Pharmaceutical Medicine

, Volume 22, Issue 4, pp 235–244 | Cite as

Therapeutic Drug Monitoring in Clinical Research

  • Cees NeefEmail author
  • Daniel J. Touw
  • Leo M. Stolk
Review Article


The development of a new drug is characterized by distinct developmental stages, usually described as phases I to IV. Dose tolerance and dose response exploration studies are undertaken in phase II or III. Pharmacokinetic studies are often involved in these phases, but frequently only as an objective of minor importance. The usefulness of therapeutic drug monitoring (TDM) is not consequently investigated for new drugs. Usually the need for TDM is only discovered much later, when the drug is already on the market. TDM is particularly valuable under the following circumstances: (i) if there is a stronger relationship between the drug concentration and effect than between the dose and effect; (ii) if there is no simple and clear clinical parameter available to evaluate the clinical efficacy of the drug; (iii) if the therapeutic window is small; (iv) to document interactions; (v) to monitor drug compliance; and (vi) if there is large intra- and interindividual variability and unpredictability in pharmacokinetic parameters. Our recommendation is that randomized concentration controlled trials should be performed during the early stages of drug development and that it should be obligatory for drug licensing.


Pharmacokinetic Parameter Voriconazole Therapeutic Drug Monitoring Exhale Breath Condensate Pharmacodynamic Parameter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    EMEA. Note for guidance on general considerations for clinical trials. ICH Topic E8: general considerations for clinical trials. Step 5. CPMP/ICH/291/95 [online]. Available from URL: [Accessed 2008 Jul 8]Google Scholar
  2. 2.
    Kraiczi H, Jang T, Ludden T, et al. Randomized concentration-controlled trials: motivations, use, and limitations. Clin Pharmacol Ther 2003; 74 (3): 203–14PubMedCrossRefGoogle Scholar
  3. 3.
    Kuypers DRJ, de Jonge H, Naesens M, et al. Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients. Clin Ther 2008; 30 (4): 673–83PubMedCrossRefGoogle Scholar
  4. 4.
    Ohman D, Cherma MD, Norlander B, et al. Determination of serum reboxetine enantiomers in patients on chronic medication with racemic reboxetine. Ther Drug Monit 2003; 25 (2): 174–82PubMedCrossRefGoogle Scholar
  5. 5.
    Ulrich S, Lauter J. Comprehensive survey of the relationship between serum concentration and therapeutic effect of amitriptyline in depression. Clin Pharmacokinet 2002; 41 (11): 853–76PubMedCrossRefGoogle Scholar
  6. 6.
    Leibenguth P, Le Guellec C, Besnier JM, et al. Therapeutic drug monitoring of HIV protease inhibitors using high-performance liquid chromatography with ultraviolet or photodiode array detection. Ther Drug Monit 2001; 23 (6): 679–88PubMedCrossRefGoogle Scholar
  7. 7.
    Marquet P. Functions of the Therapeutic Drug Monitoring (TDM) Group of the French Society of Pharmacology. Therapie 2001; 56 (3): 235–7PubMedGoogle Scholar
  8. 8.
    John L, Marra F, Ensom MHH. Role of therapeutic drug monitoring for protease inhibitors. Ann Pharmacother 2001; 35 (6): 745–54PubMedCrossRefGoogle Scholar
  9. 9.
    Barclay ML, Kirkpatrick CMJ, Begg EJ. Once daily aminoglycoside therapy: is it less toxic than multiple daily doses and how should it be monitored? Clin Pharmacokinet 1999; 36 (2): 89–98PubMedCrossRefGoogle Scholar
  10. 10.
    Lieberman R, McMichael J. Role of pharmacokinetic-pharmacodynamic principles in rational and cost-effective drug development. Ther Drug Monit 1996; 18 (4): 423–8PubMedCrossRefGoogle Scholar
  11. 11.
    Lindholm A. Cyclosporine-A: clinical-experience and therapeutic drug-monitoring. Ther Drug Monit 1995; 17 (6): 631–7PubMedCrossRefGoogle Scholar
  12. 12.
    VanderZwaag C, Mcgee M, Mcevoy JP, et al. Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry 1996; 153 (12): 1579–84PubMedGoogle Scholar
  13. 13.
    International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Standards of Practice Committee [online]. Available from URL: [Accessed 2008 Jul 24]Google Scholar
  14. 14.
    Schellens JHM, Grouls R, Guchelaar HJ, et al. The Dutch model for clinical pharmacology: collaboration between physician- and pharmacist — clinical pharmacologists. Br J Clin Pharmacol 2008 Jul; 66 (1): 146–7PubMedCrossRefGoogle Scholar
  15. 15.
    Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353 (5): 487–97PubMedCrossRefGoogle Scholar
  16. 16.
    Aarnoutse RE, Schapiro JM, Boucher CA, et al. Therapeutic drug monitoring: an aid to optimising response to antiretroviral drugs? Drugs 2003; 63 (8): 741–53PubMedCrossRefGoogle Scholar
  17. 17.
    Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50 (4): 1570–2PubMedCrossRefGoogle Scholar
  18. 18.
    Trifilio S, Pennick G, Pi J, et al. Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients. Cancer 2007; 109 (8): 1532–5PubMedCrossRefGoogle Scholar
  19. 19.
    Imhof A, Schaer DJ, Schanz U, et al. Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring. Swiss Med Wkly 2006; 136 (45–46): 739–42PubMedGoogle Scholar
  20. 20.
    Lozano J, Garcia-Algar O, Vall O, et al. Biological matrices for the evaluation of in utero exposure to drugs of abuse. Ther Drug Monit 2007; 29 (6): 711–34PubMedCrossRefGoogle Scholar
  21. 21.
    Kintz P. Drug testing in addicts: a comparison between urine, sweat, and hair. Ther Drug Monit 1996; 18 (4): 450–5PubMedCrossRefGoogle Scholar
  22. 22.
    Kintz P, Samyn N. Use of alternative specimens: drugs of abuse in saliva and doping agents in hair. Ther Drug Monit 2002; 24 (2): 239–46PubMedCrossRefGoogle Scholar
  23. 23.
    Concheiro M, Villain M, Bouchet S, et al. Windows of detection of tetrazepam in urine, oral fluid, beard, and hair, with a special focus on drug-facilitated crimes. Ther Drug Monit 2005; 27 (5): 565–70PubMedCrossRefGoogle Scholar
  24. 24.
    Kintz P, Villain M, Cirimele V. Hair analysis for drug detection. Ther Drug Monit 2006; 28 (3): 442–6PubMedCrossRefGoogle Scholar
  25. 25.
    Boeynaems JM, De LA, Dessars B, et al. Evaluation of a new generation of plastic evacuated blood-collection tubes in clinical chemistry, therapeutic drug monitoring, hormone and trace metal analysis. Clin Chem Lab Med 2004; 42 (1): 67–71PubMedCrossRefGoogle Scholar
  26. 26.
    Jelliffe RW, Iglesias T, Hurst AK, et al. Individualising gentamicin dosage regimens: a comparative review of selected models, data fitting methods and monitoring strategies. Clin Pharmacokinet 1991; 21 (6): 461–78PubMedCrossRefGoogle Scholar
  27. 27.
    Touw DJ, Van Weissenbruch MM, Lafeber HN. The predictive performance of therapeutic drug monitoring (TDM) of amikacin in neonates using an early single determination of the serum concentration together with a population model. Br J Clin Pharmacol 2000; 50 Suppl.: 487–8Google Scholar
  28. 28.
    Hoogtanders K, van der Heijden J, Christiaans M, et al. Therapeutic drug monitoring of tacrolimus with the dried blood spot method. J Pharm Biomed Anal 2007; 44 (3): 658–64PubMedCrossRefGoogle Scholar
  29. 29.
    Wijnen PA, Op den Buijsch RA, Cheung SC, et al. Genotyping with a dried blood spot method: a useful technique for application in pharmacogenetics. Clin Chim Acta 2008; 388 (1–2): 189–91PubMedCrossRefGoogle Scholar
  30. 30.
    Cheung CY, van der HJ, Hoogtanders K, et al. Dried blood spot measurement: application in tacrolimus monitoring using limited sampling strategy and abbreviated AUC estimation. Transplant Int 2008; 21 (2): 140–5Google Scholar
  31. 31.
    Drobitch RK, Svensson CK. Therapeutic drug monitoring in saliva. An update. Clin Pharmacokinet 1992; 23 (5): 365–79CrossRefGoogle Scholar
  32. 32.
    Bartels H, Gunther E, Wallis S. Monitoring therapy by analysis of the drug concentration of saliva [in German]. Monatsschr Kinderheilkd 1983; 131 (1): 13–6PubMedGoogle Scholar
  33. 33.
    Bartels H, Oldigs HD, Gunther E. Use of saliva in monitoring carbamazepine medication in epileptic children. Eur J Pediatr 1977; 126 (1–2): 37–44PubMedCrossRefGoogle Scholar
  34. 34.
    Feller K, le Petit G. On the distribution of drugs in saliva and blood plasma. Int J Clin Pharmacol Biopharm 1977; 15 (10): 468–9PubMedGoogle Scholar
  35. 35.
    Graham GG. Noninvasive chemical methods of estimating pharmacokinetic parameters. Pharmacol Ther 1982; 18 (3): 333–49PubMedCrossRefGoogle Scholar
  36. 36.
    Langman LJ. The use of oral fluid for therapeutic drug management: clinical and forensic toxicology. Oral Based Diagn 2007; 1098: 145–66Google Scholar
  37. 37.
    Fucci N, De Giovanni N. Methadone in hair and sweat from patients in long-term maintenance therapy. Ther Drug Monit 2007; 29 (4): 452–4PubMedCrossRefGoogle Scholar
  38. 38.
    Verstraete AG. Detection times of drugs of abuse in blood, urine, and oral fluid. Ther Drug Monit 2004; 26 (2): 200–5PubMedCrossRefGoogle Scholar
  39. 39.
    Kintz P, Cirimele V, Ludes B. Detection of cannabis in oral fluid (saliva) and forehead wipes (sweat) from impaired drivers. J Analyt Toxicol 2000; 24 (7): 557–61Google Scholar
  40. 40.
    Ellmen JK, Renkonen OV, Anttila MA, et al. Antibiotic concentrations in liquor compared to the minimal inhibitory concentrations of isolates in pediatric bacterial-meningitis. Chemotherapy 1991; 37 (1): 1–5PubMedGoogle Scholar
  41. 41.
    Hunt J. Exhaled breath condensate: an evolving tool for noninvasive evaluation of lung disease. J Allergy Clin Immunol 2002; 110 (1): 28–34PubMedCrossRefGoogle Scholar
  42. 42.
    Gareri J, Klein J, Koren G. Drugs of abuse testing in meconium. Clin Chim Acta 2006; 366 (1–2): 101–11PubMedCrossRefGoogle Scholar
  43. 43.
    Koren G, Hutson J, Gareri J. Novel methods for the detection of drug and alcohol exposure during pregnancy: Implications for maternal and child health. Clin Pharmacol Ther 2008; 83 (4): 631–4PubMedCrossRefGoogle Scholar
  44. 44.
    Engwegen JYMN. Clinical proteomics in colorectal and renal cell cancer [thesis; online]. Available from URL: [Accessed 2008 Jul 7]Google Scholar
  45. 45.
    Proost JH, Meijer DK. MW/Pharm, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring. Comput Biol Med 1992; 22 (3): 155–63PubMedCrossRefGoogle Scholar
  46. 46.
    Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetics parameters: I. Michaelis-Menten model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm 1980; 8 (6): 553–71PubMedGoogle Scholar
  47. 47.
    Sheiner BL, Beal SL. Evaluation of methods for estimating population pharmacokinetic parameters: II. Biexponential model and experimental pharmacokinetic data. J Pharmacokinet Biopharm 1981; 9 (5): 635–51PubMedGoogle Scholar
  48. 48.
    Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetic parameters: III. Monoexponential model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm 1983; 11 (3): 303–19PubMedGoogle Scholar
  49. 49.
    Bustad A, Terziivanov D, Leary R, et al. Parametric and nonparametric population methods: their comparative performance in analysing a clinical dataset and two Monte Carlo simulation studies. Clin Pharmacokinet 2006; 45 (4): 365–83PubMedCrossRefGoogle Scholar
  50. 50.
    EMEA. Note for guidance on the evaluation of pharmacokinetics of medicinal products in patients with impaired renal function. CPMP/EWP/225/02 [online]. Available from URL: [Accessed 2008 Jul 7]Google Scholar
  51. 51.
    EMEA. Guideline on the evaluation of pharmacokinetics of medicinal products in patients with impaired hepatic function. CPMP/EWP/2339/02 [online]. Available from URL: [Accessed 2008 Jul 7]Google Scholar
  52. 52.
    Op den Buijsch RAM, Christiaans MHL, Stolk LML, et al. Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol 2007; 21 (4): 427–35CrossRefGoogle Scholar
  53. 53.
    Touw DJ, Neef C, Thomson AH, et al. Cost-effectiveness of therapeutic drug monitoring: a systematic review. Ther Drug Monit 2005; 27 (1): 10–7PubMedCrossRefGoogle Scholar
  54. 54.
    Touw DJ, Neef C, Thomson AH, et al. Cost-effectiveness of therapeutic drug monitoring: an update. EJHP Science 2007; 13 (4): 83–91Google Scholar
  55. 55.
    Raehl CL, Bond CA, Pitterle ME. 1995 National Clinical Pharmacy Services Study. Pharmacotherapy 1998; 18 (2): 302–26PubMedGoogle Scholar
  56. 56.
    Bond CA, Raehl CL. Clinical and economic outcomes of pharmacist-managed aminoglycoside or vancomycin therapy. Am J Health System Pharm 2005; 62 (15): 1596–605CrossRefGoogle Scholar
  57. 57.
    Lent-Evers NAEM, Mathot RAA, Geus WP, et al. Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Ther Drug Monit 1999; 21 (1): 63–73PubMedCrossRefGoogle Scholar
  58. 58.
    Andes D. In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis. Antimicrob Agents Chemother 2003; 47 (4): 1179–86PubMedCrossRefGoogle Scholar
  59. 59.
    Andes D. Clinical utility of antifungal pharmacokinetics and pharmacodynamics. Curr Opin Infect Dis 2004; 17 (6): 533–40PubMedCrossRefGoogle Scholar
  60. 60.
    Hugen PWH, Burger DM, Aarnoutse RE, et al. Therapeutic drug monitoring of HIV-protease inhibitors to assess noncompliance. Ther Drug Monit 2002; 24 (5): 579–87PubMedCrossRefGoogle Scholar
  61. 61.
    Hugen PWH, Langebeek N, Burger DM, et al. Assessment of adherence to HIV protease inhibitors: comparison and combination of various methods, including MEMS (electronic monitoring), patient and nurse report, and therapeutic drug monitoring. J Acquired Immune Def Syndr 2002; 30 (3): 324–34Google Scholar
  62. 62.
    Burger DM, Hugen PWH, Aarnoutse RE, et al. Treatment failure of nelfinavir-containing triple therapy can largely be explained by low nelfinavir plasma concentrations. Ther Drug Monit 2003; 25 (1): 73–80PubMedCrossRefGoogle Scholar
  63. 63.
    Rathore SS, Curtis JP, Wang YF, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289 (7): 871–8PubMedCrossRefGoogle Scholar
  64. 64.
    Bond CA, Raehl CL. Clinical and economic outcomes of pharmacist-managed antiepileptic drug therapy. Pharmacotherapy 2006; 26 (10): 1369–78PubMedCrossRefGoogle Scholar
  65. 65.
    Rane CT, Dalvi SS, Gogtay NJ, et al. A pharmacoeconomic analysis of the impact of therapeutic drug monitoring in adult patients with generalized tonic-clonic epilepsy. Br J Clin Pharmacol 2001; 52 (2): 193–5PubMedCrossRefGoogle Scholar
  66. 66.
    Lundmark J, Bengtsson F, Nordin C, et al. Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients. Acta Psychiatr Scand 2000; 101 (5): 354–9PubMedCrossRefGoogle Scholar
  67. 67.
    Kearns GL, Fischer TJ, Hunter RH. Use of serum theophylline determinations during acute asthma therapy in children. Ann Allergy 1982; 48 (2): 71–4PubMedGoogle Scholar
  68. 68.
    Preskorn SH, Dorey RC, Jerkovich GS. Therapeutic drug monitoring of tricyclic antidepressants. Clin Chem 1988; 34 (5): 822–8PubMedGoogle Scholar
  69. 69.
    de Jonge ME, Huitema AD, Schellens JH, et al. Individualised cancer chemotherapy: strategies and performance of prospective studies on therapeutic drug monitoring with dose adaptation: a review. Clin Pharmacokinet 2005; 44 (2): 147–73PubMedCrossRefGoogle Scholar
  70. 70.
    Liekweg A, Westfeld M, Jaehde U. From oncology pharmacy to pharmaceutical care: new contributions to multidisciplinary cancer care. Support Care Cancer 2004; 12 (2): 73–9PubMedCrossRefGoogle Scholar
  71. 71.
    Lennard L. Therapeutic drug monitoring of antimetabolic cytotoxic drugs. Br J Clin Pharmacol 1999; 47 (2): 131–43PubMedCrossRefGoogle Scholar
  72. 72.
    Lennard L. Therapeutic drug monitoring of cytotoxic drugs. Br J Clin Pharmacol 2001; 52 Suppl. 1: 75–87CrossRefGoogle Scholar
  73. 73.
    Thomson AH, Whiting B. Bayesian parameter estimation and population pharmacokinetics. Clin Pharmacokinet 1992; 22 (6): 447–67PubMedCrossRefGoogle Scholar
  74. 74.
    Alnaim L. Therapeutic drug monitoring of cancer chemotherapy. J Oncol Pharm Pract 2007; 13 (4): 207–21PubMedCrossRefGoogle Scholar
  75. 75.
    Ziegler EJ, Fisher CJ, Sprung CL, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med 1991; 324 (7): 429–36PubMedCrossRefGoogle Scholar
  76. 76.
    McCloskey RV, Straube RC, Sanders C, et al., CHESS Trial Study Group. Treatment of septic shock with human monoclonal antibody HA-1A: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1994; 121 (1): 1–5PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Department of Clinical Pharmacy and ToxicologyUniversity Hospital of MaastrichtMaastrichtthe Netherlands
  2. 2.The Hague Central PharmacyThe Haguethe Netherlands

Personalised recommendations