Evelina Cardoso1,2, Monia Guidi1,2, Benoît Blanchet3,4, Marie Paule Schneider2, Laurent A Decosterd1, Thierry Buclin1, Chantal Csajka1,2, Nicolas Widmer1,2,5. 1. Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne. 2. Institute of Pharmaceutical Sciences of Western, University of Geneva, Geneva, Switzerland. 3. Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris. 4. UMR8638 CNRS, Pharmacy UFR, University of Paris Descartes, PRES Sorbonne Paris Cité, France; and. 5. Pharmacy of Eastern Vaud Hospitals, Vevey, Switzerland.
Abstract
BACKGROUND: Therapeutic response to oral targeted anticancer protein kinase inhibitors (PKIs) varies widely between patients, with insufficient efficacy of some of them and unacceptable adverse reactions of others. There are several possible causes for this heterogeneity, such as pharmacokinetic (PK) variability affecting blood concentrations, fluctuating medication adherence, and constitutional or acquired drug resistance of cancer cells. The appropriate management of oncology patients with PKI treatments thus requires concerted efforts to optimize the utilization of these drug agents, which have probably not yet revealed their full potential. METHODS: An extensive literature review was performed on MEDLINE on the PK, pharmacodynamics, and therapeutic drug monitoring (TDM) of PKIs (up to April 2019). RESULTS: This review provides the criteria for determining PKIs suitable candidates for TDM (eg, availability of analytical methods, observational PK studies, PK-pharmacodynamics relationship analysis, and randomized controlled studies). It reviews the major characteristics and limitations of PKIs, the expected benefits of TDM for cancer patients receiving them, and the prerequisites for the appropriate utilization of TDM. Finally, it discusses various important practical aspects and pitfalls of TDM for supporting better implementation in the field of cancer treatment. CONCLUSIONS: Adaptation of PKIs dosage regimens at the individual patient level, through a rational TDM approach, could prevent oncology patients from being exposed to ineffective or unnecessarily toxic drug concentrations in the era of personalized medicine.
BACKGROUND: Therapeutic response to oral targeted anticancer protein kinase inhibitors (PKIs) varies widely between patients, with insufficient efficacy of some of them and unacceptable adverse reactions of others. There are several possible causes for this heterogeneity, such as pharmacokinetic (PK) variability affecting blood concentrations, fluctuating medication adherence, and constitutional or acquired drug resistance of cancer cells. The appropriate management of oncology patients with PKI treatments thus requires concerted efforts to optimize the utilization of these drug agents, which have probably not yet revealed their full potential. METHODS: An extensive literature review was performed on MEDLINE on the PK, pharmacodynamics, and therapeutic drug monitoring (TDM) of PKIs (up to April 2019). RESULTS: This review provides the criteria for determining PKIs suitable candidates for TDM (eg, availability of analytical methods, observational PK studies, PK-pharmacodynamics relationship analysis, and randomized controlled studies). It reviews the major characteristics and limitations of PKIs, the expected benefits of TDM for cancerpatients receiving them, and the prerequisites for the appropriate utilization of TDM. Finally, it discusses various important practical aspects and pitfalls of TDM for supporting better implementation in the field of cancer treatment. CONCLUSIONS: Adaptation of PKIs dosage regimens at the individual patient level, through a rational TDM approach, could prevent oncology patients from being exposed to ineffective or unnecessarily toxic drug concentrations in the era of personalized medicine.
Authors: Thomas Gp Grünewald; Marta Alonso; Sofia Avnet; Ana Banito; Stefan Burdach; Florencia Cidre-Aranaz; Gemma Di Pompo; Martin Distel; Heathcliff Dorado-Garcia; Javier Garcia-Castro; Laura González-González; Agamemnon E Grigoriadis; Merve Kasan; Christian Koelsche; Manuela Krumbholz; Fernando Lecanda; Silvia Lemma; Dario L Longo; Claudia Madrigal-Esquivel; Álvaro Morales-Molina; Julian Musa; Shunya Ohmura; Benjamin Ory; Miguel Pereira-Silva; Francesca Perut; Rene Rodriguez; Carolin Seeling; Nada Al Shaaili; Shabnam Shaabani; Kristina Shiavone; Snehadri Sinha; Eleni M Tomazou; Marcel Trautmann; Maria Vela; Yvonne Mh Versleijen-Jonkers; Julia Visgauss; Marta Zalacain; Sebastian J Schober; Andrej Lissat; William R English; Nicola Baldini; Dominique Heymann Journal: EMBO Mol Med Date: 2020-10-13 Impact factor: 12.137