Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis

Abstract

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited.Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV).Results: Peak plasma concentrations (Cmax) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman’s rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients.Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes.

Therapeutic Drug Monitoring of Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis: Where Are We Now?

“…Conversely, the steady state C max for IVA/LUM found in a real-life setting, i.e., outside the stringent frame of clinical trials, was reported to be up to 10 times lower than that of a single-dose level in the labeling information. Moreover, the observed LUM exposure in CF patients was found to correspond to half of that measured in healthy controls (Table S2) [14,26].…”

“…An increase in the AUC of up to four-fold was reported for IVA when taken with fatty meals. Moreover, in their international multicentric clinical PK study, Hanafin et al noticed notable differences in C max values for IVA and LUM in the various participating centers from different continents, but also among neighboring countries, suggesting that the type of food and socio-cultural eating habits might also modulate caftors' PK [14].…”

“…The following supporting information can be downloaded at: https://www. mdpi.com/article/10.3390/pharmaceutics14081674/s1, Table S1: Impact of Other Drugs on Elexacaftor, Tezacaftor and/or Ivacaftor [4]; Table S2: PK parameters of ivacaftor and ivacaftor-lumacaftor standard therapy [14].…”

Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy

“…Noteworthy, these studies were conducted with single modulators only and not as the combination therapy used clinically. However, previous work has shown that CFTR modulators can have drug-drug interactions that affect pharmacokinetic properties and hence therapeutic outcomes (Hanafin et al, 2021). Consequently, preclinical prenatal safety studies of concomitant use of combination therapies are urgently needed.…”