The Pharmacokinetic Interaction between Ivacaftor and Ritonavir
Citation:LIDDY, ANNE MARIE, The Pharmacokinetic Interaction between Ivacaftor and Ritonavir, Trinity College Dublin.School of Medicine, 2019
The PK interaction between ivacaftor and ritonavir.pdf (PhD thesis, examined and approved) 9.631Mb
Ivacaftor is the first small molecule for the treatment of cystic fibrosis (CF) that directly targets the inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR). In phase III clinical trials ivacaftor showed a significant relative improvement in mean percentage predicted forced expiratory volume in 1 second (ppFEV1) of 10.6% compared to placebo. There were also significant improvements in number of exacerbations, hospitalisations, weight and quality of life. The enthusiasm at the introduction of ivacaftor was tempered by its high cost—in Ireland, the cost of ivacaftor is almost €30 million per annum for approximately 130 patients.(1) There is also large variability in the clinical response to ivacaftor; 25% of patients in the phase III trial had an improvement in ppFEV1 of 5% or less, some had no improvement at all. The drivers behind this variability in response were not discovered, but of note the relationship of variability in plasma levels of ivacaftor to response was not reported.(2) The aim of this study was to investigate the pharmacokinetic (PK) interaction between ivacaftor and ritonavir to explore the possibility of using ritonavir to boost plasma levels of ivacaftor in clinical practice. A liquid chromatography mass spectrometry (LC-MS) assay was developed to measure ivacaftor and its main active metabolite hydroxymethyl-ivacaftor (M1) in plasma. (3) A clinical trial to investigate the PK interaction between ivacaftor and ritonavir in vivo was completed with 12 healthy volunteers. This consisted of 3 single-dose studies of ivacaftor: ivacaftor 150mg alone (study A), ivacaftor 150mg with ritonavir 50mg daily (study B) and ivacaftor 150mg with ritonavir 50mg daily after two weeks of ritonavir treatment at 50mg daily (study C). The resulting PK profiles were analysed using non-compartmental analysis (NCA) to produce PK parameters for ivacaftor and M1 in each of studies A, B and C. Ivacaftor and M1 data were then fit to a compartmental PK model to allow dose simulation to ascertain the dose of ivacaftor with ritonavir that would be equivalent to standard dosing of ivacaftor alone. A budget-impact model was then constructed to estimate to potential cost saving of the implementation of ritonavir boosting of ivacaftor in clinical practice. The ivacaftor and M1 assays met validation criteria. Inter-day and intra-day accuracy, as represented by mean bias, and precision, as represented by the coefficient of variation (CV), were all within 15%. Significantly higher exposure to ivacaftor was found when ivacaftor was administered with ritonavir in both studies B and C compared with ivacaftor alone in study A. Area under the concentration–time curve extrapolated to iii infinity (AUC0-inf obv) (95% CI) was 10.94 (8.259–14.48) μg.hr.mL-1 in study A compared to 215.6 (146.4–317.4) μg.hr.mL-1 in study B and 216 (165.5–281.8) μg.hr.mL-1 in study C. Maximum concentration (Cmax) (GM [95% CI]) was 0.9944 (0.7819–1.265) μg in study A, 1.812 (1.323–2.482) μg in study B and 2.267 (1.863–2.757) in study C respectively. Elimination half-life (T1/2) (GM [95% CI]) of ivacaftor in study A was 7.121 (5.59–9.07) hours compared to 79.24 (65.5–96.1) hours in study B and 65.99 (57.43–75.82) hours in study C. AUC0–12 of M1 was significantly decreased in study B and in study C in comparison to study A. AUC 0–12 (GM 95% CI) was 11.77 (8.620 – 16.07) in study A, 2.961 (2.014 – 4.355) in study B and 0.6999 (0.4187 – 1.170) in study C. Ivacaftor data was found to fit best a one-compartment model with lag time absorption. Dosing simulation using this model showed that exposure to ivacaftor with 75mg twice weekly or 50mg three times weekly dosing with ritonavir was not reduced in comparison to ivacaftor 150mg alone twice daily. Median AUC504-672 was 133.24 μg.hr.mL-1 for ivacaftor alone compared to 196.99 μg.hr.mL-1 for ivacaftor 75mg twice weekly with ritonavir 50mg daily and 293.96 μg.hr.mL-1 for ivacaftor 50mg three times weekly with ritonavir 50mg daily. Budget-impact modelling showed that the base case—uptake of ivacaftor plus ritonavir in 25% of adult population on ivacaftor in year 1 growing to 75% by year 5—resulted in a 5-year budget saving of €49,021,152. Scenario analyses resulted in a range of savings from €1,001,953 should only 1 patient take up ivacaftor plus ritonavir dosing to €176,303,641 should all patients on ivacaftor be switched to ivacaftor plus ritonavir over 5 years. As we move into an era of ultra-high-cost drugs for orphan diseases, we need innovative solutions to overcome the challenges of providing healthcare that is both equitable and at an acceptable opportunity cost. The potential benefits of using a CYP3A4 inhibitor in the CF setting warrants further exploration given the proof of the concept that ivacaftor plasma levels can be significantly increased with the use of a small dose of ritonavir.
Author: LIDDY, ANNE MARIE
Publisher:Trinity College Dublin. School of Medicine. Discipline of Pharmacology & Therapeutics
Type of material:Thesis
Availability:Full text available