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azithromycin for Injection, USP - ADD-VANTAGE Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Azithromycin is a macrolide antibacterial drug [see Microbiology (12.4)].

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 hour is higher than the mean Cmax 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.

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∙h/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∙ 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 who received the same 3-hour dosage regimen for 2-5 days.

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.

Infusion Concentration, Duration

Time after starting the infusion (hr)

  
0.5

1

2

3

4

6

8

12

  
24

2 mg/mL, 1 hra

2.98 ±1.12

3.63 ±1.73

0.60 ±0.31

0.40 ±0.23

0.33 ±0.16

0.26 ±0.14

0.27 ±0.15

0.20 ±0.12

0.20 ±0.15

1 mg/mL, 3 hrb

0.91 ±0.13

1.02 ±0.11

1.14 ±0.13

1.13 ±0.16

0.32 ±0.05

0.28 ±0.04

0.27 ±0.03

0.22 ±0.02

0.18 ±0.02

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∙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 mcg/mL, trough: 0.06 mcg/mL, and AUC24: 5.0 mcg∙h/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 hours 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 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 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 (8.5)].

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
*
- 90% Confidence interval not reported

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 for 8 days

500 mg/day orally on days 6-8

12

0.83

(0.63 to 1.08)

1.01

(0.81 to 1.25)

Carbamazepine

200 mg/day for 2 days, then 200 mg twice a day for 18 days

500 mg/day orally for days 16-18

7

0.97

(0.88 to 1.06)

0.96

(0.88 to 1.06)

Cetirizine

20 mg/day for 11 days

500 mg orally 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 orally twice a day for 21 days

1,200 mg/day orally

on days 8-21

6

1.44

(0.85 to 2.43)

1.14

(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

(0.98 to 1.11)

1.01

(0.97 to 1.05)

Indinavir

800 mg three times a day for 5 days

1,200 mg orally on day 5

18

0.96

(0.86 to 1.08)

0.90

(0.81 to 1.00)

Midazolam

15 mg orally on day 3

500 mg/day orally for 3 days

12

1.27

(0.89 to 1.81)

1.26

(1.01 to 1.56)

Nelfinavir

750 mg three times a day for 11 days

1,200 mg orally on day 9

14

0.90

(0.81 to 1.01)

0.85

(0.78 to 0.93)

Sildenafil

100 mg on days 1 and 4

500 mg/day orally for 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 orally 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 orally twice a day for 15 days

500 mg orally 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 orally on day 1,

then 250 mg/day on day 2

12

1.06*

1.02*

Trimethoprim/

Sulfamethoxazole

160 mg/800 mg/day orally for 7 days

1,200 mg orally 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 orally for 21 days

600 mg/day orally for 14 days

5

1.12

(0.42 to 3.02)

0.94

(0.52 to 1.70)

Zidovudine

500 mg/day orally for 21 days

1,200 mg/day orally for 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 Drug Interactions (7.3)].
*
- 90% Confidence interval not reported

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 for 7 days

600 mg orally on day 7

14

1.22

(1.04 to 1.42)

0.92*

Fluconazole

200 mg orally single dose

1,200 mg orally single dose

18

0.82

(0.66 to 1.02)

1.07

(0.94 to 1.22)

Nelfinavir

750 mg three times a day for 11 days

1,200 mg orally on day 9

14

2.36

(1.77 to 3.15)

2.12

(1.80 to 2.50)

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                                                     Other Bacteria

Staphylococcus aureus                                                        Chlamydophila pneumoniae
Streptococcus pneumoniae                                                  Chlamydia trachomatis
                                                                                             Mycoplasma hominis
Gram-negative Bacteria                                                    Mycoplasma pneumoniae

Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
Legionella pneumophila

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
Anaerobic Bacteria
Peptostreptococcus species
Prevotella bivia
Other Bacteria
Ureaplasma urealyticum
Gram-Negative Bacteria
Bordetella pertussis

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.

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