CFTR modulator plasma concentrations and correlation with mental and physical health adverse events
Investigating Cystic Fibrosis Transmembrane Conductance Regulator Modulator Concentrations and Adverse Events in Cystic Fibrosis
Abi Colwell
Primary Investigator
Emma Tillman
Primary Investigator
Brief description of study
The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI) has been life changing for many persons with CF (PwCF) by reducing CF exacerbations. Although ETI has shown benefit for many PwCF, adverse events (AEs) have been reported. The objective of this proposal is to, generate key preliminary data that can be used to design a prospective multicenter clinical trial that aims to define mechanisms driving AEs following CFTR restoration. The rationale for the proposed research is that ETI blood concentrations have high patient variability, yet we do not understand if drug concentrations correlate with AEs. To answer questions that are necessary to inform a large clinical trial, we will conduct the following specific aims: Examine the feasibility of evaluating ETI associated AEs based on a pharmacokinetic (PK) study of PwCF and; Determine if ETI-associated AEs are concentration dependent. We anticipate at the completion of this study will determine if ETI blood concentrations correlate with AEs and determine the value of proceeding with a large-scale trial.
Detailed description of study
This is an observational PK study designed to observe persons with CF at normal response to ETI medication and those currently experiencing an AE at the time of a 12-hour study visit. The study will enroll subjects 12 years and older for a total of 12 cases and 12 controls.
Study visits will be performed at the clinical research center (CRC). Study participants will be consented prior to the visit. For cases, participants must be currently experiencing an AE at the time of the study visit.
During the study visit, the following assessments will be done:
A pre-ETI trough concentration will be drawn prior to AM dose; the dose of ETI will be given with a standardized high-fat meal.
Blood sampling will be done before drug dose, 1 hr, 2 hr, 4 hr, 6 hr, and 12 hr post-dose.
A sweat chloride test will be performed.
Patients will also be genotyped for specific genes that may impact ETI metabolism. All demographic data, CFTR gene mutation, past medical history, renal function, liver function, serum albumin, pulmonary function tests, and medications will be collected from the most recent clinical data from the past year included in the electronic medical record.
A detailed medication history will be performed to collect any potential DDIs and participants will answer questionnaires to inquire about potential AEs including: the validated Patient Health Questionnaire 9-Item Scale (PHQ-9) to assess for depression,47 Generalized Anxiety Disorder-7 Item Scale (GAD-7) to assess anxiety,48 PROMIS-10 to measure quality of life,49 PROMIS cognitive function short form 8a.50 and questions from the Well-ME: Wellness in the modulator Era survey.51
Participants will also be asked to complete the modified Naranjo Scale (see Appendix),18 for any potential AE reported. Additional assessments of AEs will be added based on type of AE reported.
Eligibility of study
You may be eligible for this study if you meet the following criteria:
- Conditions: Cystic Fibrosis, CF, Riley
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Age: 12 years or above
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Gender: All
Inclusion Criteria
Participants ≥12 years old
Currently taking elexacaftor/tezacaftor/ivacaftor (ETI) or Vanacaftor/tezacaftor/deutivacaftor (VTD)
Tolerating (control) or with current AEs with ETI (case)
Participants could potentially participate in both the ETI and VTD study if the participant is first taking ETI with AEs and later changes to VTD and still has AEs or still tolerant
Exclusion Criteria
- Currently taking moderate or strong CYP3A inhibitors including the following: Aprepitant, Certinib, Ciprofloxacin, Clarithromycin, Crizotinib, Delaviridine, Diltazem, Erythromycin, Fluconazole, Grapefruit juice, Idelalisib, Imatnib, Indinavir, Itraconazole, Ketoconazole, Letermovir, Mibefradil, Nefazodone, Nelfinavir, Netupitant, Ribociclib, Ritonavir, Simeprevir, Telaprevir, Telithromycin, Tucatinib, Verapamil, Voriconazole
- Pharmacotherapy was changed within 6 weeks of enrollment
- Controls
- No questionable or possible AE’s from ETI
- Symptomatic neuropsychiatric illness that is not adequately treated (PHQ-9 score >10 or moderate depression; GAD-7 score >10 or moderate anxiety; or other moderate or severe neuropsychiatric illness) and unrelated to ETI therapy
- Cases
- Active pulmonary exacerbation by Fuchs criteria45 or physician diagnosis within the past two weeks, or who are deemed unfit for participation based on site PI’s or primary CF doctor’s discretion
This study investigates the relationship between CFTR modulator blood concentrations and adverse events in individuals with cystic fibrosis (CF). CFTR modulators are medications that help manage CF, a genetic disorder affecting the lungs and digestive system. The study focuses on understanding if different levels of these medications in the blood are linked to side effects, known as adverse events (AEs).
Participants will undergo a 12-hour observational study visit where various tests will be conducted. These include blood sampling at multiple intervals to measure drug concentrations, a sweat chloride test to assess CF impact, and genetic testing to understand drug metabolism. Participants will also complete questionnaires to evaluate mental health and quality of life, and provide detailed medication histories to identify potential drug interactions.
- Who can participate: Participants must be 12 years or older, currently taking CFTR modulators, and either tolerating the medication or experiencing adverse events. Those taking medications interacting with CFTR modulators are excluded.
- Study details: Participants will receive a standardized high-fat meal with their medication and have blood samples taken to measure drug levels. They will also complete mental health and quality of life questionnaires.
- Study visits: The study requires 1 visit.
