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Therapeutic drug monitoring for tomorrow

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Abstract

Therapeutic drug monitoring (TDM) represents an early approach to personalised medicine. It helps the clinician to individualise drug treatment and guide dosage to reach systemic drug concentrations associated with therapeutic efficacy and/or to reduce the risk of concentration-dependent adverse effects. Well into the fifth decade of TDM as a service to healthcare, this concept is still expanding, and new areas for clinical implementation continue to emerge. The aim of this overview is to discuss promising new therapeutic areas in future TDM services, how to improve the clinical interpretation of single drug measurements and how recent technology development opens the doors to research and new applications.

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References

  1. Birkett D, Brøsen K, Cascorbi I, Gustafsson LL, Maxwell S, Rago L, Rawlins M, Reidenberg M, Sjöqvist F, Smith T, Thuerman P, Walubo A, Orme M, Sjöqvist F (2010) Clinical pharmacology in research, teaching and health care: considerations by IUPHAR, the International Union of Basic and Clinical Pharmacology. Basic Clin Pharmacol Toxicol 107:531–559

    Article  PubMed  Google Scholar 

  2. Asberg M, Cronholm B, Sjöqvist F, Tuck D (1971) Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J 3:331–334

    Article  PubMed  CAS  Google Scholar 

  3. Noone P, Parsons TM, Pattison JR, Slack RC, Garfield-Davies D, Hughes K (1974) Experience in monitoring gentamicin therapy during treatment of serious Gram-negative sepsis. Br Med J 1:477–481

    Article  PubMed  CAS  Google Scholar 

  4. Duhme DW, Greenblatt DJ, Koch-Weser J (1974) Reduction of digoxin toxicity associated with measurement of serum levels. A report from the Boston Collaborative Drug Surveillance Program. Ann Intern Med 80:516–519

    Article  PubMed  CAS  Google Scholar 

  5. Levy G, Ellis EF, Koysooko R (1974) Indirect plasma-theophylline monitoring in asthmatic children by determination of theophylline concentration in saliva. Pediatrics 53:873–876

    PubMed  CAS  Google Scholar 

  6. Eichelbaum M, Bertilsson L, Lund L, Palmér L, Sjöqvist F (1976) Plasma levels of carbamazepine and carbamazepine-10,11-epoxide during treatment of epilepsy. Eur J Clin Pharmacol 9:417–421

    Article  CAS  Google Scholar 

  7. Sjöqvist F, Eliasson E (2007) The convergence of conventional therapeutic drug monitoring and pharmacogenetic testing in personalized medicine: focus on antidepressants. Clin Pharmacol Ther 81:899–902

    Article  PubMed  Google Scholar 

  8. Dahl M-L, Sjöqvist F (2000) Pharmacogenetic methods as a comment to therapeutic monitoring of antidepressants and neuroleptics. Ther Drug Monit 22:114–116

    Article  PubMed  CAS  Google Scholar 

  9. Saint-Marcoux F, Sauvage FL, Marquet P (2007) Current role of LC-MS in therapeutic drug monitoring. Anal Bioanal Chem 388:1327–1340

    Article  PubMed  CAS  Google Scholar 

  10. Sallustio BC (2010) LC-MS/MS for immunosuppressant therapeutic drug monitoring. Bioanalysis 2:1141–1153

    Article  PubMed  CAS  Google Scholar 

  11. Meyer MR, Maurer HH (2012) Current applications of high-resolution mass spectrometry in drug metabolism studies. Anal Bioanal Chem 403:1221–1231

    Article  PubMed  CAS  Google Scholar 

  12. Mittelstrass K, Ried JS, Yu Z, Krumsiek J, Gieger C, Prehn C, Roemisch-Margl W, Polonikov A, Peters A, Theis FJ, Meitinger F, Krononberg F, Weidinger S, Wichmann HE, Suhre K, Wang-Sattler R, Adamski J, Illig T (2011) Discovery of sexual dimorphism in metabolic and genetic biomarkers. PLoS Genet 7:1–11

    Article  Google Scholar 

  13. Broecker S, Herre S, Wüst B, Zweigenbaum J, Pragst F (2011) Development and practical application of a library of CID accurate mass spectra of more than 2,500 toxic compounds for systematic toxicological analysis by LC-QTOF-MS with data-dependent acquisition. Anal Bioanal Chem 400:101–117

    Article  PubMed  CAS  Google Scholar 

  14. Heine R, Beijnen JH, Huitema AD (2009) Bioanalytical issues in patient friendly sampling methods for therapeutic drug monitoring: focus on antiretroviral drugs. Bioanalysis 1:1329–1338

    Article  PubMed  Google Scholar 

  15. Gallardo E, Barroso M, Queiroz JA (2009) Current technologies and considerations for drug bioanalysis in oral fluid. Bioanalysis 1:637–667

    Article  PubMed  CAS  Google Scholar 

  16. Sime FB, Roberts MS, Peake SL, Lipman J, Roberts JA (2012) Does beta-lactam pharmacokinetic variability in critically ill patients justify therapeutic drug monitoring? A systematic review. Ann Intensive Care 2:35

    Article  PubMed  Google Scholar 

  17. Roberts DM, Roberts JA, Roberts MS, Liu X, Nair P, Cole L, Lipman J, Bellomo R, RENAL Replacement Therapy Study Investigators (2012) Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study. Crit Care Med 40:1523–1528

    Article  PubMed  CAS  Google Scholar 

  18. Udy AA, Roberts JA, De Waele JJ, Paterson DL, Lipman J (2012) What’s behind the failure of emerging antibiotics in the critically ill? Understanding the impact of altered pharmacokinetics and augmented renal clearance. Int J Antimicrob Agents 39:455–457

    Article  PubMed  CAS  Google Scholar 

  19. González de Molina FJ, Ferrer R (2011) Appropriate antibiotic dosing in severe sepsis and acute renal failure: factors to consider. Crit Care 15:175

    Article  PubMed  Google Scholar 

  20. Taccone FS, Laterre PF, Dugernier T, Spapen H, Delattre I, Wittebole X, De Backer D, Layeux B, Wallemacq P, Vincent JL, Jacobs F (2010) Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care 14:R126

    Article  PubMed  Google Scholar 

  21. Hanberger H, Edlund C, Furebring M, G Giske C, Melhus A, Nilsson LE, Petersson J, Sjölin J, Ternhag A, Werner M, Eliasson E; Swedish Reference Group for Antibiotics (SRGA) (2012) Rational use of aminoglycosides—Review and recommendations by the Swedish Reference Group for Antibiotics (SRGA). Scand J Infect Dis 45(3):161–75

  22. Pasqualotto AC, Howard SJ, Moore CB, Denning DW (2007) Flucytosine therapeutic monitoring: 15 years’ experience from the UK. J Antimicrob Chemother 59:791–793

    Article  PubMed  CAS  Google Scholar 

  23. Rybak M, Lomaestro B, Rotschafer JC et al (2009) Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 66:82–98

    Article  PubMed  CAS  Google Scholar 

  24. Hazlewood KA, Brouse SD, Pitcher WD, Hall RG (2010) Vancomycin-associated nephrotoxicity: grave concern or death by character assassination? Am J Med 123:182.e1–182.e7

    Article  Google Scholar 

  25. Lodise TP, Lomaestro B, Graves J, Drusano GL (2008) Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 52:1330–1336

    Article  PubMed  CAS  Google Scholar 

  26. Van Herendael B, Jeurissen A, Tulkens PM, Vlieghe E, Verbrugghe W, Jorens PG, Ieven M (2012) Continuous infusion of antibiotics in the critically ill: the new holy grail for beta-lactams and vancomycin? Ann Intensive Care 2:22

    Article  PubMed  Google Scholar 

  27. Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, Lipman J (2010) Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents 36:332–339

    Article  PubMed  CAS  Google Scholar 

  28. Udy AA, Varghese JM, Altukroni M, Briscoe S, McWhinney BC, Ungerer JP, Lipman J, Roberts JA (2012) Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest 142:30–39

    Article  PubMed  CAS  Google Scholar 

  29. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–10

    Article  PubMed  CAS  Google Scholar 

  30. Dahl M-L, Bertilsson L (1993) Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics 3:61–70

    Article  PubMed  CAS  Google Scholar 

  31. Jerling M, Lindström L, Bondesson U, Bertilsson L (1994) Fluvoxamine inhibition and carebamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 16:368–374

    Article  PubMed  CAS  Google Scholar 

  32. Bertilsson L, Carrillo JA, Dahl M-L, LLerena A, Alm C, Bondesson U, Lindström L, Rodriquez de la Rubia I, Ramos S, Benitez J (1994) Clozapine disposition covaries with the CYP1A2 activity determined by a caffeine test. Br J Clin Pharmacol 38:471–473

    Article  PubMed  CAS  Google Scholar 

  33. Bengtsson F (2004) Therapeutic drug monitoring of psychotropic drugs, TDM “nouveau”. Ther Drug Monit 26:145–151

    Article  PubMed  Google Scholar 

  34. Brünen S, Vincent PD, Baumann P, Hiemke C, Havemann-Reinecke U (2011) Therapeutic drug monitoring for drugs used in the treatment fo substance-related disorders: Literature review using a therapeutic drug monitoring appropriateness rating scale. Ther Drug Monit 33:561–572

    PubMed  Google Scholar 

  35. Carlquist JF, Anderson JL (2011) Using pharmacogenetics in real time to guide warfarin initiation: a clinician update. Circulation 124:2554–2559

    Article  PubMed  Google Scholar 

  36. Lindh JD, Holm L, Andersson ML, Rane A (2009) Influence of CYP2C9 genotype on warfarin dose requirements—a systematic review and meta-analysis. Eur J Clin Pharmacol 65:365–375

    Article  PubMed  CAS  Google Scholar 

  37. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, Holm L, McGinnis R, Rane A, Deloukas P (2009) The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 113:784–792

    Article  PubMed  CAS  Google Scholar 

  38. Lazo-Langner A, Kovacs MJ (2010) Predicting warfarin dose. Curr Opin Pulm Med 16:426–431

    Article  PubMed  CAS  Google Scholar 

  39. Malmström RE (2009) New anticoagulants: focus on currently approved oral factor Xa and factor IIa inhibitors. In: Antovic JP, Blombäck M (eds) Essential guide to blood coagulation. Wiley-Blackwell, Oxford, pp 91–102

    Google Scholar 

  40. Conolly SJ, for the RE-LY Steering Committee and Investigators et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151

    Article  Google Scholar 

  41. Patel MR et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891

    Article  PubMed  CAS  Google Scholar 

  42. Granger CB et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365(11):981–992

    Article  PubMed  CAS  Google Scholar 

  43. Federal Drug Administration (2010) Questions dabigatran. Available at: www.fda.gov

  44. European Medicines Agency (EMA). Summary of product characteristics. Pradaxa (dabigatran). Available at: www.ema.europa.eu

  45. European Medicines Agency (EMA). Summary of product characteristics. Xarelto (rivaroxaban). Available at: www.ema.europa.eu

  46. European Medicines Agency (EMA).Summary of product characteristics. Eliquis (apixaban). Available at: www.ema.europa.eu

  47. Samama MM, Guinet C, Le Flem L, Ninin E, Debue JM (2013) Measurement of dabigatran and rivaroxaban in primary prevention of venous thromboembolism in 106 patients, who have undergone major orthopedic surgery: an observational study. J Thromb Thrombolysis 35:140–146

    Article  PubMed  CAS  Google Scholar 

  48. Antovic JP, Skeppholm M, Eintrei J, Eriksson-Boija E, Söderblom L, Rönquist Y, Pohanka A, Beck O, Norberg E-M, Hjemdahl P, Malmström RE (2013). How to monitor dabigatran when needed: comparison of coagulation laboratory methods and dabigatran concentrations in plasma. Abstract. 24th ISTH Congress and 59th Annual Scientific and Standardization Committee (SSC) Meeting, Amsterdam

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Eliasson, E., Lindh, J.D., Malmström, R.E. et al. Therapeutic drug monitoring for tomorrow. Eur J Clin Pharmacol 69 (Suppl 1), 25–32 (2013). https://doi.org/10.1007/s00228-013-1504-x

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  • DOI: https://doi.org/10.1007/s00228-013-1504-x

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