1)]

Gram-positive Bacteria
Staphylococcus aureus
Streptococcus pneumoniae
Gram-negative Bacteria
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
Legionella pneumophila


Other Bacteria
Chlamydophila pneumoniae
Chlamydia trachomatis
Mycoplasma hominis
Mycoplasma pneumoniae
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for azithromycin against isolates of similar genus or organism group. However, the efficacy of azithromycin in treating clinical infections caused by these bacteria has not been established in adequate and well controlled clinical trials.

Aerobic Gram Positive Bacteria
Streptococci (Groups C, F, G)
Viridans group streptococci

Gram Negative Bacteria
Bordetella pertussis
Anaerobic Bacteria
Peptostreptococcus species
Prevotella bivia

Other Bacteria
Ureaplasma urealyticum

Susceptibility Testing
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.