Abstract
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
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References
Faber MS, Jetter A, Fuhr U (2005) Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol 97(3):125–134
Ma Q, Lu AY (2003) Origins of individual variability in P4501A induction. Chem Res Toxicol 16(3):249–260
Gunes A, Dahl ML (2008) Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms. Pharmacogenomics 9(5):625–637
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):239–249
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):119–127
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):468–474
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):68–76
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):169–172
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):117–125
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):539–543
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):1049–1053
McCarthy RH (1994) Seizures following smoking cessation in a clozapine responder. Pharmacopsychiatry 27(5):210–211
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):157–165
FDA (2003) Guidance document: exposure-response relationships—study design, data analysis and final regulatory applications
EMA (2010) Draft guidance on drug interactions
Edginton AN, Willmann S (2008) Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis. Clin Pharmacokinet 47(11):743–752
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):189–206
Houston JB (1994) Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 47(9):1469–1479
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):473–497
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):211–223
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):53–75
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):687
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):33–45
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):1481–1493
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):193–209
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):131–144
Blanchard J, Sawers SJ (1983) The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol 24(1):93–98
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):1393–1409
Hunt SN, Jusko WJ, Yurchak AM (1976) Effect of smoking on theophylline disposition. Clin Pharmacol Ther 19(5 Pt 1):546–551
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):271–280
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):208–216
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):244–246
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):70–78
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):473–480
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):277–286
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):381–385
Acknowledgements
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.
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Plowchalk, D.R., Rowland Yeo, K. Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2. Eur J Clin Pharmacol 68, 951–960 (2012). https://doi.org/10.1007/s00228-011-1189-y
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DOI: https://doi.org/10.1007/s00228-011-1189-y