Therapeutic Drug Monitoring of Targeted Anticancer Protein Kinase Inhibitors in Routine Clinical Use: A Critical Review

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.

Sarcoma treatment in the era of molecular medicine

“…Biomarker‐guided basket trials, such as the CREATE trial, which evaluates multiple disease types with a common oncogenic driver matched to a specific targeted therapy, may be considered in this respect (Péron et al , 2019). Moreover, characterization of interpatient pharmacokinetic variability will be a valuable tool to predict and overcome the development of resistance (Cardoso et al , 2020).…”

Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors

“…Many of these agents are metabolized through the CYP3A4 pathway, which may vary between individuals and be affected by concurrent medications. As with any oral drug, absorption may potentially be affected by food or the use of antacids that affects gastric pH [ 133 , 134 , 135 ]. In addition, treatment of young children often requires oral solutions instead of capsules or tablets.…”

“…Some agents are not available in this formulation and for some medications such as pazopanib, there was a nearly three-fold difference in the MTD for the suspension compared to tablets [ 136 ]. Given these pharmacologic variabilities, as well as studies showing that 20% of adults receiving the recommended dose of pazopanib do not achieve therapeutic drug levels [ 137 ], some investigators have considered therapeutic drug monitoring [ 133 ]. This could prevent long periods of subtherapeutic dosing as well unnecessary overexposure, risk of toxicity and treatment cessation, which are associated with shortened PFS [ 138 ].…”

Optimizing Oral Targeted Anticancer Therapies Study for Patients With Solid Cancer: Protocol for a Randomized Controlled Medication Adherence Program Along With Systematic Collection and Modeling of Pharmacokinetic and Pharmacodynamic Data

“…The characterization of pharmacokinetic variability is essential in oncology, given the risk of under- or overexposure, which may contribute to insufficient efficacy or undesirable toxicity in patients with cancer, respectively. Moreover, considerable efforts remain to be undertaken to characterize the correlation between drug plasma concentrations and the therapeutic response of most PKIs and to define the therapeutic targets associated with clinical benefits in the context of therapeutic drug monitoring [ 19 ].…”