Many cystic fibrosis (CF) patients take several medications at one time to manage symptoms and the disease. In 2012, FDA approved Ivacaftor (Kalydeco®) for treatment of the underlying cause of CF in a small subset of the patient population. In 2015, a combination treatment of Ivacaftor and Lumacaftor (Orkambi®), followed by a combination of Ivacaftor and Texacaftor (Symdeko®) in 2018. In 2019, the first triple combination of Elexacaftor/Texacaftor/Ivacaftor (Trikafta®) for patients 12 and up, accounting for about 90% of patients with CF was approved.
Many CF patients that take modulator regimens of the above dual combinations will need to transition to the triple combination. An assessment of whether adequate exposures to achieve clinical efficacy are maintained during this transition was needed, as this has not been directly addressed in clinical trials. PBPK modeling using Simcyp was used for this analysis, specifically to understand the CYP3A4 interactions during the CF transmembrane conductance regulator (CFTR) process. Individual models for each drug were developed, followed by simulations of various combination to assess exposure.
The PBPK modeling demonstrated that immediate transfer from the three dual combinations to the triple combination resulted in sustained CFTR in patients 12 years and higher. Clinical trials on younger patients are ongoing.
**https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis
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