The pharmacokinetic interaction between ivacaftor and ritonavir in healthy volunteers

Liddy, Anne Marie; McLaughlin, Gavin; Schmitz, Susanne; D’Arcy, Deirdre M.; Barry, Michael

doi:10.1111/bcp.13324

Cited by 15 publications

(16 citation statements)

References 18 publications

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“…For verification simulations, the dose and schedule of drugs were matched to the design of the corresponding clinical DDI studies in healthy participants. 11 , 12 , 13 , 21 To quantify the DDIs, the geometric mean ratios of AUC or C max with or without the presence of CYP3A4 modulators were calculated. The assessment of DDI prediction success was based on whether predictions were within a twofold range of the observed data.…”

Section: Methodsmentioning

confidence: 99%

Physiologically‐Based Pharmacokinetic‐Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor‐Tezacaftor‐Ivacaftor With Nirmatrelvir‐Ritonavir for the Treatment of COVID‐19

Hong

Almond

Chung

et al. 2022

Clin Pharma and Therapeutics

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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.

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Section: Methodsmentioning

confidence: 99%

Physiologically‐Based Pharmacokinetic‐Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor‐Tezacaftor‐Ivacaftor With Nirmatrelvir‐Ritonavir for the Treatment of COVID‐19

Hong

Almond

Chung

et al. 2022

Clin Pharma and Therapeutics

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“…In this study, we examined the P-gp structure in the presence of ivacaftor. In order to minimize non-specific binding of the hydrophobic drug, we employed a concentration likely to be encountered in vivo [28] and at a sub-stoichiometric ratio with the protein. This approach had the advantage of allowing both drug-bound and drug-free forms of the protein to coexist as a mixture in the protein/drug solution immediately prior to flash freezing and cryo-electron microscopy.…”

Section: Introductionmentioning

confidence: 99%

Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor

et al. 2021

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ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of the protein within the membrane is an intrinsic part of its mechanism of action, but this has made structural studies challenging. Here, we have studied different conformations of P-glycoprotein simultaneously in the presence of ivacaftor, a known competitive inhibitor. In order to conduct this, we used high contrast cryo-electron microscopy imaging with a Volta phase plate. We associate the presence of ivacaftor with the appearance of an additional density in one of the conformational states detected. The additional density is in the central aqueous cavity and is associated with a wider separation of the two halves of the transporter in the inward-facing state. Conformational changes to the nucleotide-binding domains are also observed and may help to explain the stimulation of ATPase activity that occurs when transported substrate is bound in many ATP binding cassette transporters.

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“…In particular, we aimed to provide guidance for ETI dose adjustment with ritonavir, the CYP3A inhibitor and the component of nirmatrelvir/ritonavir for the treatment of COVID-19. From the ETI-ritonavir DDI simulations, we found that when ritonavir 100mg q12h was administered for 5 days, it led to the AUC ratio of ivacaftor as 9.31 (90% CI: 8.28, 10.47) which far exceeded the observed and simulated AUC ratio (3.06) when ivacaftor was administered with ritonavir 50 mg q24h(22). The increase in interaction with the therapeutic regimen shows that dose adjustments should not be estimated purely on the basis of the available clinical study.…”

Section: Discussionmentioning

confidence: 94%

“…For tezacaftor, the itraconazole solution (200 mg) was administered BID on Day 1 and QD from Day 2 to Day 14 and tezacaftor 25 mg was administered daily from Day 1 to Day 14 (12). For ivacaftor, four clinical DDI studies were conducted with ritonavir, ketoconazole, fluconazole, or rifampin (11,22). For ritonavir, 50mg was administered daily from Day 1 to Day 18 and a single 150 mg dose of ivacaftor was administered on Day 15.…”

Section: Model Verification: Ddi Simulationsmentioning

confidence: 99%

PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19

Hong

Almond

Chung

et al. 2022

Preprint

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Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (pwCF) due to the potential for significant drug-drug interactions (DDI). However, pwCF are more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. Methods: CYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A4 inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators. Results: When ritonavir was administered on day 1 through 5, the predicted 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 ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. Conclusions: Coadministration of nirmatrelvir-ritonavir requires a significant reduction in the ETI dosing frequency with delayed resumption of full dose due to the mechanism-based inhibition with ritonavir.

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The pharmacokinetic interaction between ivacaftor and ritonavir in healthy volunteers

Cited by 15 publications

References 18 publications

Physiologically‐Based Pharmacokinetic‐Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor‐Tezacaftor‐Ivacaftor With Nirmatrelvir‐Ritonavir for the Treatment of COVID‐19

Physiologically‐Based Pharmacokinetic‐Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor‐Tezacaftor‐Ivacaftor With Nirmatrelvir‐Ritonavir for the Treatment of COVID‐19

Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor

PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19

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