Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma

Abstract

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng·h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC OHD /AUC DAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56); p = 0.023 and 10.61 (2.34-48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50); p = 0.032 and HR = 1.23 (1.35-10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUC OHD /AUC DAB deserves more investigation in a larger cohort of MM patients.

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

“…Relevant interindividual variability in drug exposure has particularly been described for dabrafenib [ 9 , 10 , 11 ], which undergoes metabolism via the cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 to form the active metabolites hydroxy-, carboxy-, and desmethyl-dabrafenib. Only hydroxy-dabrafenib has been considered relevant for the pharmacodynamic activity of dabrafenib [ 2 , 12 , 13 ]. Genetic polymorphisms and co-medication with inhibiting or inducing drugs are well-described causes of altered CYP expression [ 14 ].…”

“…Genetic polymorphisms and co-medication with inhibiting or inducing drugs are well-described causes of altered CYP expression [ 14 ]. Lower pharmacokinetic (PK) variability has been observed for trametinib as metabolism is mediated by hydrolytic enzymes less prone to interindividual variability [ 3 , 9 , 10 , 12 , 15 ]. Both compounds are substrates of the multidrug transporter P-glycoprotein (P-gp) [ 2 , 3 , 16 , 17 ].…”

“…Present knowledge of the associations of age, sex, and weight with exposure remains contradictory [ 5 , 12 , 15 , 18 , 19 ]. Likewise, investigations on exposure–efficacy relationships have revealed inconsistent results regarding the associations between progression-free survival, duration of response, and overall survival and dabrafenib or trametinib exposure [ 9 , 10 , 12 , 15 , 19 , 20 , 21 , 22 ]. The same holds true for evidence on the associations of exposure with toxicity.…”

“…The same holds true for evidence on the associations of exposure with toxicity. While some studies suggest that AE occur more frequently in patients with elevated dabrafenib [ 9 , 12 , 23 ] or trametinib [ 10 ] exposure, an exposure–toxicity relationship could not be confirmed by other investigations [ 9 , 10 , 12 , 19 , 24 ].…”

Targeted Therapies for Melanoma

“…To adjust the therapeutic protocols and to improve the efficacy of anti-melanoma therapy, pharmacokinetic measurements of the therapeutics are desirable. This approach highlights the importance of individualised pharmacokinetic monitoring [ 9 ]. To monitor the efficiency of MAPK inhibitors, TERT (telomerase reverse transcriptase) promoter region mutations can be used as a biomarker.…”