European Journal of Clinical Pharmacology

, Volume 68, Issue 6, pp 951–960 | Cite as

Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2

  • David R. PlowchalkEmail author
  • Karen Rowland Yeo
Pharmacokinetics and Disposition



To derive estimates of CYP1A2 abundance as a function of daily cigarette consumption and use these values to predict the clearances of CYP1A2 substrates in smokers.


Smoking-induced changes in hepatic CYP1A2 abundance were extrapolated from reported in vivo caffeine clearance data for sub-groups of a smoking population that were categorized according to their daily cigarette consumption. These abundance values together with in vitro–in vivo extrapolation (IVIVE) within the Simcyp population-based Simulator were used to predict the clearances of caffeine, theophylline, and clozapine in smokers. The model was used subsequently to predict differences in oral clearance between smoker and non-smoker cohorts in a Phase 1 clinical trial involving PF-2400013, a drug metabolized by CYP1A2.


Estimated hepatic CYP1A2 abundance values were 52, 64, 79, 90, and 94 pmol/mg microsomal protein for subjects smoking 0, 1–5, 6–10, 11–20, and >20 cigarettes/day respectively. Predicted -fold increases in oral clearance of caffeine, theophylline and clozapine in smokers relative to non-smokers were consistent with observed data. The validated model was able to recover the smoking-induced increase in oral clearance of PF-2400013; predicted and observed mean (CV%) values in male nonsmokers and smokers were 90 L/h (40%) and 141 L/h (34%) respectively, and 100 L/h (58%) and 131 L/h (33%) respectively.


This study demonstrates that it may be possible to predict the clearance of CYP1A2 substrates in smoking populations using quantitative estimates of CYP1A2 abundance based on daily cigarette consumption in conjunction with an IVIVE approach.


CYP1A2 Induction Modeling Smoking Clozapine Caffeine Theophylline 



We would like to thank the PF-2400013 clinical team for providing the internal validation data sets for smoker and nonsmokers from the Phase 1 study for PF-2400013.

Competing interests

KRY is an employee of and a shareholder of the company Simcyp Limited.


  1. 1.
    Faber MS, Jetter A, Fuhr U (2005) Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol 97(3):125–134PubMedCrossRefGoogle Scholar
  2. 2.
    Ma Q, Lu AY (2003) Origins of individual variability in P4501A induction. Chem Res Toxicol 16(3):249–260PubMedCrossRefGoogle Scholar
  3. 3.
    Gunes A, Dahl ML (2008) Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms. Pharmacogenomics 9(5):625–637PubMedCrossRefGoogle Scholar
  4. 4.
    Schweikl H, Taylor JA, Kitareewan S, Linko P, Nagorney D, Goldstein JA (1993) Expression of CYP1A1 and CYP1A2 genes in human liver. Pharmacogenetics 3(5):239–249PubMedCrossRefGoogle Scholar
  5. 5.
    Carrillo JA, Herraiz AG, Ramos SI, Gervasini G, Vizcaino S, Benitez J (2003) Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 23(2):119–127PubMedCrossRefGoogle Scholar
  6. 6.
    Obase Y, Shimoda T, Kawano T, Saeki S, Tomari SY, Mitsuta IK, Matsuse H, Kinoshita M, Kohno S (2003) Polymorphisms in the CYP1A2 gene and theophylline metabolism in patients with asthma. Clin Pharmacol Ther 73(5):468–474PubMedCrossRefGoogle Scholar
  7. 7.
    Sachse C, Bhambra U, Smith G, Lightfoot TJ, Barrett JH, Scollay J, Garner RC, Boobis AR, Wolf CR, Gooderham NJ, Colorectal Cancer Study G (2003) Polymorphisms in the cytochrome P450 CYP1A2 gene CYP1A2 in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol 55(1):68–76PubMedCrossRefGoogle Scholar
  8. 8.
    Van der Weide J, Steijns LS, van Weelden MJ (2003) The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics 13(3):169–172PubMedCrossRefGoogle Scholar
  9. 9.
    Dobrinas M, Cornuz J, Oneda B, Kohler Serra M, Puhl M, Eap CB (2011) Impact of smoking, smoking cessation, and genetic polymorphisms on CYP1A2 activity and inducibility. Clin Pharmacol Ther 90 (1):117–125PubMedCrossRefGoogle Scholar
  10. 10.
    Bondolfi G, Morel F, Crettol S, Rachid F, Baumann P, Eap CB (2005) Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients. Therapeutic Drug Monit 27(4):539–543CrossRefGoogle Scholar
  11. 11.
    Haslemo T, Eikeseth PH, Tanum L, Molden E, Refsum H (2006) The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol 62(12):1049–1053PubMedCrossRefGoogle Scholar
  12. 12.
    McCarthy RH (1994) Seizures following smoking cessation in a clozapine responder. Pharmacopsychiatry 27(5):210–211PubMedCrossRefGoogle Scholar
  13. 13.
    Bigos KL, Pollock BG, Coley KC, Miller DD, Marder SR, Aravagiri M, Kirshner MA, Schneider LS, Bies RR (2008) Sex, race, and smoking impact olanzapine exposure. J Clin Pharmacol 48(2):157–165PubMedCrossRefGoogle Scholar
  14. 14.
    FDA (2003) Guidance document: exposure-response relationships—study design, data analysis and final regulatory applicationsGoogle Scholar
  15. 15.
    EMA (2010) Draft guidance on drug interactionsGoogle Scholar
  16. 16.
    Edginton AN, Willmann S (2008) Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis. Clin Pharmacokinet 47(11):743–752PubMedCrossRefGoogle Scholar
  17. 17.
    Johnson TN, Boussery K, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A (2010) A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance. Clin Pharmacokinet 49(3):189–206PubMedCrossRefGoogle Scholar
  18. 18.
    Houston JB (1994) Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 47(9):1469–1479PubMedCrossRefGoogle Scholar
  19. 19.
    Howgate EM, Rowland Yeo K, Proctor NJ, Tucker GT, Rostami-Hodjegan A (2006) Prediction of in vivo drug clearance from in vitro data. I. Impact of inter-individual variability. Xenobiotica 36(6):473–497PubMedCrossRefGoogle Scholar
  20. 20.
    Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, Rostami-Hodjegan A (2009) The Simcyp population-based ADME simulator. Expert Opinion Drug Metab Toxicol 5(2):211–223CrossRefGoogle Scholar
  21. 21.
    Jamei M, Dickinson GL, Rostami-Hodjegan A (2009) A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: A tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. [Review] [150 refs] [Erratum appears in Drug Metab Pharmacokinet. 2009;24(5):488]. Drug Metab Pharmacokinet 24(1):53–75PubMedCrossRefGoogle Scholar
  22. 22.
    Rowland-Yeo K, Rostami-Hodjegan A, Tucker GT (2004) Abundance of cytochrome P450 in human liver: a meta-analysis. Br J Clin Pharmacol 57(5):687Google Scholar
  23. 23.
    Barter ZE, Bayliss MK, Beaune PH, Boobis AR, Carlile DJ, Edwards RJ, Houston JB, Lake BG, Lipscomb JC, Pelkonen OR, Tucker GT, Rostami-Hodjegan A (2007) Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. [Review] [80 references]. Curr Drug Metabol 8(1):33–45CrossRefGoogle Scholar
  24. 24.
    Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A (2005) Changes in liver volume from birth to adulthood: a meta-analysis. Liver Transpl 11(12):1481–1493PubMedCrossRefGoogle Scholar
  25. 25.
    Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM (2004) The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol 199(3):193–209PubMedCrossRefGoogle Scholar
  26. 26.
    Tantcheva-Poór I, Zaigler M, Rietbrock S, Fuhr U (1999) Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics 9(2):131–144PubMedGoogle Scholar
  27. 27.
    Blanchard J, Sawers SJ (1983) The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol 24(1):93–98PubMedCrossRefGoogle Scholar
  28. 28.
    Terziivanov D, Bozhinova K, Dimitrova V, Atanasova I (2003) Nonparametric expectation maximisation (NPEM) population pharmacokinetic analysis of caffeine disposition from sparse data in adult Caucasians: systemic caffeine clearance as a biomarker for cytochrome P450 1A2 activity. Clin Pharmacokinet 42(15):1393–1409PubMedCrossRefGoogle Scholar
  29. 29.
    Hunt SN, Jusko WJ, Yurchak AM (1976) Effect of smoking on theophylline disposition. Clin Pharmacol Ther 19(5 Pt 1):546–551PubMedGoogle Scholar
  30. 30.
    Gardner MJ, Tornatore KM, Jusko WJ, Kanarkowski R (1983) Effects of tobacco smoking and oral contraceptive use on theophylline disposition. Br J Clin Pharmacol 16(3):271–280PubMedGoogle Scholar
  31. 31.
    Jennings TS, Nafziger AN, Davidson L, Bertino JS Jr (1993) Gender differences in hepatic induction and inhibition of theophylline pharmacokinetics and metabolism. J Lab Clin Med 122(2):208–216PubMedGoogle Scholar
  32. 32.
    Seppälä NH, Leinonen EV, Lehtonen ML, Kivistö KT (1999) Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients. Pharmacol Toxicol 85(5):244–246PubMedCrossRefGoogle Scholar
  33. 33.
    Rostami HA, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ (2004) Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol 24(1):70–78CrossRefGoogle Scholar
  34. 34.
    Palego L, Biondi L, Giannaccini G, Sarno N, Elmi S, Ciapparelli A, Cassano GB, Lucacchini A, Martini C, Dell OL (2002) Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: influence of patient-related variables. Prog Neuropsychopharmacol Biol Psychiatry 26(3):473–480PubMedCrossRefGoogle Scholar
  35. 35.
    Rostami-Hodjegan A, Kroemer HK, Tucker GT (1999) In-vivo indices of enzyme activity: the effect of renal impairment on the assessment of CYP2D6 activity. Pharmacogenetics 9(3):277–286PubMedCrossRefGoogle Scholar
  36. 36.
    Djordjevic N, Ghotbi R, Bertilsson L, Jankovic S, Aklillu E (2008) Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes. Eur J Clin Pharmacol 64(4):381–385PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Clinical Pharmacology, Primary Care BUPfizer IncGrotonUSA
  2. 2.Simcyp Limited, Blades Enterprise CentreSheffieldUK

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