2010 - Berlin - Germany

PAGE 2010: Methodology- PBPK
Jörg Lippert

Influence of CYP1A1 induction by cigarette smoke on pharmacokinetics of erlotinib: a computer-based evaluation of smoke-induced CYP1A1 activity in different tissues

M. Meyer (1), S. Willmann (1), C. Becker (2), R. Burghaus (2), W. Mueck (2), J. Lippert (1)

(1) Systems Biology and Computational Solutions, Bayer Technology Services GmbH, Leverkusen, Germany; (2) Clinical Pharmacology, Bayer Schering Pharma AG, Wuppertal

Objectives: Human cytochrome P-450 1A1 (CYP1A1) is located primarily in extrahepatic tissues and is known to be inducible by polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke and chargrilled meat [1-3]. Higher tissue levels of CYP1A1 can lead to a significant reduction in drug exposure in smokers or individuals with high consumption of barbecued meat and thus to a decrease in therapeutic efficacy. In order to evaluate the degree of CYP1A1 induction by tobacco smoke in different tissues, pharmacokinetics of erlotinib, a known substrate of CYP1A1, was analyzed using physiologically-based pharmacokinetic (PBPK) modeling.

Methods: A PBPK model for single dose intravenous (iv) and per oral (po) administration of erlotinib was developed integrating reported relative baseline expression levels for the relevant metabolizing enzymes CYP3A4 and CYP1A1 in liver, lung, and intestine [4, 5]. The model was implemented in the software tools PK-Sim® and MoBi® [6, 7] and adjusted to experimental plasma concentrations [8] taking into account study data to CYP3A4 inhibition with ketoconazole for estimation of residual CYP1A1 activity [9] and study data of smokers vs. non-smokers for evaluation of CYP1A1 induction [10].

Results: Two scenarios were evaluated. The first scenario assumed identical CYP1A1 induction in lung, liver, and intestine, leading to a predicted relative increase in enzymatic activity in all three tissues of 5.5 +/- 0.3 %. The second scenario allowed for local differences in CYP1A1 induction representing the expectation that CYP1A1 induction should be highest in lung since it is the tissue exposed to the highest concentrations of PAHs. In line with this expectation model scenario 2 predicted a relative increase of CYP1A1 activity in smokers of 12 +/- 6 % in lung, 5.4 +/- 0.3 % in liver, and 2.6 +/- 1.2 % in intestine, respectively. The model-based analysis of erlotinib pharmacokinetics in smokers and non-smokers predicted CYP1A1 induction levels in different tissues which are in accordance with experimental expression levels reported in literature [11-13].

Conclusions: PBPK modeling provides a valuable means of predicting drug pharmacokinetics in response to environmental chemicals such as PAHs in cigarette smoke or other compounds known to modify protein expression levels using information to relative changes in enzymatic activities.

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Reference: PAGE 19 (2010) Abstr 1870 [www.page-meeting.org/?abstract=1870]
Poster: Methodology- PBPK