Azithromycin (Page 4 of 6)

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 ± 1.6 mcg/mL, while the 24-hour trough level was 0.2 ± 0.15 mcg/mL, and the AUC24 was 9.6 ± 4.8 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 to 5 days.

*
500 mg (2 mg/mL) for 2 to 5 days in community-acquired pneumonia patients.
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 hr * 2.98±1.12 3.63 ±1.73 0.6 ±0.31 0.4 ±0.23 0.33 ±0.16 0.26±0.14 0.27±0.15 0.2 ±0.12 0.2 ±0.15
1 mg/mL, 3 hr 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·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 to 85 years old) were similar to those in younger volunteers (18 to 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 Interactions Studies
Drug interaction studies were performed with oral azithromycin and other drugs likely to be coadministered. The effects of coadministration 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.
Coadministration 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 coadministered with azithromycin. Coadministration 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 Coadministered Drugs in the Presence of Azithromycin
*
– 90% Confidence interval not reported
Coadministered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean C max Mean AUC
Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6 to 8 12 0.83(0.63 to 1.08) 1.01(0.81 to 1.25)
Carbamazepine 200 mg/day for 2 days, then200 mg twice a day for 18days 500 mg/day orally for days 16 to 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 250mg/day on days 8 to 11 14 1.03(0.93 to 1.14) 1.02(0.92 to 1.13)
Didanosine 200 mg orally twice a day for21 days 1,200 mg/day orally on days 8 to 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 for5 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 for11 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 to 11 10 1.19(1.02 to 1.40) 1.02(0.86 to 1.22)
Theophylline 300 mg orally BID x15 days 500 mg orally on day 6, then 250mg/day on days 7 to 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/ 160 mg/800 mg/day orallyfor 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)
Sulfamethoxazole
Zidovudine 500 mg/day orally for 21days 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 21days 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 Coadministered Drugs [see Drug Interactions (7.3)].
*
-90% Confidence interval not reported
Coadministered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without coadministered 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)

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.