Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses

Abstract

The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean ± standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67: 0.48 to 3.72 t 1.26 mgtliter. h per 100-mg dose over the 100-to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.81% of the administered dose, respectivety. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of darithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.The new 14-membered macrolide antimicrobial agent clarithromycin (A-56268, TE-031) is active in vitro against several important gram-positive and gram-negative pathogens, such as Streptococcus pyogenes, Staphylococcus aureus, Haemophilus species, Legionella species, Mycobacterium avium complex, and Chlamydia species (2, 4, 6, 8-10, 16, 19). Clarithromycin is active intracellularly, and its action is static or bactericidal, depending on the organism and antimicrobial agent concentration (2). Clarithromycin is more acid stable than erythromycin and in animal models achieves higher concentrations in plasma and tissue than erythromycin, especially in the lung (12, 13,15). The Food and Drug Administration-approved dosage regimen for clarithromycin ranges from 250 to 500 mg twice daily (respiratory tract and skin or skin structure infections).The present study was designed to assess the pharmacokinetics and safety of oral clarithromycin in a single-ascending-dose study in healthy young adult male volunteers.( graphy, and audiometry criteria. No subjects were receiving chronic medication.The study was approved by the Institutional Review Board of Quincy Research Center, Kansas City, Mo., and all subjects provided written, informed...

Prediction of the in Vivo Interaction Between Midazolam and Macrolides Based on in Vitro Studies Using Human Liver Microsomes

“…The K m value for 4-hydroxylation of midazolam was about 3.5-fold higher than that for the ␣-hydroxylation pathway, 24,500 (ml) ‫ء‬ ‫ء‬ Calculated using eqs. 12 to 16 to fit the reported erythromycin (Birkett et al, 1990), clarithromycin (Chu et al, 1992), or azithromycin blood concentration (Foulds et al, 1990). A, Olkkola et al, 1993;B, Zimmermann et al, 1996;C, Yeates et al, 1996;D, Gorski et al, 1998;H, Benet et al, 1996;I, Birkett et al, 1990;J, Yago et al, 1996;K, Chu et al, 1992;L, Foulds et al, 1990. 948 ITO ET AL.…”

“…Concentration profiles of midazolam and macrolides simulated by the kinetic parameters in Tables 1 and 2 were compared with the reported profiles (Birkett et al, 1990;Foulds et al, 1990;Chu et al, 1992;Olkkola et al, 1993). Figure 3 shows the concentration profiles of midazolam in blood after a single intravenous or oral administration and those of macrolides after a single oral administration.…”

“…C, erythromycin concentration profile in blood after single oral administration of erythromycin (250 mg) (Birkett et al, 1990). D, clarithromycin concentration profile in blood after single oral administration of clarithromycin (200 mg) (Chu et al, 1992). E, azithromycin concentration profile in blood after single oral administration of azithromycin (500 mg) (Foulds et al, 1990).…”

Pharmacokinetics of clarithromycin after single intravenous and intracrop bolus administrations to broiler chickens

“…However, the lack of pharmacokinetic studies precludes the rational use of this antimicrobial agent in targeted animal species. Pharmacokinetics of clarithromycin has been studied in human being (Ferrero et al 1990), (Chu et al 1992a) (Traunmuller et al 2007), desert tortoise (Wimsatt et al 1999); foals (Jacks et al 2002), beagle dogs (Zhang et al 2008) and cats (Katayama et al 2012). The present study was designed to characterize pharmacokinetic profile of clarithromycin in a not-yet-studied animal species that is broiler chickens after single intravenous (i.v.)…”

High rate of erythromycin and clarithromycin resistance among Streptococcus pneumoniae isolates from blood cultures from Providence, R.I

“…Clarithromycin is a newly synthesized 14-member macrolide that has improved pharmacokinetic and pharmacodynamic properties compared with those of erythromycin (2,3). The in vitro activity of clarithromycin against S. pneumoniae was compared with that of erythromycin.…”