ritonavir and Cystic-Fibrosis

The aim of this study was to determine the pharmacokinetic interaction between ivacaftor and ritonavir.. A liquid chromatography mass spectrometry (LC-MS) method was developed for the measurement of ivacaftor in plasma. An open-label, sequential, cross-over study was conducted with 12 healthy volunteers. Three pharmacokinetic profiles were assessed for each volunteer: ivacaftor 150 mg alone (study A), ivacaftor 150 mg plus ritonavir 50 mg daily (study B), and ivacaftor 150 mg plus ritonavir 50 mg daily after two weeks of ritonavir 50 mg daily (study C).. Addition of ritonavir 50 mg daily to ivacaftor 150 mg resulted in significant inhibition of the metabolism of ivacaftor. Area under the plasma concentration-time curve from time 0 to infinity (AUC. Ritonavir resulted in significant inhibition of the metabolism of ivacaftor. These data suggest that ritonavir may be used to inhibit the metabolism of ivacaftor in patients with cystic fibrosis (CF). Such an approach may increase the effectiveness of ivacaftor in 'poor responders' by maintaining higher plasma concentrations. It also has the potential to significantly reduce the cost of ivacaftor therapy.

Topics: Adult; Aminophenols; Area Under Curve; Chloride Channel Agonists; Chromatography, Liquid; Cross-Over Studies; Cystic Fibrosis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Administration Schedule; Drug Interactions; Female; Half-Life; Healthy Volunteers; Humans; Male; Quinolones; Ritonavir; Tandem Mass Spectrometry; Young Adult

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor-tezacaftor-ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A-mediated DDI of elexacaftor-tezacaftor-ivacaftor was evaluated using a physiologically-based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug-dependent parameters of elexacaftor-tezacaftor-ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor-tezacaftor-ivacaftor. The elexacaftor-tezacaftor-ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor-tezacaftor-ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor-tezacaftor-ivacaftor should be reduced when coadministered with nirmatrelvir-ritonavir to elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full-dose elexacaftor-tezacaftor-ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of elexacaftor-tezacaftor-ivacaftor administered concomitantly with nirmatrelvir-ritonavir in people with CF that will likely decrease the impact of the drug interaction.

Topics: Aminophenols; Benzodioxoles; Chloride Channel Agonists; COVID-19 Drug Treatment; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytochrome P-450 CYP3A; Drug Combinations; Drug Interactions; Humans; Indoles; Lactams; Leucine; Mutation; Nitriles; Proline; Pyrazoles; Pyridines; Pyrrolidines; Quinolines; Quinolones; Ritonavir

Ivacaftor is currently the only CFTR potentiator approved and is increasingly used since the development of CFTR correctors. Ivacaftor is metabolized by CYP3A4 and therefore dose reduction is required when treating patients on ivacaftor with CYP3A4 inhibiting drugs. As this advice is based on studies in healthy volunteers and not in cystic fibrosis (CF) patients, we need to investigate this in both groups to be able to extrapolate these data to CF.. A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor.. We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times.. Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.

Topics: Adult; Aminophenols; Azithromycin; Case-Control Studies; Chloride Channel Agonists; Cystic Fibrosis; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Quinolones; Ritonavir

We report the case of a man affected by cystic fibrosis who developed a severe SARS-CoV-2 related pneumonia in March 2020. In addition to lopinavir/ritonavir and hydroxychloroquine, he was treated with two doses of tocilizumab, displaying a significant clinical improvement. This is the first case described in the literature of an adult patient affected by cystic fibrosis who received tocilizumab for COVID-19, with documented total recovery, also assessed by a spirometry.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Cystic Fibrosis; Drug Combinations; Humans; Hydroxychloroquine; Lopinavir; Lung; Male; Oxygen Inhalation Therapy; Pneumonia, Viral; Receptors, Interleukin-6; Respiratory Function Tests; Respiratory Tract Infections; Ritonavir; SARS-CoV-2; Tomography, X-Ray Computed; Treatment Outcome