Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic–pharmacodynamic real-life study

Goldwirt, Lauriane; Louveau, Baptiste; Baroudjian, Barouyr; Allayous, Clara; Jouenne, Fanélie; Meda, Laetitia Da; Vu, L.-T.; Sauvageon, Hélène; Herms, F.; Delyon, Julie; Lebbe, Célèste

doi:10.1007/s00280-021-04299-x

Cited by 6 publications

(15 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dabrafenib and trametinib are administered at a standard fixed dose despite high interindividual pharmacokinetic variability and existing evidence for the benefits of therapeutic drug monitoring (TDM) and precision dosing of oral targeted cancer therapies [ 6 , 7 , 8 ]. 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 ].…”

Section: Introductionmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, some investigations used observed trough concentrations (C min ) to analyze the effects of covariates and exposure-toxicity relationships [ 9 , 19 , 23 ]. In contrast, others used the population pharmacokinetic (popPK) model to predict the area under the curve (AUC) or both [ 10 , 12 , 24 ]. A previously published popPK model for dabrafenib has shown that C min is not dose-related [ 18 ], suggesting that AUC may be the more precise parameter to investigate exposure.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Isberner

Gesierich

Balakirouchenane

et al. 2022

Cancers

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Isberner

Gesierich

Balakirouchenane

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

van der Kleij,

Guchelaar,

Mathijssen

et al. 2023

Clin Pharmacokinet

View full text Add to dashboard Cite

Although kinase inhibitors (KI) frequently portray large interpatient variability, a ‘one size fits all’ regimen is still often used. In the meantime, relationships between exposure-response and exposure-toxicity have been established for several KIs, so this regimen could lead to unnecessary toxicity and suboptimal efficacy. Dose adjustments based on measured systemic pharmacokinetic levels—i.e., therapeutic drug monitoring (TDM)—could therefore improve treatment efficacy and reduce the incidence of toxicities. Therefore, the aim of this comprehensive review is to give an overview of the available evidence for TDM for the 77 FDA/EMA kinase inhibitors currently approved (as of July 1st, 2023) used in hematology and oncology. We elaborate on exposure-response and exposure-toxicity relationships for these kinase inhibitors and provide practical recommendations for TDM and discuss corresponding pharmacokinetic targets when possible.

show abstract

Development and validation of an LC–MS/MS method to measure the BRAF inhibitors dabrafenib and encorafenib quantitatively and four major metabolites semi-quantitatively in human plasma

Myszkiewicz,

Puzanov,

Goey

2023

Journal of Pharmaceutical and Biomedical Analysis

View full text Add to dashboard Cite

Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic–pharmacodynamic real-life study

Cited by 6 publications

References 24 publications

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

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

Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Development and validation of an LC–MS/MS method to measure the BRAF inhibitors dabrafenib and encorafenib quantitatively and four major metabolites semi-quantitatively in human plasma

Contact Info

Product

Resources

About