Meeting clinicians' and patients' needs in the practice of therapeutic monitoring
Thierry Buclin, Pascal André, Chantal Csajka
Service of Clinical Pharmacology, University Hospital of Lausanne (CHUV), Switzerland
Objectives:
- To heighten awareness of the clinical importance of Pharmacometrics for elaborating efficient strategies of treatment individualization at the patient’s level through therapeutic monitoring – an underappreciated aspect of Precision Medicine;
- To outline a structured overview of how healthcare providers can interpret and draw the best benefit from therapeutic monitoring tests, namely either drug concentration or biomarker measurement results;
- To draw attention onto the inexorable advances in point-of-care monitoring technologies and connected decision support systems that are currently redesigning therapeutic practices.
Overview/Description of presentation:
We will revisit the development of therapeutic concentration monitoring for imatinib, the archetypal targeted anticancer agent, whose story might apply with few changes to manifold drugs. The phases of this development roughly parallel the cognitive steps to follow during the interpretation of a monitoring result:
- Population PK studies are instrumental to quantify and to partly explain the variability in concentration exposure under standard dosage. Ideally aggregated in a meta-analysis [1], they bring an answer to the question of “normality” or expectedness of a concentration result in a given patient, which is well illustrated using a priori prediction percentiles.
- PKPD studies [2] contribute to clarify the issue of optimal level of exposure and to answer the question of “suitability” or appropriateness of a concentration result, usually summarized through target ranges (either population or individualized).
- Population PKPD modeling enables Bayesian adaptation [3] to devise proper dosage adjustment based on concentration results, and need to re-monitor; a posteriori maximum likelihood trajectory with prediction percentiles is ideally suited to graphically present this information.
- Clinical evidence of usefulness is required for any monitoring tool whatever its technical merits. Confirmation trials in therapeutic monitoring raise specific challenges [4] but bring the last word to the question of the indication to use the corresponding test in medical practice.
Conclusions/Take home message:
Pharmacometric approaches are now deeply integrated in the clinical development of medicinal drugs. Still in many instances, they have failed to provide physicians and patients with optimal directions for prescription individualization, in particular when therapeutic monitoring tests, based on either concentrations or biomarkers measurement, could have been anticipated to optimize a drug’s clinical benefit [5]. The usually unfavourable position of decision makers in pharmaceutical companies towards therapeutic monitoring is not the only explanation for this situation [6]. It also results from a relative lack of convenient monitoring tests readily accessible at the point of care, of user-friendly interpretation tools, of evidence-based supporting data and of general monitoring culture among healthcare providers [7]. Fortunately, progress is underway and the appraisal of possibilities offered by therapeutic monitoring is due to improve and to become systematic. The pharmacometrics community will hopefully take the responsibilities and the leadership that such developments need.
References:
[1] Gotta V, Buclin T, Csajka C, Widmer N. Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes. Ther Drug Monit. 2013;35(2):150-67.
[2] Gotta V, Bouchet S, Widmer N, Schuld P, Decosterd LA, Buclin T, Mahon FX, Csajka C, Molimard M. Large-scale imatinib dose-concentration-effect study in CML patients under routine care conditions. Leuk Res. 2014;38(7):764-72.
[3] Gotta V, Widmer N, Montemurro M, Leyvraz S, Haouala A, Decosterd LA, Csajka C, Buclin T. Therapeutic drug monitoring of imatinib: Bayesian and alternative methods to predict trough levels. Clin Pharmacokinet. 2012;51(3):187-201.
[4] Gotta V, Widmer N, Decosterd LA, Chalandon Y, Heim D, Gregor M, Benz R, Leoncini-Franscini L, Baerlocher GM, Duchosal MA, Csajka C, Buclin T. Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial. Cancer Chemother Pharmacol. 2014;74(6):1307-19.
[5] Holford NH, Buclin T. Safe and effective variability-a criterion for dose individualization. Ther Drug Monit. 2012;34(5):565-8.
[6] Buclin T, Widmer N, Biollaz J, Decosterd LA. Who is in charge of assessing therapeutic drug monitoring? The case of imatinib. Lancet Oncol. 2011;12(1):9-11.
[7] Buclin T, Gotta V, Fuchs A, Widmer N, Aronson J. Monitoring drug therapy. Br J Clin Pharmacol. 2012;73(6):917-23.
