TY  - JOUR
A1  - Isberner, Nora
A1  - Gesierich, Anja
A1  - Balakirouchenane, David
A1  - Schilling, Bastian
A1  - Aghai-Trommeschlaeger, Fatemeh
A1  - Zimmermann, Sebastian
A1  - Kurlbaum, Max
A1  - Puszkiel, Alicja
A1  - Blanchet, Benoit
A1  - Klinker, Hartwig
A1  - Scherf-Clavel, Oliver
T1  - Monitoring of dabrafenib and trametinib in serum and self-sampled capillary blood in patients with BRAFV600-mutant melanoma
JF  - Cancers
N2  - 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 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.
KW  - dabrafenib
KW  - trametinib
KW  - hydroxy-dabrafenib
KW  - melanoma
KW  - BRAF mutation
KW  - volumetric absorptive micro-sampling (VAMS)
KW  - at-home sampling
KW  - drug monitoring
KW  - population pharmacokinetics
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288109
SN  - 2072-6694
VL  - 14
IS  - 19
ER  -