Single‐ and Multiple‐dose Pharmacokinetics of Clarithromycin, a New Macrolide Antimicrobial

The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarithromycin. To determine if an interaction exists when these two drugs are coadministered, the pharmacokinetics of amprenavir and clarithromycin were investigated in healthy adult male volunteers. This was a Phase I, open-label, randomized, balanced, multiple-dose, three-period crossover study. Fourteen subjects received the following three regimens: amprenavir, 1,200 mg twice daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 days (seven doses of each drug). Twelve subjects completed all treatments and the follow-up period. The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit. Coadministration of clarithromycin and amprenavir significantly increased the mean amprenavir AUC ss , C max,ss , and C min,ss by 18, 15, and 39%, respectively. Amprenavir had no significant effect on the AUC ss of clarithromycin, but the median T max,ss for clarithromycin increased by 2.0 h, renal clearance increased by 34%, and the AUC ss for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with amprenavir. Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered. The baseline ERMBT value did not correlate with clearance of amprenavir or clarithromycin. A pharmacokinetic interaction occurs when amprenavir and clarithromycin are coadministered, but the effects are not likely to be clinically important, and coadministration does not require a dosage adjustment for either drug.

Section: Discussionsupporting

confidence: 91%

Pharmacokinetic Interaction between Amprenavir and Clarithromycin in Healthy Male Volunteers

Brophy¹,

Israel

Pastor

et al. 2000

“…Probably, fast and high-level intracellular uptake of clarithromycin into lysosomes, likely assisted by a phenomenon called "ion-trapping," is one explanation for the unexpectedly low concentrations of clarithromycin in the interstitium (5,9). The elimination half-life of clarithromycin in tissues and plasma was about 2 h in our study collective after a single dose of 250 mg. As observed previously in other studies (7,22), a nonlinear plasma and tissue pharmacokinetic profile of clarithromycin was detected following administration of the higher dose of 500 mg twice a day in a 12-h interval ( Table 2). The nonlinear increase in AUC values and prolongation of half-life is most likely attributable to the inhibition of the activity of cytochrome P 450 3A4 caused by clarithromycin itself after repetitive dosing (25).…”

Section: Discussionsupporting

confidence: 83%

“…Data of four previous publications about the plasma concentrations of the 14-hydroxy metabolite in humans are largely in agreement, with an overall ratio of the AUC metabolite to the AUC parent compound of 34.9 Ϯ 2.1% (4,7,8,18). Interstitial concentrations of the more hydrophilic 14-hydroxy metabolite are unknown at present.…”

Section: Discussionsupporting

confidence: 74%

Pharmacokinetics of Single- and Multiple-Dose Oral Clarithromycin in Soft Tissues Determined by Microdialysis

Traunmüller

Zeitlinger

Zeleny

et al. 2007

Clarithromycin, a 14-membered ring macrolide, is antimicrobially active against a broad range of gram-positive and certain gram-negative pathogens frequently isolated from softtissue infections and bite wounds (11). Clarithromycin is considered a therapeutic alternative in special cases of minor softtissue infections and penicillin allergy or in cases of nontuberculous mycobacterial skin infections (19,20). High tissue concentrations of the class of the macrolides have been reported previously in the literature (10,13,21). Indeed, intracellular accumulation of macrolides in isolated peripheral blood phagocytes, alveolar macrophages, and tissue culture cells of human origin has been demonstrated previously (9, 16). To date, investigations of in vivo tissue pharmacokinetics (PK) of clarithromycin have been confined to concentrations derived from homogenized biopsy samples of the upper and lower respiratory tract and epithelial lining fluid collection obtained by bronchoalveolar lavage (10, 13, 21). The results derived from homogenized biopsy samples, as frequently used in previous studies, represent an average concentration of all tissue components extracted, including blood cells, intracellular fluid, interstitial fluid, and structural tissue components, and may therefore cause confusion with regard to the actual concentration of an antimicrobial agent in a defined compartment. These data, thus, provide only limited insight into the time course of concentration at the relevant site of most bacterial infections, namely, the extracellular-space fluid. Hence, we used the microdialysis technique, which is capable of the continuous assessment of unbound, i.e., microbiologically active concentrations of clarithromycin in the interstitial-space fluid of soft tissues (15).Knowledge about the concentration-time profiles of free clarithromycin in the interstitial-space fluid of soft tissues can be considered a prerequisite for dosage recommendations in the treatment of extracellularly proliferating bacteria causing soft-tissue infections. Hence, the aim of the present study was to determine free interstitial concentrations of clarithromycin in subcutaneous adipose tissue and skeletal muscle after oral single-and multiple-dose administration to healthy male volunteers. MATERIALS AND METHODSThe study took place at the Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. The study protocol was approved by the local Ethics Committee, and the study was performed in accordance with the Declaration of Helsinki 1964 (including current revisions), the Austrian Drug Law, and the Good Clinical Practice Guidelines.Healthy volunteers. Seven healthy male volunteers between the ages of 25 and 37 years were enrolled into the study. Written informed consent was obtained from each volunteer prior to any study-related investigation or intervention. Each volunteer underwent a screening examination consisting of the following: medical history, physical examination, routine laboratory tests, heart rate, blood pres...

“…in the present study are higher than those reported for adults taking 250-mg doses, 4.6 versus 1.1 ,ug/ml for clarithromycin and 1.64 versus 0.6 ,ug/ml for the metabolite, respectively. The 28 and 57% increases in mean Cmx and AUC after multiple dosing compared with the values after a single dose were comparable to the data for adults (3), indicating that there is no unusual accumulation in children. These pharmacokinetic data provide the basis for consideration of the use of the clarithromycin suspension for management of infectious conditions caused by susceptible bacteria in infants and children.…”

Section: Materiails and Methodssupporting

confidence: 73%

Pharmacokinetics of a clarithromycin suspension in infants and children

Gan

Chu

Kusmiesz

et al. 1992

The single-and multiple-dose pharmacokinetics of clarithromycin and its 14-(R)-hydroxylated metabolite in infants and children were studied after oral administration under fasting and nonfasting conditions. Drug absorption appeared to be rapid following a brief delay in its onset; the mean peak concentrations in plasma (C..,1) for clarithromycin were reached within about 3 h under both conditions. The mean Cm. for Clarithromycin (6-o-methylerythromycin) is a new macrolide antibiotic which differs from erythromycin only by methyl substitution at the 6-hydroxy position of the 14-membered macrolide ring. The difference in structure results in improved gastric acid stability, increased gastrointestinal tolerance (7), and increased spectrum of antibacterial activity against a variety of aerobic and anaerobic gram-positive and gram-negative organisms compared with erythromycin (1, 5). After an oral dose, a substantial fraction of the absorbed dose of clarithromycin undergoes first-pass metabolism through the liver to form the active 14-(R)-hydroxylated metabolite. This 14-hydroxylated metabolite has been reported to be more active than clarithromycin against multiple strains of Haemophilus influenzae (4), which is important in the consideration of using this drug in children.Pharmacokinetic studies performed with adult volunteers with the tablet formulation have shown that clarithromycin has a more favorable pharmacokinetic profile than erythromycin. Clarithromycin was rapidly absorbed, reaching peak concentrations in plasma approximately 2 h after dosing. Its concentration-time profiles in plasma were adequately described by using the one-compartment model, but the underlying disposition kinetics were nonlinear and the half-life appeared to be dose dependent (6).Because clarithromycin has potential usefulness for treatment of a variety of infectious conditions, the pharmacokinetics of clarithromycin and its metabolite in infants and children who were given the oral suspension formulation were investigated. MATERIAILS AND METHODSPatients. The study was conducted in the outpatient clinic of Children's Medical Center, Dallas, Tex. Infants and children aged 6 months to 10 years, with pharyngitis, otitis media, or skin infections and for whom an orally administered antibiotic had been prescribed were considered eligible for the study. The parents or guardians of each patient were * Corresponding author.informed of the nature of the study, and written consent was obtained prior to enrollment in the study. The exclusion criteria were a history of hypersensitivity to macrolide antibiotics, renal or hepatic impairment, and concomitant administration of other medications such as antibiotics, theophylline, carbamazepine, or digitalis.Children were assigned to receive the clarithromycin suspension according to one of the following treatment regimens. Groups 1 and 2 received the clarithromycin suspension at 7.5 mg/kg of body weight once, group 1 under fasting conditions and group 2 under nonfasting states. The fasting condition...