Monitoring of dabrafenib and trametinib in serum and self-sampled capillary blood in patients with BRAFV600-mutant melanoma

Please always quote using this URN: urn:nbn:de:bvb:20-opus-288109
  • Simple Summary In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary bloodSimple Summary In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary blood concentrations to serum concentrations was developed. (Hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or AE. Co-medication with P-glycoprotein inducers was associated with lower trough concentrations of trametinib but not (hydroxy-)dabrafenib. The applicability of the self-sampling of capillary blood was demonstrated. Our conversion model was adequate for estimating serum exposure from micro-samples. The monitoring of dabrafenib and trametinib may be useful for dose modification and can be optimized by at-home sampling and our new conversion model. Abstract Patients treated with dabrafenib and trametinib for BRAF\(^{V600}\)-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.show moreshow less

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Metadaten
Author: Nora Isberner, Anja Gesierich, David Balakirouchenane, Bastian Schilling, Fatemeh Aghai-Trommeschlaeger, Sebastian Zimmermann, Max Kurlbaum, Alicja Puszkiel, Benoit Blanchet, Hartwig Klinker, Oliver Scherf-Clavel
URN:urn:nbn:de:bvb:20-opus-288109
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
Medizinische Fakultät / Medizinische Klinik und Poliklinik I
Medizinische Fakultät / Medizinische Klinik und Poliklinik II
Fakultät für Chemie und Pharmazie / Institut für Pharmazie und Lebensmittelchemie
Language:English
Parent Title (English):Cancers
ISSN:2072-6694
Year of Completion:2022
Volume:14
Issue:19
Article Number:4566
Source:Cancers (2022) 14:19, 4566. doi:10.3390/cancers14194566
DOI:https://doi.org/10.3390/cancers14194566
Sonstige beteiligte Institutionen:Zentraleinheit Klinische Massenspektrometrie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:BRAF mutation; at-home sampling; dabrafenib; drug monitoring; hydroxy-dabrafenib; melanoma; population pharmacokinetics; trametinib; volumetric absorptive micro-sampling (VAMS)
Release Date:2023/04/21
Date of first Publication:2022/09/20
Open-Access-Publikationsfonds / Förderzeitraum 2022
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International