The complexities of elexacaftor/tezacaftor/ivacaftor therapeutic drug monitoring in a person with cystic fibrosis and Mycobacterium abscessus pulmonary disease

Abstract

Therapeutic drug monitoring (TDM) of elexacaftor/tezacaftor/ivacaftor (ETI) remains challenging due to a lack of clarity around the parameters that govern ETI plasma concentrations, whilst the use of concomitant CYP3A inducers rifabutin and rifampicin is not recommended. We present the complexities of TDM for ETI performed in a person with cystic fibrosis and refractory Mycobacterium abscessus pulmonary disease. Utilising National Association of Testing Authorities (NATA) accredited assays and target considerations published by the Therapeutic Goods Administration (TGA), Australia, ETI plasma concentration variability was monitored over the course of an acute admission with added complexity from an antibiotic regimen including rifabutin, a moderate cytochrome P450 3A (CYP3A) inducer, and clofazimine, a mild CYP3A inhibitor. This case highlights the challenges surrounding ETI TDM in the context of acute severe illness, malnutrition, chronic infection, and drug-to-drug interactions. The marked clinical improvement seen, alongside sustained ETI plasma concentrations and suppressed sweat chloride levels on serial testing, provided reassurance of the use of ETI and rifabutin concomitantly in this case, and highlights the potential utility of TDM in helping guide clinical practice. Though a current barrier to the application of TDM includes ETI only being available as a fixed dose combination.

Keywords: Cystic Fibrosis; Kaftrio; Therapeutic drug monitoring; Trikafta; elexacaftor/tezacaftor/ivacaftor; non-tuberculous mycobacteria.

Figure 1.

Serum levels of elexacaftor (blue), tezacaftor (red), and ivacaftor (green) with major associated metabolites. a: plasma concentrations collected over 12 hours in ICU immediately following commencement of IV antibiotics targeting Mabs, b: plasma concentrations collected over 12 hours following sustained clinical improvement 13 days after initiation of Mabs targeted therapy. Improvements in plasma concentration with peak levels for all constituent parts falling within one standard deviation of tga-published C_max, c: plasma concentrations collected over 8 hours, 6 days after initiation of rifabutin and clofazimine alongside IV antibiotic therapy. Concentrations of all three constituent parts are noted to have reduced, but increased metabolite levels are seen for tezacaftor-M1 and ivacaftor-M6. C_max values were obtained from TGA product information for ETI (mean ± standard deviation) [5].

Figure 2.

Disease trajectory over the course of treatment initiation for Mabs pulmonary disease. Clinical trajectory shown with BMI (blue), FEV1% predicted (green), sputum smear and culture status, time points of ETI TDM, and antibiotic regimen. Two separate inpatient stays are highlighted by the grey patterned areas. Sputum culture conversion represented the first negative mycobacterial culture results in 10 years.

Figure 3.

Area under the curve (AUC) across three time points of ETI TDM with levels taken on day 3 of admission (ICU), following improvement in clinical condition on day 16, and following initiation of rifabutin and clofazimine on day 32. While the AUC have reduced following initiation of rifabutin and clofazimine, they remain higher than compared to the levels taken in ICU. Additionally, levels of therapeutically active metabolites, particularly tezacaftor-M1, remain elevated. Calculated using GraphPad prism 10.2.3.