title: Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies With PBPK Modeling.
abstract: NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (fmCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate fmCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human fmCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.
authors.affiliation: Drug Metabolism & Pharmacokinetics Department, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Drug Metabolism & Pharmacokinetics Department, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Tycho
authors.initials: T
authors.lastname: Heimbach
authors.affiliation: Business Development Department, CEVEC Pharmaceuticals GmbH, Cologne 51105, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Scheer
authors.affiliation: Drug Metabolism & Pharmacokinetics Department, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Avantika
authors.initials: A
authors.lastname: Barve
authors.affiliation: Drug Metabolism & Pharmacokinetics Department, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Wenkui
authors.initials: W
authors.lastname: Li
authors.affiliation: Drug Metabolism & Pharmacokinetics Department, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.affiliation: Drug Metabolism & Pharmacokinetics Department, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936. Electronic address: handan.he@novartis.com.
authors.forename: Handan
authors.initials: H
authors.lastname: He
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D019438:Ritonavir / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir
keywords: CYP enzymes; clinical pharmacokinetics; drug interaction; drug metabolizing enzymes; elimination; hepatic clearance; interspecies scaling; physiologically based pharmacokinetic modeling; preclinical pharmacokinetics; simulations