Safety of elexacaftor/tezacaftor/ivacaftor dose reduction: Mechanistic exploration through physiologically based pharmacokinetic modeling and a clinical case series.

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) treatment is associated with significant improvement in lung function in people with cystic fibrosis (pwCF); however, some patients experience adverse effects (AEs) including hepatotoxicity. One potential strategy is dose reduction in ETI with the goal of maintaining therapeutic efficacy while resolving AEs. We report our experience of dose reduction in individuals who experienced AEs following ETI therapy. We provide mechanistic support for ETI dose reduction by exploring predicted lung exposures and underlying pharmacokinetics-pharmacodynamics (PK-PD) relationships. METHOD: Adults prescribed ETI who underwent dose reduction due to the AEs were included in this case series, and their percent predicted forced expiratory volume in 1 s (ppFEV1 ) and self-reported respiratory symptoms were collected. The full physiologically based pharmacokinetic (PBPK) models of ETI were developed incorporating physiological information and drug-dependent parameters. The models were validated against available pharmacokinetic and dose-response relationship data. The models were then used to predict lung concentrations of ETI at steady-state. RESULTS: Fifteen patients underwent dose reduction in ETI due to AEs. Clinical stability without significant changes in ppFEV1 after dose reduction was observed in all patients. Resolution or improvement of AEs occurred in 13 of the 15 cases. The model-predicted lung concentrations of reduced dose ETI exceeded the reported half maximal effective concentration (EC50 ) from measurement of in vitro chloride transport, providing a hypothesis as to why therapeutic efficacy was maintained. CONCLUSION: Albeit in a small number of patients, this study provides evidence that reduced ETI doses in pwCF who have experienced AEs may be effective. The PBPK models enable exploration of a mechanistic basis for this finding by simulating target tissue concentrations of ETI that can be compared with drug efficacy in vitro.

Patient Values and Preferences Regarding Opioids for Chronic Noncancer Pain: A Systematic Review.

Objective: Shared-care decision-making between patients and clinicians involves making trade-offs between desirable and undesirable consequences of management strategies. Although patient values and preferences should provide the basis for these trade-offs, few guidelines consider the relevant evidence when formulating recommendations. To inform a guideline for use of opioids in patients with chronic noncancer pain, we conducted a systematic review of studies exploring values and preferences of affected patients toward opioid therapy. Methods: We searched MEDLINE, CINAHL, EMBASE, and PsycINFO from the inception of each database through October 2016. We included studies examining patient preferences for alternative approaches to managing chronic noncancer pain and studies that assessed how opioid-using chronic noncancer pain patients value alternative health states and their experiences with treatment. We compiled structured summaries of the results. Results: Pain relief and nausea and vomiting were ranked as highly significant outcomes across studies. When considered, the adverse effect of personality changes was rated as equally important. Constipation was assessed in most studies and was an important outcome, secondary to pain relief and nausea and vomiting. Of only two studies that evaluated addiction, both found it less important to patients than pain relief. No studies examined opioid overdose, death, or diversion. Conclusion: Our findings suggest that the adverse effects of opioids, especially nausea and vomiting, may reduce or eliminate any net benefit of opioid therapy unless pain relief is significant (>2 points on a 10-point scale). Further research should investigate patient values and preferences regarding opioid overdose, diversion, and death.