Cystic fibrosis (CF) is one of the most common life-threatening autosomal recessive disorder. Morbidity and mortality in people with CF are mainly caused by progressive obstructive lung disease, with perpetual cycles of airway infection and inflammation, resulting in decline in lung function over time. CF symptoms are caused by an imbalance in ion and water homeostasis in the secretory epithelia of these organs due to loss of function of the apical chloride and bicarbonate channel CFTR (cystic fibrosis transmembrane conductance regulator). There are many mutations in CF with diverse molecular effects, contributing to the variable phenotype of the disease. Elexacaftor which is the latest approved CFTR corrector, together with tezacaftor and ivacaftor has proven to be the most effective combination in the treatment of CF. Metabolism of the newly developed CFTR modulators is mainly by the cytochrome P450 (CYP) family of enzymes.
Patients with CF face a therapeutic dilemma since the CFTR modulator medication, elexacaftor-tezacaftor-ivacaftor, is mostly degraded by cytochrome P450 3A4 (CYP3A4)-mediated metabolism and has the potential for major drug-drug interactions (DDIs). Viral respiratory tract infections in persons with CF can cause lung function-damaging acute pulmonary exacerbations. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), associated with the coronavirus disease 2019 (COVID-19) pandemic, has had a huge impact worldwide. The presence of co-morbidities, such as CF, has been identified as a risk factor for severe disease. The antiviral treatment using nirmatrelvir–ritonavir probably reduce risk of death and hospital admission without increasing adverse events. However, ritonavir is an inhibitor of CYP3A4, an enzyme responsible for the metabolism of about half of all drugs. Clinicians must remain vigilant for potential drug interactions
The population of people with cystic fibrosis who are infected with COVID-19 may be at a high risk of developing a serious illness because COVID-19 infection sets off a cytokine storm that can result in the potentially fatal respiratory distress syndrome. There are no precise dose recommendations or clinical data currently addressing the interactions of elexacaftor-tezacaftorivacaftor with nirmatrelvir-ritonavir. In order to stop COVID-19 from progressing to a severe condition, persons with CF must receive the correct instructions for using nirmatrelvir-ritonavir (brandname Paxlovid).
In a new study published in the journal Clinical Pharmacology & Therapeutics, Eunjin Hong, Dr. Lisa Almond, Peter Chung, Adupa Rao and led by Professor Paul Beringer from the University of Southern California reported the impact of the drug interactions between ritonavir, elexacaftor, tezacaftor, and ivacaftor, to simulate potential treatment scenarios, and to offer dosing recommendations to avoid the interaction. In order to assess clinically significant drug-drug interactions involving elexacaftor-tezacaftor-ivacaftor, the study offered physiologically based pharmacokinetic (PBPK) techniques. The research team used simulations to determine that elexacaftor-tezacaftor-ivacaftor has to have its dosage significantly reduced to lessen the likelihood of adverse drug interaction with nirmatrelvir-ritonavir.
Elexacaftor-tezacaftor-ivacaftor are sensitive CYP3A4 substrates, according to a study of clinical drug-drug interactions with potent CYP3A4 inhibitors (ketoconazole and itraconazole) or inducers (rifampin). As a result, managing DDI with concurrent CF medicines makes it more difficult to use CFTR modulators safely and effectively because CYP3A4 modification by inducers or inhibitors can change systemic exposure and result in variability in drug response. The employed elexacaftor-tezacaftorivacaftor PBPK-DDI model was able to accurately predict the observed drug interactions of elexacaftor-tezacaftor-ivacaftor as well as the PK parameters, and as a result, it can offer a method for the assessment and management of other potential DDIs involving CFTR modulators. To treat COVID-19, researchers specifically sought to provide recommendations for elexacaftor-tezacaftor-ivacaftor dose modification with ritonavir, the CYP3A inhibitor and component of nirmatrelvir-ritonavir. The anticipated area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate), when ritonavir was taken on Days 1 through 5, was 9.31, indicating that its metabolism was severely hindered. Since the dosing of the inhibitor varies, dose modifications shouldn’t be predicted based on clinical data, as seen by the increase in interactions with the higher dose of ritonavir. Additionally, they discovered from the simulations that the irreversible suppression of CYP3A4 caused the high concentrations of elexacaftor-tezacaftor-ivacaftor to persist for several days after ritonavir is eliminated.
However, this investigation is limited by the lack of clinically observed ritonavir-tezacaftor or ritonavir-elexacaftor DDI data to support their hypothesis. In the lack of clinical evidence, authors bridged the gap with the urgent requirement for the right dose recommendations by using the PBPK modeling technique to provide timely guidance for the treatment of COVID-19 with nirmatrelvir-ritonavir in persons with CF receiving concurrent CFTR modulator therapy. Another drawback of the study is that the modeling did not consider population system factors particular to the CF population because there was a lack of data.
In conclusion, researchers found that an adjusted dose of elexacaftor-tezacaftor-ivacaftor, when given along with nirmatrelvir and ritonavir, will probably lessen the effects of a medication interaction. The findings demonstrate that COVID-19 in CF patients can be treated with nirmatrelvir-ritonavir while they continue to receive highly active CFTR modulators. Additionally, the study offers innovative tools for assessing and resolving clinically significant DDIs associated with highly active CFTR modulator therapy.
Hong E, Almond LM, Chung PS, Rao AP, Beringer PM. Physiologically‐Based Pharmacokinetic‐Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor‐Tezacaftor‐Ivacaftor With Nirmatrelvir‐Ritonavir for the Treatment of COVID‐19. Clinical Pharmacology & Therapeutics. 2022