Physiologically‐Based Pharmacokinetic‐Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor‐Tezacaftor‐Ivacaftor With Nirmatrelvir‐Ritonavir for the Treatment of COVID‐19
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
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.
Article activity feed
-
-
SciScore for 10.1101/2022.01.20.22269253: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:A limitation of this study is that in the absence of data, population system parameters, such as plasma protein levels in pwCF was not incorporated into the modelling. However, changes in demography reflecting CF population were incorporated. Furthermore, a prior study evaluating the hepatic clearance of drugs showing that CYP3A enzyme …
SciScore for 10.1101/2022.01.20.22269253: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:A limitation of this study is that in the absence of data, population system parameters, such as plasma protein levels in pwCF was not incorporated into the modelling. However, changes in demography reflecting CF population were incorporated. Furthermore, a prior study evaluating the hepatic clearance of drugs showing that CYP3A enzyme activity is unaffected in pwCF(25) and the current weight of evidence based on comparisons of ETI PK in healthy volunteers compared to patients suggests they are comparable(11-13). Previous studies indicate that differences in pharmacokinetics of drugs in CF is attributed to differences in body composition and plasma protein concentrations secondary to nutritional deficiencies(26). However, the BMI of pwCF has increased over the years with continued improvements in CF-care, including highly effective CF modulators and nutritional support(9), to the extent it is now similar to that of healthy volunteers(10). A potential limitation of this work is that we did not include models of all active metabolites of ETI. M1-tezacaftor is an important metabolite due to its similar potency with parent drug as well as its high metabolite to parent AUC ratio (157.8%)(12). Since M1-tezacaftor is also metabolized by CYP3A4(12), its formation and elimination may be altered with ritonavir co-administration. Using the PBPK model of M1-tezacaftor, we were able to determine that the reduced dose of ETI provided mean AUC(0-96h) for M1-tezacaftor during the co-administ...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
-
-