Therapeutic drug monitoring-based precision dosing of oral targeted therapies in oncology: a prospective multicenter study

S. L. Groenland*, R. A.G. van Eerden, Dutch Pharmacology Oncology Group (DPOG), K. Westerdijk, M. Meertens, S. L.W. Koolen, D. J.A.R. Moes, N. de Vries, H. Rosing, H. Otten, A. J.E. Vulink, I. M.E. Desar, A. L.T. Imholz, H. Gelderblom, N. P. van Erp, J. H. Beijnen, R. H.J. Mathijssen, A. D.R. Huitema, N. Steeghs

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Background: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems. Patients and methods: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug–drug interactions, concomitant intake with food, splitting intake moments or dose increments). Results: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%). Conclusions: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.

Original languageEnglish
Pages (from-to)1071-1082
Number of pages12
JournalAnnals of Oncology
Volume33
Issue number10
DOIs
Publication statusPublished - 1 Oct 2022

Bibliographical note

Funding Information:
This work was supported by unrestricted research grants from Ipsen; Merck; Novartis; Pfizer; and Roche (no grant number). They had no involvement in any other aspect of this study. IMED reported funding for investigator-initiated research by Novartis. NPvE reported funding for investigator-initiated research by Janssen-Cilag, and Astellas, and a speaker fee by Bayer (outside the submitted work). RHJM reported funding for investigator-initiated research by Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi and Servier (outside the submitted work). NS reported consultation or attendance of advisory boards for AIMM Therapeutics, Boehringer-Ingelheim and Ellipses Pharma; research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, Lilly, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho and Takeda (outside the submitted work). All other authors have declared no conflicts of interest. All authors confirm that they had full access to all data in the study and accept responsibility to submit for publication. Data from this study can be made available to other researchers in the field upon request and approval by the Dutch Pharmacology Oncology Group and subject to appropriate data transfer agreements. Requests should be directed to SLG and NS.

Funding Information:
This work was supported by unrestricted research grants from Ipsen; Merck; Novartis; Pfizer; and Roche (no grant number). They had no involvement in any other aspect of this study.

Publisher Copyright:
© 2022

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