Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

10.2    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.

Pharmacokinetic Properties

10.3     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) mcg·hr/mL; Cmax=0.5 (0.2) mcg/mL; Tmax=2.2 (0.9) hours. Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet.

In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1500 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             Day 1                Day 3                Day 1                       Day 5 (SD)]
Cmax (serum, mcg/mL)               0.44 (0.22)              0.54 (0.25)       0.43 (0.20)                 0.24 (0.06) Serum AUC0-∞ (mcg·hr/mL)                            17.4 (6.2)*                                14.9 (3.1)* Serum T1/2                                   71.8 hr                                    68.9 hr *Total AUC for the entire 3-day and 5-day regimens.

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 oral suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and AUC was unchanged.

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.

The antibacterial 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.

Azithromycin has been shown to penetrate into human tissues, including skin, lung, tonsil, and cervix. 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, very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of noninflamed 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 resulting in 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.
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.

Specific Populations
Patients with Renal Impermeant
Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 x 250 mg capsules), 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 parameters in older volunteers (65 to 85 years old) were similar to those in young adults (18 to 40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen. [see Geriatric Use (7.4)] 
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 in 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 mcg/mL, Tmax=1.9 hr, and AUC0-24=1.822 mcg·hr/mL for the 1 to 5-year-old group and were Cmax=0.383 mcg/mL, Tmax=2.4 hr, and AUC0-24=3.109 mcg·hr/mL for the 5 to 15-year-old group.

In another 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 azithromycin pharmacokinetics following a low fat breakfast. In this study, 
azithromycin concentrations were determined over a 24 hr period following the last daily dose. Patients weighing above 41.7 kg received the maximum adult daily dose of 500 mg. Seventeen patients (weighing 41.7 kg or less) 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                          5-Day Regimen
[mean (SD)]                               (12 mg/kg for 5 days)
N                                             17
Cmax (mcg/mL)                                    0.5 (0.4)
Tmax (hr)                                      2.2 (0.8)
AUC0-24(mcg⋅hr/mL)                                 3.9 (1.9)

Single dose pharmacokinetics of azithromycin in pediatric patients given doses of 30 mg/kg have not been studied. [see Dosage and Administration (2)]

Drug Interaction Studies
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 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 (6.3)] 
Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin 
Ratio (with/without azithromycin) of Co- administered Drug Pharmacokinetic
Co-administered        Dose of Co-administered
Dose of Azithromycin           n      Parameters (90% CI); No Effect = 1.00 Drug                       Drug
Mean Cmax              Mean AUC
500 mg/day orally on days                    0.83                   1.01 Atorvastatin          10 mg/day for 8 days                                          12 6-8                           (0.63 to 1.08)         (0.81 to 1.25)
200 mg/day for 2 days, then
0.97                   0.96
Carbamazepine         200 mg twice a day for 18    500 mg/day orally for days 16-18   7 (0.88 to 1.06)         (0.88 to 1.06) days
500 mg orally on day 7, then 250                1.03                   1.02 Cetirizine           20 mg/day for 11 days                                         14 mg/day on days 8-11                   (0.93 to 1.14)         (0.92 to 1.13) 200 mg orally twice a day      1200 mg/day orally on days                    1.44                   1.14 Didanosine                                                                          6 for 21 days                         8-21                          (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* 1.04                   1.01
Fluconazole         200 mg orally single dose       1200 mg orally single dose      18 (0.98 to 1.11)         (0.97 to 1.05)
800 mg three times a day                                                    0.96                   0.90 Indinavir                                           1200 mg orally on day 5        18 for 5 days                                                       (0.86 to 1.08)         (0.81 to 1.00) 1.27                   1.26
Midazolam             15 mg orally on day 3        500 mg/day orally for 3 days     12 (0.89 to 1.81)         (1.01 to 1.56)
750 mg three times a day                                                    0.90                   0.85 Nelfinavir                                          1,200 mg orally on day 9       14 for 11 days                                                      (0.81 to 1.01)         (0.78 to 0.93) 1.16                   0.92
Sildenafil          100 mg on days 1 and 4        500 mg/day orally for 3 days     12 (0.86 to 1.57)         (0.75 to 1.12)
4 mg/kg IV on days 1, 11,      500 mg orally on day 7, 250                   1.19                   1.02 Theophylline                                                                         10 25                     mg/day on days 8-11                   (1.02 to 1.40)         (0.86 to 1.22) 300 mg orally twice a day    500 mg orally on day 6, then 250                1.09                   1.08 Theophylline                                                                         8 for 15 days                 mg/day on days 7-10                   (0.92 to 1.29)         (0.89 to 1.31) 500 mg orally on day 1, then 250
Triazolam              0.125 mg on day 2                                           12          1.06*                  1.02* mg/day on day 2
Trimethoprim/         160 mg/800 mg/day orally                                                      0.85                  0.87 1200 mg orally on day 7        12
Sulfamethoxazole              for 7 days                                                     (0.75 to 0.97)/0.90    (0.80 to 0.95/0.96 
Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin 
Ratio (with/without azithromycin) of Co- administered Drug Pharmacokinetic
Co-administered          Dose of Co-administered
Dose of Azithromycin              n    Parameters (90% CI); No Effect = 1.00 Drug                         Drug
Mean Cmax             Mean AUC
(0.78 to 1.03)         (0.88 to 1.03)
500 mg/day orally for 21                                                     1.12                   0.94 Zidovudine                                       600 mg/day orally for 14 days        5 days                                                           (0.42 to 3.02)         (0.52 to 1.70) 500 mg/day orally for 21                                                     1.31                   1.30 Zidovudine                                      1200 mg/day orally for 14 days        4 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 (6)]
Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic
Co-administered    Dose of Co-administered
Dose of Azithromycin            n        Parameters (90% CI); No Effect = 1.00 Drug                    Drug
Mean Cmax             Mean AUC
1.22
Efavirenz            400 mg/day for 7 days       600 mg orally on day 7          14                                    0.92* (1.04 to 1.42)
0.82                   1.07
Fluconazole           200 mg orally single dose   1,200 mg orally single dose       18 (0.66 to 1.02)         (0.94 to 1.22)
750 mg three times a day                                                     2.36                   2.12 Nelfinavir                                       1,200 mg orally on day 9        14 for 11 days                                                       (1.77 to 3.15)         (1.80 to 2.50) * - 90% Confidence interval not reported


10.4       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 most isolates of the following microorganisms, both in vitro and in clinical infections.

Gram-Positive Bacteria
Staphylococcus aureus
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes

Gram-Negative Bacteria
Haemophilus ducreyi
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
Other Bacteria
Chlamydophila pneumoniae
Chlamydia trachomatis
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.

Gram-Positive Bacteria
Beta-hemolytic streptococci (Groups C, F, G)
Viridans group streptococci

Gram-Negative Bacteria
Bordetella pertussis
Legionella pneumophila
Anaerobic Bacteria
Prevotella bivia
Peptostreptococcus species

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.