Abstract
Pharmacometric methods have hugely benefited from progress in analytical and computer sciences during the past decades, and play nowadays a central role in the clinical development of new medicinal drugs. It is time that these methods translate into patient care through therapeutic drug monitoring (TDM), due to become a mainstay of precision medicine no less than genomic approaches to control variability in drug response and improve the efficacy and safety of treatments. In this review, we make the case for structuring TDM development along five generic questions: 1) Is the concerned drug a candidate to TDM? 2) What is the normal range for the drug's concentration? 3) What is the therapeutic target for the drug's concentration? 4) How to adjust the dosage of the drug to drive concentrations close to target? 5) Does evidence support the usefulness of TDM for this drug? We exemplify this approach through an overview of our development of the TDM of imatinib, the very first targeted anticancer agent. We express our position that a similar story shall apply to other drugs in this class, as well as to a wide range of treatments critical for the control of various life-threatening conditions. Despite hurdles that still jeopardize progress in TDM, there is no doubt that upcoming technological advances will shape and foster many innovative therapeutic monitoring methods.
Highlights
The methodology of clinical drug development has evolved impressively during the past few decades
Pharmacometric methods can be traced back to the late sixties and owes much to the seminal contributions of Lewis Sheiner at the University of California San Francisco (Holford and Sheiner, 1982). His efforts started with the aim of improving patient care through therapeutic drug monitoring (TDM) (Sheiner et al, 1975), i.e., the measurement of circulating concentrations of a drug to adjust its dosing regimen, so as to reach a defined target exposure associated with optimal efficacy and minimal toxicity (Clarke, 2016)
As soon as the method is applied to clinical samples, the first question coming when facing a TDM result is about the expectedness of the blood levels measured: “Is this concentration normal under the dosing regimen received by this patient with such individual characteristics?” An answer to this question can typically be brought based on results from observational population PK studies
Summary
The methodology of clinical drug development has evolved impressively during the past few decades. The Steps to TDM pharmacometric methods can be traced back to the late sixties and owes much to the seminal contributions of Lewis Sheiner at the University of California San Francisco (Holford and Sheiner, 1982) His efforts started with the aim of improving patient care through therapeutic drug monitoring (TDM) (Sheiner et al, 1975), i.e., the measurement of circulating concentrations of a drug to adjust its dosing regimen, so as to reach a defined target exposure associated with optimal efficacy and minimal toxicity (Clarke, 2016). Recommendations for TDM have been expressed about hundreds of therapeutic agents, e.g. anticancer drugs (Widmer et al, 2014), biologics (Imamura, 2019), antiretrovirals (Punyawudho et al, 2016), antiinfectives (Muller et al, 2018), psychotropic agents (Schoretsanitis et al, 2018) etc If such measurements are to become largely available in routine medical practice, traditional empiricism will not suffice anymore to support the clinical interpretation of drug concentration results by practitioners. We discuss the hurdles and the hopes that prevail today in this area
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