Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary Blood in Patients with BRAFV600-Mutant Melanoma

Abstract

Patients treated with dabrafenib and trametinib for BRAFV600-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.

Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules

“…Many bioactive compounds, including the small molecules in this study, are lipophilic ( Table 1 ), and continued association with host cell plasma membranes or modification upon entry into the RBC to effectuate sequestration may facilitate antiparasitic potency during infection. Interestingly, in melanoma patients trametinib was observed to accumulate onto RBCs ( Isberner et al., 2022 ); given our findings that an effect of the drug on the RBC does not persist beyond transient exposure, association of trametinib with the host cell is likely dynamic. We note that in our measurements across a broad panel of compounds, we observed minimal PS exposure for both FTY720 and Sorafenib ( Supplementary Table 2 ), each of which have otherwise been reported in individual studies to stimulate the signal on erythrocytes ( Eberhard et al., 2010 ; Lupescu et al., 2012 ).…”