Modelling the auto-inhibition of clarithromycin metabolism during repeated oral administration

Abstract number: P1655

Jakob V., Abduljalil K., Kinzig M., Bulitta J., Horkovics-Kovats S., Fuhr U., Sörgel F.

Objectives: Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of co-administered drugs. This study aimed at understanding the time course of these changes.

Methods: Plasma concentration time profiles of clarithromycin and its active metabolite, 14(R)-hydroxy-clarithromycin, from 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg bid for 7 doses) were modelled by population pharmacokinetic analysis in NONMEM.

Results: Non-linearity of clarithromycin metabolism was considered during model development and metabolite disposition kinetics was assumed to be linear. The absorption kinetics of clarithromycin was best described by a Weibull function model. Pharmacokinetics of clarithromycin and its 14(R)-hydroxyl metabolite were adequately described by a one-compartment model each for clarithromycin and its metabolite as well as an inhibition compartment that reflects auto-inhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 L/h) was susceptible to reversible auto-inhibition, depending on the concentration in the inhibition compartment. The proposed semi-mechanistic population pharmacokinetic model successfully described the auto-inhibition of clarithromycin metabolism and may be used to adjust doses of other drugs metabolised by CYP3A4 that are co-administered with clarithromycin.

Conclusion: Simulations showed that for the 500 mg bid standard dose no further increase of exposure occurs after approximately 48 h of treatment. For a 1000 mg bid dose reaching steady state is expected to take several days and to achieve a 3.6-fold higher clarithromycin exposure compared to 500 mg bid. This evaluation provides a rationale for a safer and more effective therapy with clarithromycin.

Session Details

Date: 16/05/2009
Time: 00:00-00:00
Session name: 19th European Congress of Clinical Microbiology and Infectious Diseases
Location: Helsinki, Finland, 16 - 19 May 2009
Presentation type:
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