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 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.

Keywords: BRAF mutation; at-home sampling; dabrafenib; drug monitoring; hydroxy-dabrafenib; melanoma; population pharmacokinetics; trametinib; volumetric absorptive micro-sampling (VAMS).

Figure 1

Development of the population pharmacokinetic (popPK) model-informed VAMS-to-serum conversion model. PopPK models by Balakirouchenane et al. [12] were used to generate serum maximum a posteriori (MAP) estimates from volumetric absorptive micro-sampling (VAMS) for dabrafenib (A) and trametinib (B). AUC, area under the curve; BLOOD, whole blood compartment; C_blood, concentration in whole blood; C_plasma, concentration in plasma; CENT, central compartment; CL/F, oral clearance from central compartment; Hct, hematocrit; IIV, inter-individual variability; IOV, inter-occasion variability; k_a, absorption rate constant; K_bp, partition ratio between blood cells and plasma; PER, peripheral compartment; Q/F, intercompartmental clearance; Tlag, lag time before beginning of absorption process.

Figure 2

Observed hydroxy−dabrafenib (A) and dabrafenib (B) serum concentrations. Concentrations are presented as mean concentration per patient at steady state stratified by sampling time interval. Patients may have contributed samples at multiple time intervals.

Figure 2

Observed hydroxy−dabrafenib (A) and dabrafenib (B) serum concentrations. Concentrations are presented as mean concentration per patient at steady state stratified by sampling time interval. Patients may have contributed samples at multiple time intervals.

Figure 3

Observed trametinib serum concentrations. Concentrations are presented as mean concentration per patient in steady state stratified by sampling time interval. Patients may have contributed samples at multiple time intervals.

Figure 4

Visual predictive check of at-home sampled VAMS concentrations. (A): dabrafenib VAMS concentrations (90 samples, eight patients). (B): trametinib VAMS concentrations (84 samples, seven patients). Solid lines represent the 5th (lower blue), 50th (red), and 95th (upper blue) percentiles of the observed data. Shaded regions represent the 90% confidence intervals surrounding the 5th, 50th, and 95th percentiles from the predicted data. The plot demonstrates that the model predictions captured the majority of observed dabrafenib and trametinib concentrations within the 5th and 95th percentiles of the simulated values.

Figure 4

Visual predictive check of at-home sampled VAMS concentrations. (A): dabrafenib VAMS concentrations (90 samples, eight patients). (B): trametinib VAMS concentrations (84 samples, seven patients). Solid lines represent the 5th (lower blue), 50th (red), and 95th (upper blue) percentiles of the observed data. Shaded regions represent the 90% confidence intervals surrounding the 5th, 50th, and 95th percentiles from the predicted data. The plot demonstrates that the model predictions captured the majority of observed dabrafenib and trametinib concentrations within the 5th and 95th percentiles of the simulated values.