Verification of a physiologically based pharmacokinetic model of ritonavir to estimate drug–drug interaction potential of CYP3A4 substrates

Verification of a physiologically based pharmacokinetic model of ritonavir to estimate... Ritonavir is one of several ketoconazole alternatives used to evaluate strong CYP3A4 inhibition potential in clinical drug–drug interaction (DDI) studies. In this study, four physiologically based pharmacokinetic (PBPK) models of ritonavir as an in vivo time‐dependent inhibitor of CYP3A4 were created and verified for oral doses of 20, 50, 100 and 200 mg using the fraction absorbed (Fa) and oral clearance (CLoral) values reported in the literature, because transporter and CYP enzyme reaction phenotyping data were not available. The models were used subsequently to predict and compare the magnitude of the AUC increase in nine reference DDI studies evaluating the effect of ritonavir at steady‐state on midazolam (CYP3A4 substrate) exposure. Midazolam AUC and Cmax ratios were predicted within 2‐fold of the respective observations in seven studies. Simulations of the hepatic and gut CYP3A4 abundance after multiple oral dosing of ritonavir indicated that a 3‐day treatment with ritonavir 100 mg twice daily is sufficient to reach maximal CYP3A4 inhibition and subsequent systemic exposure increase of a CYP3A4 substrate, resulting in the reliable estimation of fm,CYP3A4. The ritonavir model was submitted as part of the new drug application for Kisqali® (ribociclib) and accepted by health authorities. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biopharmaceutics and Drug Disposition Wiley

Verification of a physiologically based pharmacokinetic model of ritonavir to estimate drug–drug interaction potential of CYP3A4 substrates

Loading next page...
 
/lp/wiley/verification-of-a-physiologically-based-pharmacokinetic-model-of-GIAr1Cvdvq
Publisher
Wiley
Copyright
Copyright © 2018 John Wiley & Sons, Ltd.
ISSN
0142-2782
eISSN
1099-081X
D.O.I.
10.1002/bdd.2122
Publisher site
See Article on Publisher Site

Abstract

Ritonavir is one of several ketoconazole alternatives used to evaluate strong CYP3A4 inhibition potential in clinical drug–drug interaction (DDI) studies. In this study, four physiologically based pharmacokinetic (PBPK) models of ritonavir as an in vivo time‐dependent inhibitor of CYP3A4 were created and verified for oral doses of 20, 50, 100 and 200 mg using the fraction absorbed (Fa) and oral clearance (CLoral) values reported in the literature, because transporter and CYP enzyme reaction phenotyping data were not available. The models were used subsequently to predict and compare the magnitude of the AUC increase in nine reference DDI studies evaluating the effect of ritonavir at steady‐state on midazolam (CYP3A4 substrate) exposure. Midazolam AUC and Cmax ratios were predicted within 2‐fold of the respective observations in seven studies. Simulations of the hepatic and gut CYP3A4 abundance after multiple oral dosing of ritonavir indicated that a 3‐day treatment with ritonavir 100 mg twice daily is sufficient to reach maximal CYP3A4 inhibition and subsequent systemic exposure increase of a CYP3A4 substrate, resulting in the reliable estimation of fm,CYP3A4. The ritonavir model was submitted as part of the new drug application for Kisqali® (ribociclib) and accepted by health authorities.

Journal

Biopharmaceutics and Drug DispositionWiley

Published: Jan 1, 2018

Keywords: ; ; ; ;

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off