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

• Published in: Annals of oncology Vol. 33; no. 10; pp. 1071 - 1082
• Main Authors: Groenland, S.L., van Eerden, R.A.G., Westerdijk, K., Meertens, M., Koolen, S.L.W., Moes, D.J.A.R., de Vries, N., Rosing, H., Otten, H., Vulink, A.J.E., Desar, I.M.E., Imholz, A.L.T., Gelderblom, H., van Erp, N.P., Beijnen, J.H., Mathijssen, R.H.J., Huitema, A.D.R., Steeghs, N.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-10-2022
• Subjects: dose optimization; kinase inhibitors; oncology; personalized medicine; targeted therapies; therapeutic drug monitoring; kinase inhibitors; targeted therapies; dose optimization; therapeutic drug monitoring; oncology; personalized medicine
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1016/j.annonc.2022.06.010

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 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).
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%).
Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.
•Half of the patients treated with oral targeted therapies are underexposed at a certain time point during treatment.•In the majority of the underexposed patients a dose adjustment could be carried out.•PK-guided dose adjustments were successful in the majority of patients without inducing additional toxicity.•PK-guided dose optimization of oral targeted therapies reduces the proportion of underexposed patients considerably.