Population Pharmacokinetics of Trametinib and Impact of Nonadherence on Drug Exposure in Oncology Patients as Part of the Optimizing Oral Targeted Anticancer Therapies Study
Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims t...
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| Published in: | Cancers Vol. 16; no. 12; p. 2193 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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11-06-2024
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| Abstract | Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients' drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient's journey to address patients' needs regarding trametinib and support medication adherence. |
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| AbstractList | Poor adherence to trametinib, an oral anticancer drug, may be the consequence of side effects that severely impact the patient’s quality of life. The significant interindividual variability associated with poor adherence results in suboptimal drug exposure and consequently in unfavourable patient outcomes. By characterizing the pharmacokinetics of trametinib, this study aims to assess (i) the adequacy of recommended doses to achieve efficacy thresholds and (ii) the impact of non-adherence on drug exposure. The latter was assessed by simulating different scenarios of missing one or more doses per week to highlight the risk of treatment failure associated with poor adherence. These results promote interprofessional collaboration and patient partnership to address patients’ needs in order to ensure adherence to trametinib and in fine therapeutic success. Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients’ drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient’s journey to address patients’ needs regarding trametinib and support medication adherence. Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients' drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient's journey to address patients' needs regarding trametinib and support medication adherence. Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients' drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient's journey to address patients' needs regarding trametinib and support medication adherence.Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients' drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient's journey to address patients' needs regarding trametinib and support medication adherence. Simple SummaryPoor adherence to trametinib, an oral anticancer drug, may be the consequence of side effects that severely impact the patient’s quality of life. The significant interindividual variability associated with poor adherence results in suboptimal drug exposure and consequently in unfavourable patient outcomes. By characterizing the pharmacokinetics of trametinib, this study aims to assess (i) the adequacy of recommended doses to achieve efficacy thresholds and (ii) the impact of non-adherence on drug exposure. The latter was assessed by simulating different scenarios of missing one or more doses per week to highlight the risk of treatment failure associated with poor adherence. These results promote interprofessional collaboration and patient partnership to address patients’ needs in order to ensure adherence to trametinib and in fine therapeutic success.AbstractTrametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability increases the risk of suboptimal exposure, which can lead to treatment failure or increased toxicity. Using model-based simulation, this study aims to characterize and investigate the pharmacokinetics and the adequacy of the currently recommended doses of trametinib. Additionally, the simulation of various suboptimal adherence scenarios allowed for an assessment of the impact of patients’ drug adherence on the treatment outcome. The population data collected in 33 adult patients, providing 113 plasmatic trametinib concentrations, were best described by a two-compartment model with linear absorption and elimination. The study also identified a significant positive effect of fat-free mass and a negative effect of age on clearance, explaining 66% and 21% of the initial associated variability, respectively. Simulations showed that a maximum dose of 2 mg daily achieved the therapeutic target in 36% of male patients compared to 72% of female patients. A dose of 1.5 mg per day in patients over 65 years of age achieved similar rates, with 44% and 79% for male and female patients, respectively, reaching the therapeutic target. Poor adherence leads to a significant drop in concentrations and a high risk of subtherapeutic drug levels. These results underline the importance of interprofessional collaboration and patient partnership along the patient’s journey to address patients’ needs regarding trametinib and support medication adherence. Poor adherence to trametinib, an oral anticancer drug, may be the consequence of side effects that severely impact the patient’s quality of life. The significant interindividual variability associated with poor adherence results in suboptimal drug exposure and consequently in unfavourable patient outcomes. By characterizing the pharmacokinetics of trametinib, this study aims to assess (i) the adequacy of recommended doses to achieve efficacy thresholds and (ii) the impact of non-adherence on drug exposure. The latter was assessed by simulating different scenarios of missing one or more doses per week to highlight the risk of treatment failure associated with poor adherence. These results promote interprofessional collaboration and patient partnership to address patients’ needs in order to ensure adherence to trametinib and in fine therapeutic success. |
| Audience | Academic |
| Author | Ravix, Anne Csajka, Chantal Bandiera, Carole Cardoso, Evelina Wagner, Anna Dorothea Chtioui, Haithem Decosterd, Laurent Arthur Lata-Pedreira, Adrian Schneider, Marie Paule Guidi, Monia |
| AuthorAffiliation | 3 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland 5 Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland 4 Centre for Primary Care and Public Health (Unisanté), University of Lausanne, 1011 Lausanne, Switzerland 7 Department of Oncology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland 6 Laboratory of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland 1 Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland 2 Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland marie.schneider@unige.ch (M.P.S.) |
| AuthorAffiliation_xml | – name: 5 Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland – name: 7 Department of Oncology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland – name: 2 Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland marie.schneider@unige.ch (M.P.S.) – name: 6 Laboratory of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland – name: 3 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland – name: 1 Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland – name: 4 Centre for Primary Care and Public Health (Unisanté), University of Lausanne, 1011 Lausanne, Switzerland |
| Author_xml | – sequence: 1 givenname: Anne surname: Ravix fullname: Ravix, Anne organization: Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland – sequence: 2 givenname: Carole orcidid: 0000-0002-9996-3100 surname: Bandiera fullname: Bandiera, Carole organization: Centre for Primary Care and Public Health (Unisanté), University of Lausanne, 1011 Lausanne, Switzerland – sequence: 3 givenname: Evelina orcidid: 0000-0001-7446-4594 surname: Cardoso fullname: Cardoso, Evelina organization: Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland – sequence: 4 givenname: Adrian surname: Lata-Pedreira fullname: Lata-Pedreira, Adrian organization: Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1211 Geneva, Switzerland – sequence: 5 givenname: Haithem surname: Chtioui fullname: Chtioui, Haithem organization: Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland – sequence: 6 givenname: Laurent Arthur surname: Decosterd fullname: Decosterd, Laurent Arthur organization: Laboratory of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland – sequence: 7 givenname: Anna Dorothea orcidid: 0000-0003-4728-7013 surname: Wagner fullname: Wagner, Anna Dorothea organization: Department of Oncology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland – sequence: 8 givenname: Marie Paule orcidid: 0000-0002-7557-9278 surname: Schneider fullname: Schneider, Marie Paule organization: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland – sequence: 9 givenname: Chantal orcidid: 0000-0002-0660-082X surname: Csajka fullname: Csajka, Chantal organization: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211 Geneva, Switzerland – sequence: 10 givenname: Monia orcidid: 0000-0002-6419-9317 surname: Guidi fullname: Guidi, Monia organization: Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38927898$$D View this record in MEDLINE/PubMed |
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| Keywords | trametinib medication adherence oral anticancer therapy population pharmacokinetics simulations |
| Language | English |
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| Snippet | Trametinib is a targeted therapy used for the treatment of solid tumours, with significant variability reported in real-life studies. This variability... Poor adherence to trametinib, an oral anticancer drug, may be the consequence of side effects that severely impact the patient’s quality of life. The... Simple SummaryPoor adherence to trametinib, an oral anticancer drug, may be the consequence of side effects that severely impact the patient’s quality of life.... |
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| SubjectTerms | Antineoplastic drugs Body mass index Cancer therapies Cell growth Chemotherapy Drug dosages Fat-free body mass Health aspects Hospitals Kinases Melanoma Patient compliance Pharmacokinetics Population studies Proteins Quality of life Simulation methods Solid tumors Therapeutic targets Toxicity Women |
| Title | Population Pharmacokinetics of Trametinib and Impact of Nonadherence on Drug Exposure in Oncology Patients as Part of the Optimizing Oral Targeted Anticancer Therapies Study |
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