12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Azithromycin is a macrolide antibacterial drug. [see Microbiology (12.4)]
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.
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.
The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18–40 years old) are portrayed in the following chart:
(serum, except as indicated)
| Urinary Excretion|
(% of dose)
|500 mg/250 mg capsule||12||1||0.41||2.5||0.05||2.6*||–||4.5|
|and 250 mg on Days 2–5||12||5||0.24||3.2||0.05||2.1*||–||6.5|
|1200 mg/600 mg tablets||12||1||0.66||2.5||0.074||6.8†||40||–|
|600 mg tablet/day||7||1||0.33||2.0||0.039||2.4*|
|600 mg tablet/day (leukocytes)||7||22||252||10.9||146||4763*||82.8||-|
With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2–5, Cmin and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin Cmin levels required 5 to 7 days to reach steady state.
In asymptomatic HIV-positive adult subjects receiving 600 mg ZITHROMAX tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing.
The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.
The 1 gram single-dose packet is bioequivalent to four 250 mg azithromycin capsule.
When the oral suspension of azithromycin was administered with food, the Cmax increased by 46% and the AUC by 14%.
The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased Cmax by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%).
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.
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 tissues in humans, 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 importance of these tissue concentration data is unknown.
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 hr of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.
Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 µg/mL. Concentration remained above 32 µg/mL, for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte-to-plasma Cmax ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%) respectively. The clinical relevance of these findings is unknown.
Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 µg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 µg/mL (±33%). The mean leukocyte-to-serum Cmax ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown.
In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.
Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hr. 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.
Patients with Renal Impairment
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 × 250 mg capsules), the mean Cmax and AUC0–120 increased by 5.1% and 4.2%, respectively, in subjects with 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 end-stage renal disease (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 on the basis of gender.
Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in younger volunteers (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 (8.5)]
For information regarding the pharmacokinetics of ZITHROMAX (azithromycin for oral suspension) in pediatric patients, see the prescribing information for ZITHROMAX (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles.
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 (7.3)]
|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)
(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)
(0.88 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)
(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)
(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)
(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)
(0.81 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)
(1.01 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)
(0.78 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)
(0.75 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)
(0.86 to 1.22)
|Theophylline||300 mg orally BID ×15 days||500 mg orally on day 6, then 250 mg/day on days 7–10||8||1.09|
(0.92 to 1.29)
(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*|
|160 mg/800 mg/day orally for 7 days||1,200 mg orally on day 7||12||0.85|
(0.75 to 0.97)/
(0.78 to 1.03)
(0.80 to 0.95/
(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)
(0.52 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)
(0.69 to 2.43)
|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)
|Fluconazole||200 mg orally single dose||1,200 mg orally single dose||18||0.82|
(0.66 to 1.02)
(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)
(1.80 to 2.50)
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.
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). The mechanism of acquired mutational resistance in isolates of Mycobacterium avium complex (i.e., 23S rRNA genemutation) is the same for both clarithromycin and azithromycin.
Azithromycin has been shown to be active against the following microorganisms, both in vitro and in clinical infections. [see Indications and Usage (1)]
- Mycobacterium avium complex (MAC) consisting of:
- Mycobacterium avium
- Mycobacterium intracellulare