Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration

Khaled Abduljalil, Martina Kinzig, Jürgen Bulitta, Stefan Horkovics-Kovats, Fritz Sörgel, Michael Rodamer, Uwe Fuhr

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14(R)-hydroxyclarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The 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 the autoinhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.

Original languageEnglish
Pages (from-to)2892-2901
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume53
Issue number7
DOIs
Publication statusPublished - Jul 2009
Externally publishedYes

Cite this

Abduljalil, K., Kinzig, M., Bulitta, J., Horkovics-Kovats, S., Sörgel, F., Rodamer, M., & Fuhr, U. (2009). Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration. Antimicrobial Agents and Chemotherapy, 53(7), 2892-2901. https://doi.org/10.1128/AAC.01193-08
Abduljalil, Khaled ; Kinzig, Martina ; Bulitta, Jürgen ; Horkovics-Kovats, Stefan ; Sörgel, Fritz ; Rodamer, Michael ; Fuhr, Uwe. / Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration. In: Antimicrobial Agents and Chemotherapy. 2009 ; Vol. 53, No. 7. pp. 2892-2901.
@article{08dd243ed55b43acbb9cc5c28377cd10,
title = "Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration",
abstract = "Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14(R)-hydroxyclarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The 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 the autoinhibition of clarithromycin metabolism. Up to 90{\%} of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.",
author = "Khaled Abduljalil and Martina Kinzig and J{\"u}rgen Bulitta and Stefan Horkovics-Kovats and Fritz S{\"o}rgel and Michael Rodamer and Uwe Fuhr",
year = "2009",
month = "7",
doi = "10.1128/AAC.01193-08",
language = "English",
volume = "53",
pages = "2892--2901",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "1098-6596",
publisher = "American Society for Microbiology",
number = "7",

}

Abduljalil, K, Kinzig, M, Bulitta, J, Horkovics-Kovats, S, Sörgel, F, Rodamer, M & Fuhr, U 2009, 'Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration', Antimicrobial Agents and Chemotherapy, vol. 53, no. 7, pp. 2892-2901. https://doi.org/10.1128/AAC.01193-08

Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration. / Abduljalil, Khaled; Kinzig, Martina; Bulitta, Jürgen; Horkovics-Kovats, Stefan; Sörgel, Fritz; Rodamer, Michael; Fuhr, Uwe.

In: Antimicrobial Agents and Chemotherapy, Vol. 53, No. 7, 07.2009, p. 2892-2901.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration

AU - Abduljalil, Khaled

AU - Kinzig, Martina

AU - Bulitta, Jürgen

AU - Horkovics-Kovats, Stefan

AU - Sörgel, Fritz

AU - Rodamer, Michael

AU - Fuhr, Uwe

PY - 2009/7

Y1 - 2009/7

N2 - Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14(R)-hydroxyclarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The 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 the autoinhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.

AB - Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14(R)-hydroxyclarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The 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 the autoinhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.

UR - http://www.scopus.com/inward/record.url?scp=67649984935&partnerID=8YFLogxK

U2 - 10.1128/AAC.01193-08

DO - 10.1128/AAC.01193-08

M3 - Article

C2 - 19414584

AN - SCOPUS:67649984935

VL - 53

SP - 2892

EP - 2901

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 1098-6596

IS - 7

ER -

Abduljalil K, Kinzig M, Bulitta J, Horkovics-Kovats S, Sörgel F, Rodamer M et al. Modeling the autoinhibition of clarithromycin metabolism during repeated oral administration. Antimicrobial Agents and Chemotherapy. 2009 Jul;53(7):2892-2901. https://doi.org/10.1128/AAC.01193-08