Relationship between vemurafenib plasma concentrations and survival outcomes in patients with advanced melanoma

Kichenadasse, Ganessan; Hughes, Jim H.; Miners, John O.; Mangoni, Arduino A.; Rowland, Andrew; Hopkins, Ashley M.; Sorich, Michael J.

doi:10.1007/s00280-019-04002-1

Cited by 10 publications

(7 citation statements)

References 10 publications

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“…For other agents, i.e. alectinib [49], axitinib, crizotinib [49], trametinib [50] and vemurafenib [51][52][53][54], a PK target associated with either efficacy or toxicity has been established, but not yet evaluated in prospective clinical studies [13]. Lastly, no information about the value of TDM is available for some compounds.…”

Section: Therapeutic Drug Monitoring For Oral Targeted Antineoplasticmentioning

confidence: 99%

Therapeutic drug monitoring of oral targeted antineoplastic drugs

Mueller‐Schoell

Groenland

Oliver

et al. 2020

Eur J Clin Pharmacol

151

153

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Purpose This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.

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Section: Therapeutic Drug Monitoring For Oral Targeted Antineoplasticmentioning

confidence: 99%

Therapeutic drug monitoring of oral targeted antineoplastic drugs

Mueller‐Schoell

Groenland

Oliver

et al. 2020

Eur J Clin Pharmacol

151

153

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“…However, patients in "real-life" cohorts exhibit a large interindividual variability (IIV) in clinical outcomes, such as toxicity [5] and efficacy [6], which can result in dose-limiting toxicities (DLT) or early disease progression. As previously reported with vemurafenib (BRAF inhibitor), variability in drug pharmacokinetics can contribute to early progression in BRAF-mutated MM patients [7][8][9][10]. To date, no study has shown an exposure-response relationship for efficacy of DAB.…”

Section: Introductionmentioning

confidence: 93%

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

Balakirouchenane

Guégan

Csajka

et al. 2020

Cancers

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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.

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“…Strong evidence exists for imatinib in chronic myelogenous leukemia [30,31]. For alectinib [32], axitinib, crizotinib [32], trametinib [26], and vemurafenib [33][34][35][36], a PK target associated with either efficacy or toxicity has been established but has not been evaluated in clinical studies yet [37]. However, for most kinase inhibitors, no information about the potential benefit of TDM is available, as exposureresponse relationships and consequently PK targets have not been established.…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma

et al. 2020

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A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib, cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for the application in daily clinical routine has been developed and validated according to the US Food and Drug Administration and European Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples with acetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5 μm (2.1 × 50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A and methanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400 μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stable isotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min per run. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mL for afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6–1500 ng/mL for cabozantinib, dabrafenib, nilotinib, and osimertinib (coefficients of correlation ≥ 0.99). Validation assays for accuracy and precision, matrix effect, recovery, carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughput and was successfully applied to monitor concentrations of kinase inhibitors in patients.

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Relationship between vemurafenib plasma concentrations and survival outcomes in patients with advanced melanoma

Cited by 10 publications

References 10 publications

Therapeutic drug monitoring of oral targeted antineoplastic drugs

Therapeutic drug monitoring of oral targeted antineoplastic drugs

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

Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma

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