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5. Sunitinib for the treatment of metastatic gastrointestinal stromal tumors: the effect of TDM-guided dose optimization on clinical outcomes

Author

Giraud, E.L., Westerdijk, K., van der Kleij, M.B.A., Guchelaar, N.A.D., Meertens, M., Bleckman, R.F., Rieborn, A., Mohammadi, M., Roets, E., Mathijssen, R.H.J., Huitema, A.D.R., Koolen, S.L.W., Gelderblom, H., Moes, D.J.A.R., Reyners, A.K.L., Touw, D.J., Keizer-Heldens, P., Oosten, A.W., van der Graaf, W.T.A., Steeghs, N., van Erp, N.P., and Desar, I.M.E.

Published
2024
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18. The use of microtracers in food‐effect trials: An alternative study design for toxic drugs with long half‐lives exemplified by the case for alectinib.

Author

van der Heijden, L. T., Steeghs, N., Beijnen, J. H., Huitema, A. D. R., and Dorlo, T. P. C.

Subjects
*DRUG design, *EXPERIMENTAL design, *ANTINEOPLASTIC agents, *CONFIDENCE intervals, *BLOOD sampling
Abstract

The traditional design of food‐effect studies has a high patient burden for toxic drugs with long half‐lives (e.g., anticancer agents). Microtracers could be used to assess food‐effect in patients without influencing their ongoing treatment. The feasibility of a microtracer food‐effect study during steady‐state of the therapeutic drug was investigated in an in silico simulation study with alectinib as an example for a relative toxic drug with a long half‐life. Microtracer pharmacokinetics were simulated based on a previously published population pharmacokinetic model and used for estimation of a model with and a model without food as a covariate on oral bioavailability of alectinib (assuming a 40% food‐effect). Power was defined as the fraction of clinical trials where a significant (p < 0.01) food‐effect was identified. The proposed study design of 10 patients on steady‐state treatment, 10 blood samples collected within 24 h after administration and an assumed food‐effect of 40% had a power of 99.9%. The mean estimated food‐effect was 39.8% (80% confidence interval: 31.0%–48.6%). The feasibility of microtracer food‐effect studies was demonstrated. The design of the microtracer food‐effect study allowed estimation of the food‐effect with minimal influence on therapeutic treatment and reducing patient burden compared to the traditional study design for toxic drugs with long half‐lives. [ABSTRACT FROM AUTHOR]

Published
2023
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24. Exposure–Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting

Author

Boosman, R.J., Jebbink, M., Veldhuis, W.B., Groenland, S.L., Veggel, B.A.M.H. van, Moeskops, P., Langen, A.J. de, Beijnen, J.H., Smit, E.F., Huitema, A.D.R., Steeghs, N., CCA - Cancer Treatment and quality of life, and CCA - Cancer biology and immunology

Subjects
Pharmacology, osimertinib, Organic Chemistry, Pharmaceutical Science, Molecular Medicine, Pharmacology (medical), pharmacokinetics-pharmacodynamics, NSCLC, Biotechnology, exposure-response analysis
Abstract

Background: Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure–response relationships of osimertinib in a real-life setting. Methods: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C min,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship. Results: A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 – 19.1) months and 9.3 (95% CI: 7.2 – 11.1) months for patients with C min,pred < 166 µg/L and C min,pred ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a C min,pred < 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 – 2.01; p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 – 7.08; p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91). Conclusion: In our real-life cohort, no exposure–response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.

Published
2022

40. Exposure-response analyses of abiraterone and its metabolites in real-world patients with metastatic castration-resistant prostate cancer

Author

van Nuland, M, Groenland, S L, Bergman, A M, Steeghs, N, Rosing, H, Venekamp, N, Huitema, A D R, Beijnen, J H, Afd Pharmacoepi & Clinical Pharmacology, and Pharmacoepidemiology and Clinical Pharmacology

Abstract

BACKGROUND: Abiraterone acetate is an oral 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCPRC) patients. Previously, a prospective observational trial demonstrated a relationship between abiraterone trough concentrations (Cmin) in plasma and treatment efficacy. The aim of our study was to investigate the exposure-response relationship of abiraterone and its metabolites, and to study if the proposed target for abiraterone of 8.4 ng/mL is feasible in a "real-world" patient cohort. PATIENTS AND METHODS: mCRPC patients who had at least one abiraterone plasma concentration at steady-state were included in this study. Plasma abiraterone and its metabolites levels were analyzed using a validated liquid chromatography-mass spectrometry method. Using calculated Cmin values of abiraterone and its active metabolite Δ(4)-abiraterone (D4A), univariate, and multivariable Cox regression analyses were performed. RESULTS: Sixty-two patients were included in this retrospective analysis, of which 42% were underexposed (mean abiraterone Cmin ≤ 8.4 ng/mL). In multivariable analysis, Cmin ≥ 8.4 ng/mL was associated with longer prostate-specific antigen (PSA) independent progression-free survival (16.9 vs 6.1 months; p = 0.033), which resulted in a hazard ratio of 0.44 (95% confidence interval: 0.23-0.82, p = 0.01). D4A Cmin did not show a relationship with treatment efficacy. CONCLUSION: Our study shows that mCRPC patients with an abiraterone Cmin ≥ 8.4 ng/mL have a better prognosis compared with patients with low Cmin. Monitoring Cmin of abiraterone can help to identify those patients at risk of suboptimal treatment for whom treatment optimization may be appropriate.

Published
2020

41. Therapeutic drug monitoring of oral anticancer drugs - preliminary results of a prospective study

Author

Groenland, S. L., Van Eerden, R. A. G., Koolen, S. L., Moes, D. J. A. R., Desar, I. M. E., Touw, D. J., Imholz, A. L. T., Reyners, A. K. L., Gelderblom, H., van Erp, N. P., Mathijssen, R. H. J., Huitema, A. D. R., Steeghs, N., Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Research Institute for Asthma and COPD (GRIAC), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Pharmaceutical Analysis, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Targeted Gynaecologic Oncology (TARGON), and Medicinal Chemistry and Bioanalysis (MCB)

Published
2019

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