Main Research Findings

Lumacaftor/ivacaftor (LUM/IVA) combination therapy is a promising treatment for cystic fibrosis (CF) patients that can improve lung function. However, safety data for LUM/IVA combination therapy in patients with severe lung disease (percent predicted forced expiratory volume in 1s [ppFEV₁] <40) remain limited. 3 . Respiratory-related adverse events were frequently observed after LUM/IVA administration in these patients. 3 . Some patients experienced a decline in ppFEV₁ from baseline at 2 hours (median [IQR] relative change: -19 [-21 to -11]%, p<0.001) that persisted at 24 hours but recovered in most patients at 1 month. 3 . Additionally, some patients reported non-severe respiratory-related adverse events within 24 hours of LUM/IVA initiation. 3 . These side effects recovered in most patients by 1 month. 3 . Furthermore, the most common reasons for stopping lumacaftor-ivacaftor were having tezacaftor-ivacaftor as an option (n = 25) and side-effects (n = 15). 5 . Lumacaftor-ivacaftor therapy may be associated with ocular and hepatic side effects. 2 . Lumacaftor is a strong inducer of CYP3A, while ivacaftor is a CYP3A sensitive substrate. 2 . Combination therapy can decrease systemic exposure of medications that are substrates of CYP3A, decreasing therapeutic effect. 2 . Co-administration of lumacaftor-ivacaftor with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. 2 . Furthermore, many patients who discontinued lumacaftor-ivacaftor had frequent corticosteroid use. 1 .

Reasons for Side Effects

The reasons for the side effects of lumacaftor-ivacaftor combination therapy are not fully understood. However, these side effects are thought to be due to the fact that LUM/IVA combination therapy may improve CFTR protein function while simultaneously affecting the body in various ways. 2 . Additionally, lumacaftor-ivacaftor combination therapy is a strong inducer of CYP3A, which may decrease blood levels of medications that are substrates of CYP3A. 2 . Therefore, caution is needed when co-administering lumacaftor-ivacaftor combination therapy with medications that are substrates of CYP3A. 2 .

Common Side Effects

Respiratory Symptoms

Respiratory-related adverse events were frequently observed after LUM/IVA administration. 3 . Some patients experienced a decline in ppFEV₁ from baseline at 2 hours (median [IQR] relative change: -19 [-21 to -11]%, p<0.001) that persisted at 24 hours but recovered in most patients at 1 month. 3 .

Liver Dysfunction

Lumacaftor-ivacaftor combination therapy may affect the liver, and liver function monitoring is necessary. 2 .

Drug Interactions

Lumacaftor-ivacaftor combination therapy is a strong inducer of CYP3A, which may decrease blood levels of medications that are substrates of CYP3A. 2 . Therefore, caution is needed when co-administering lumacaftor-ivacaftor combination therapy with medications that are substrates of CYP3A. 2 .

Countermeasures for Side Effects

Respiratory Symptoms

Before initiating lumacaftor-ivacaftor combination therapy, patients’ lung function should be evaluated, and they should be monitored for respiratory symptoms after administration. 3 . If respiratory symptoms are severe, treatment discontinuation may need to be considered. 3 .

Liver Dysfunction

Before initiating lumacaftor-ivacaftor combination therapy, patients’ liver function should be evaluated, and regular monitoring is required during administration. 2 . If liver dysfunction is observed, treatment discontinuation may need to be considered. 2 .

Drug Interactions

The potential for drug interactions should be carefully considered when co-administering lumacaftor-ivacaftor combination therapy with medications that are substrates of CYP3A. 2 . If necessary, the dosage of medications should be adjusted, or another medication should be substituted. 2 .

Comparison between Studies

Commonalities in Research

All of these studies indicate that lumacaftor-ivacaftor combination therapy has the potential to improve lung function in CF patients. 4 , 2 . However, these studies also indicate that lumacaftor-ivacaftor combination therapy may cause respiratory-related adverse events. 3 .

Differences in Research

These studies suggest that the risk of side effects from lumacaftor-ivacaftor combination therapy may vary depending on the patient’s ppFEV₁ level. 3 , 6 . For example, patients with ppFEV₁ < 40 may have a higher risk of respiratory-related adverse events than patients with ppFEV₁ > 40. 3 . Additionally, the reasons for discontinuation of lumacaftor-ivacaftor combination therapy vary between studies. 5 . For example, in some studies, the reason for stopping lumacaftor-ivacaftor combination therapy is often due to side effects. 5 . In other studies, the reason for stopping lumacaftor-ivacaftor combination therapy is often due to the availability of tezacaftor-ivacaftor combination therapy. 5 .

Considerations for Real-Life Application

Lumacaftor-ivacaftor combination therapy is a promising treatment for CF patients that can improve lung function. 4 . However, there is a risk of side effects from lumacaftor-ivacaftor combination therapy. 3 . When considering administering lumacaftor-ivacaftor combination therapy, it is important to take into account the patient’s condition and any medications they are currently taking. 3 , 2 . Also, regular observation of patients and monitoring for the development of side effects is necessary during the administration of lumacaftor-ivacaftor combination therapy. 3 . Appropriate measures should be taken if side effects occur. 3 .

Limitations of Current Research

Research on lumacaftor-ivacaftor combination therapy is still limited. 3 . In particular, data on the safety and efficacy of lumacaftor-ivacaftor combination therapy in patients with severe CF lung disease (ppFEV₁ < 40) are limited. 3 . Additionally, the mechanisms of the side effects of lumacaftor-ivacaftor combination therapy are not yet fully understood. 2 .

Directions for Future Research

Further research is needed on the safety and efficacy of lumacaftor-ivacaftor combination therapy in patients with severe CF lung disease. 3 . Additionally, research is needed to elucidate the mechanisms of the side effects of lumacaftor-ivacaftor combination therapy. 2 .

Conclusion

Lumacaftor-ivacaftor combination therapy is a promising treatment for CF patients that can improve lung function, but there is a risk of side effects. 4 , 3 . When considering administering lumacaftor-ivacaftor combination therapy, it is important to take into account the patient’s condition and any medications they are currently taking. 3 , 2 . Also, regular observation of patients and monitoring for the development of side effects is necessary during the administration of lumacaftor-ivacaftor combination therapy. 3 .