Elexacaftor, tezacaftor and ivacaftor: a case of severe rash and approach to desensitisation

Discussion

The triple CFTR modulator therapy ELX/TEZ/IVA is indicated for the treatment of CF in patients aged 12 years and older who have at least one F508del mutation in the CFTR gene.5 6 Some adverse reactions reported in two double-blinded controlled phase 3 clinical trials included headache, upper respiratory tract infection, abdominal pain, diarrhoea, increased alanine aminotransferase and rash.3 4 The overall incidence of rash was 10% treated with triple therapy, compared with 5% in placebo-treated patients, with a higher incidence in female. It is possible that hormonal contraceptives may play a role in the occurrence of rash.3–6 This is consistent with one case report in current literature reporting the development of a rash in a young female patient8; however, our case report illustrates that male patients are similarly susceptible to this adverse reaction.

The mechanism of ELX/TEZ/IVA has been elucidated whereby elexacaftor and tezacaftor function as correctors to improve CFTR protein processing and trafficking, while ivacaftor functions as potentiator to augment channel gating.7 9 The mechanism of rash development is perhaps less understood, and is best studied in the case report by Stashower et al whereby skin biopsy was obtained for a CF patient who developed a pruritic rash after starting ELX/TEZ/IVA.10 An urticaria multiforme-type reaction was identified, and histology of epidermis and dermis showed predominantly lymphocytic infiltrates. This is however not in keeping with lymphopaenia which we observed in both the first and second trials of ELX/TEZ/IVA when our case patient developed a rash, and suggests that further research is required to elucidate the underlying mechanism.

Clinically, rash typically develops within 1–2 weeks after initiation of triple therapy. There is no recommendation in current literature regarding the management of rash secondary to ELX/TEZ/IVA; reported treatment appears to be on an individual basis, with generous use of steroids and antihistamine, depending on rash severity. Whether ELX/TEZ/IVA should be discontinued is similarly ambiguous. In clinical trials, spontaneous resolution of rash was observed in 1–2 weeks without medication cessation. In contrast, limited case reports and our own experience is that urticarial rash resolves with ELX/TEZ/IVA discontinuation.8 10 At present, judicious clinical judgement remains imperative.

Despite rash being an adverse drug reaction, desensitisation remains an effective method to establish patients on triple therapy. The normal dosage of triple therapy is two ELX/TEZ/IVA tablets in the morning and one IVA tablet in the evening.5 6 In the aforementioned case report, treatment was reintroduced by one tablet a day, increasing every 5 days to the recommended dose of three tablets daily.8 This regime would be ineffective in our case patient who re-developed the same rash within 24 hours after only half a tablet was reintroduced. Our approach of starting with one eighth of a tablet is worth considering if patients develop rash despite reduced doses. Anecdotal reports from other pulmonary centres have suggested that daily increments for oral desensitisation is successful, consistent with our experience. Concomitant use of steroids and antihistamine may be beneficial.

There may be other approaches to desensitisation, although there are practical challenges to consider. As ELX/TEZ/IVA tablet cannot be crushed and suspended, desensitisation to ivacaftor was suggested based on previously reported literature.11 Further, ivacaftor remains the common denominator in all previous generations of CFTR modulators in which rash is a reported side effect, with an incidence as high as 13% in monotherapy, suggesting its potential role in rash development.12 However, although ivacaftor tablet initially disperses in solution, the powder precipitates within 30 seconds, rendering any calculation of volume concentration inaccurate. Serial dilution using ivacaftor granules, available to the paediatric population, is an alternative approach; however, this is not cost-effective in our case. Granules are also normally mixed in with yoghurt and may be difficult to predict whether granules are dissolvable in other solvents. Desensitisation to ivacaftor alone for rash secondary to triple therapy remains to be validated.

The authors acknowledge that medical photography of the rash would have been a valuable addition to the case report. Nonetheless, this case report provides an example in management and a desensitisation regimen in rash induced by triple therapy, with the hopes that CF patients limited by adverse drug reactions may one day also experience the benefits of ELX/TEZ/IVA.