Pharmacokinetics and Pharmacogenetics: Bringing the Magic Bullet Closer to Reality

  • Janet MifsudEmail author
  • Marc Maliepaard
Part of the Advances in Predictive, Preventive and Personalised Medicine book series (APPPM, volume 9)


Why do some patients respond positively to some drugs, while others may experience adverse effects? Can we predict which patients will react in which way? Does a magic bullet exist? The trend towards pharmacogenetics and personalised medicine in the last few years has somewhat sidelined the relevance of the traditional pharmaceutical sciences, such as pharmacokinetics and pharmacodynamics. Yet these actually are part and parcel of pharmacogenetics. Indeed understanding pharmacokinetics and pharmacodynamics in pharmacogenetics is essential in assessing the risk of new chemical entities (NCEs) in populations and individuals. Clinical pharmacokinetics, in fact, can be understood to have been a precursor to the implementation of pharmacogenetic understanding in the clinical setting. In this chapter, examples will be given of the strong interrelation between pharmacogenetics and the various pharmacokinetics processes i.e. absorption, distribution, metabolism and elimination. Reference will be made to studies which have shown how pharmacogenetics can be reinterpreted into pharmacokinetic principles, thus leading to the individualisation of drug therapy in the individual patient. The impact on recent regulatory guidelines published on the role of pharmacokinetics in pharmacogenetics and their impact on regulation of new medicinal drug development will also be discussed.


Pharmacokinetics Pharmacodynamics Pharmacogenetics ADME Drug transporters Therapeutic drug monitoring Individualised therapy Drug development 


  1. 1.
    Rang H, Ritter J, Henderson G (2012) What is pharmacology? In: Rang H, Ritter J, Henderson G (eds) Rang and Dale’s pharmacology, 7th edn. Churchill Livingston, London, pp 1–3Google Scholar
  2. 2.
    Vogel F (1959) The influence of genetic factors on the response to drugs: Moderne probleme der Humangenetik. Ergeb Inn Med Kinderheilkd 12:52–125Google Scholar
  3. 3.
    Holford NH, Sheiner LB (1982) Kinetics of pharmacologic response. Pharmacol Ther 16(2):143–166Google Scholar
  4. 4.
    Gallo JM (2010) Pharmacokinetic/pharmacodynamic-driven drug development. Mt Sinai J Med (New York) 77(4):381–388. doi:10.1002/msj.20193Google Scholar
  5. 5.
    Singh BK, Haque SE, Pillai KK (2014) Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity. Expert Opin Drug Metab Toxicol 10(2):143–156. doi:10.1517/17425255.2014.856881Google Scholar
  6. 6.
    Walker DK (2004) The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development. Br J Clin Pharmacol 58(6):601–608. doi:10.1111/j.1365-2125.2004.02194.xGoogle Scholar
  7. 7.
    Gundert-Remy U, Dimovski A, Gajovic S (2012) Personalized medicine—where do we stand? Pouring some water into wine: a realistic perspective. Croat Med J 53(4):314–320Google Scholar
  8. 8.
    Evans WE, McLeod HL (2003) Pharmacogenomics–drug disposition, drug targets, and side effects. N Engl J Med 348 (6):538–549. doi:10.1056/NEJMra020526PubMedCrossRefGoogle Scholar
  9. 9.
    Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin HV, Hardwick JP, Meyer UA (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331(6155):442–446. doi:10.1038/331442a0PubMedCrossRefGoogle Scholar
  10. 10.
    Iqbal S, Lenz HJ (2001) Determinants of prognosis and response to therapy in colorectal cancer. Curr Oncol Rep 3(2):102–108Google Scholar
  11. 11.
    Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med 359(8):789–799. doi:10.1056/NEJMoa0801936Google Scholar
  12. 12.
    Rowland M, Tozer TN (2012). Clinical pharmacokinetics and pharmacodynamics: concepts and applications, 4th edn. Lippincott Williams and Wilkins, Baltimore, p 359, 367, 370, 300Google Scholar
  13. 13.
    Mayor S (2007) Fitting the drug to the patient. BMJ 334(7591):452–453. doi:10.1136/bmj.39133.452315.ADPubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Cropp CD, Yee SW, Giacomini KM (2008) Genetic variation in drug transporters in ethnic populations. Clin Pharmacol Ther 84(3):412–416. doi:10.1038/clpt.2008.98Google Scholar
  15. 15.
    Curry SH, Whelpton R (2011) Drug disposition and pharmacokinetics: from principles to applications. Wiley Blackwell, London, p 27, 29, 48Google Scholar
  16. 16.
    Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75(1):13–33. doi:10.1016/j.clpt.2003.09.012Google Scholar
  17. 17.
    Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315(5811):525–528. doi:10.1126/science.1135308CrossRefGoogle Scholar
  18. 18.
    Chowbay B, Li H, David M, Cheung YB, Lee EJ (2005) Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol 60(2):159–171. doi:10.1111/j.1365-2125.2005.02392.xGoogle Scholar
  19. 19.
    Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB (2012) PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics 22(6):466–470. doi:10.1097/FPC.0b013e32834aeedbGoogle Scholar
  20. 20.
    Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya SM (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Eng J Med 348(15):1442–1448. doi:10.1056/NEJMoa021986Google Scholar
  21. 21.
    Bournissen FG, Moretti ME, Juurlink DN, Koren G, Walker M, Finkelstein Y (2009) Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: a meta-analysis. Epilepsia 50(4):898–903. doi:10.1111/j.1528-1167.2008.01858.xGoogle Scholar
  22. 22.
    Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006) SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16(12):873–879. doi:10.1097/01.fpc.0000230416.82349.90Google Scholar
  23. 23.
    Katz DA, Murray B, Bhathena A, Sahelijo L (2008) Defining drug disposition determinants: a pharmacogenetic-pharmacokinetic strategy. Nat Rev Drug Discov 7(4):293–305. doi:10.1038/nrd2486Google Scholar
  24. 24.
    Crews KR, Gaedigk A, Dunnenberger HM, Klein TE, Shen DD, Callaghan JT, Kharasch ED, Skaar TC (2012) Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91(2):321–326. doi:10.1038/clpt.2011.287Google Scholar
  25. 25.
    Preissner SC, Hoffmann MF, Preissner R, Dunkel M, Gewiess A, Preissner S (2013) Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy. PloS one 8(12):e82562. doi:10.1371/journal.pone.0082562Google Scholar
  26. 26.
    Ward RM, Kearns GL (2013) Proton pump inhibitors in pediatrics: mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics. Paediatr Drugs 15(2):119–131. doi:10.1007/s40272-013-0012-xGoogle Scholar
  27. 27.
    Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Muller DJ, Gaedigk A, Stingl JC (2013) Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93(5):402–408. doi:10.1038/clpt.2013.2Google Scholar
  28. 28.
    Irvin WJ Jr, Walko CM, Weck KE, Ibrahim JG, Chiu WK, Dees EC, Moore SG, Olajide OA, Graham ML, Canale ST, Raab RE, Corso SW, Peppercorn JM, Anderson SM, Friedman KJ, Ogburn ET, Desta Z, Flockhart DA, McLeod HL, Evans JP, Carey LA (2011) Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6metabolism: a multicenter study. J Clin Oncol 29(24):3232–3239. doi:10.1200/jco.2010.31.4427Google Scholar
  29. 29.
    Kiyotani K, Mushiroda T, Nakamura Y, Zembutsu H (2012) Pharmacogenomics of tamoxifen: roles of drug metabolizing enzymes and transporters. Drug Metab Pharmacokinet 27(1):122–131Google Scholar
  30. 30.
    Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, Nikoloff DM, Hillman G, Fontecha MR, Lawrence HJ, Parker BA, Wu AH, Pierce JP (2011) Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther 89(5):718–725. doi:10.1038/clpt.2011.32Google Scholar
  31. 31.
    Sim SC, Kacevska M, Ingelman-Sundberg M (2013) Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J 13(1):1–11. doi:10.1038/tpj.2012.45Google Scholar
  32. 32.
    Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302(8):849–857. doi:10.1001/jama.2009.1232Google Scholar
  33. 33.
    Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304(16):1821–1830. doi:10.1001/jama.2010.1543Google Scholar
  34. 34.
    Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287(13):1690–1698Google Scholar
  35. 35.
    (NCBI) NCfBI (2014) dBSNP short genetic variations: Reference SNP (refSNP) Cluster Report: rs776746 NCBI. Accessed July 2014
  36. 36.
    Tang HL, Xie HG, Yao Y, Hu YF (2011) Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers. Pharmacogenet Genomics 21(11):713–720. doi:10.1097/FPC.0b013e32834a48caGoogle Scholar
  37. 37.
    EMA (2012) Guideline on the use of Pharmacogenetic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products EMA/ CHMP/37646/2009. EU, LondonGoogle Scholar
  38. 38.
    Noetzli M, Guidi M, Ebbing K, Eyer S, Wilhelm L, Michon A, Thomazic V, Alnawaqil AM, Maurer S, Zumbach S, Giannakopoulos P, von Gunten A, Csajka C, Eap CB (2013) Population pharmacokinetic study of memantine: effects of clinical and genetic factors. Clin Pharmacokinet 52(3):211–223. doi:10.1007/s40262-013-0032-2PubMedCrossRefGoogle Scholar
  39. 39.
    Ware N (2012) The role of genetics in drug dosing. Pediatr Nephrol (Berlin, Germany) 27(9):1489–1498. doi:10.1007/s00467-012-2105-0Google Scholar
  40. 40.
    Hamberg AK, Friberg LE, Hanseus K, Ekman-Joelsson BM, Sunnegardh J, Jonzon A, Lundell B, Jonsson EN, Wadelius M (2013) Warfarin dose prediction in children using pharmacometric bridging–comparison with published pharmacogenetic dosing algorithms. Eur J Clin Pharmacol 69(6):1275–1283. doi:10.1007/s00228-012-1466-4.Google Scholar
  41. 41.
    Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, Abdel-Rahman SZ, Stevens SM, Yale S, Mohler ER 3rd, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA 3rd, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH (2013) A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Eng J Med 369(24):2283–2293. doi:10.1056/NEJMoa1310669CrossRefGoogle Scholar
  42. 42.
    Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlstrom B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F, Wadelius M (2013) A randomized trial of genotype-guided dosing of warfarin. N Eng J Med 369 (24):2294–2303. doi:10.1056/NEJMoa1311386Google Scholar
  43. 43.
    FDA (2007) FDA Approves Updated Warfarin (Coumadin) Prescribing Information: New Genetic Information May Help Providers Improve Initial Dosing Estimates of he Anticoagulant for Individual Patients. U.S. Department of Health and Human ServicesGoogle Scholar
  44. 44.
    FDA (2013) Guidance on Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical StudiesGoogle Scholar
  45. 45.
    Maliepaard M, Nofziger C, Papaluca M, Zineh I, Uyama Y, Prasad K, Grimstein C, Pacanowski M, Ehmann F, Dossena S, Paulmichl M (2013) Pharmacogenetics in the evaluation of new drugs: a multiregional regulatory perspective. Nat Rev Drug Discov 12(2):103–115. doi:10.1038/nrd3931Google Scholar
  46. 46.
    Meckley LM, Neumann PJ (2010) Personalized medicine: factors influencing reimbursement. Health Policy 94(2):91–100. doi:10.1016/j.healthpol.2009.09.006CrossRefGoogle Scholar
  47. 47.
    PharmGKB The Pharmacogenomics Database (2014) Stanford University.

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Clinical Pharmacology and TherapeuticsUniversity of MaltaMsidaMalta
  2. 2.Clinical PharmacologistDutch Medicines Evaluation BoardUtrechtThe Netherlands

Personalised recommendations