Novel Bruton's Tyrosine Kinase inhibitor remibrutinib: Drug-drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling.

Publisher: WileyBlackwell Pub Country of Publication: United States NLM ID: 101474067 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1752-8062 (Electronic) Linking ISSN: 17528054 NLM ISO Abbreviation: Clin Transl Sci Subsets: MEDLINE

Original Publication: Malden, MA : WileyBlackwell Pub., 2008-

Drug Interactions*; Cytochrome P-450 CYP3A Inhibitors/*metabolism ; Protein-Tyrosine Kinases/*antagonists & inhibitors ; Protein-Tyrosine Kinases/*pharmacokinetics; Algorithms ; Biological Availability ; Clinical Trials as Topic ; Humans ; Liver/enzymology ; Liver/metabolism ; Metabolic Clearance Rate ; Protein-Tyrosine Kinases/administration & dosage ; Safety

Remibrutinib, a novel oral Bruton's Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first-pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady-state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27-fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically-based pharmacokinetic (PBPK) model, which well-described the therapeutic dose range of 25-100 mg. Simulations of untested scenarios revealed an absence of drug-drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration-time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks.
(© 2021 NIBR Novarti Basel Switzerland. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Drug Metab Dispos. 2003 Jul;31(7):815-32. (PMID: 12814957)
Clin Pharmacol Ther. 2018 Feb;103(2):271-280. (PMID: 29063606)
AAPS J. 2004;6(2):1-6. (PMID: 18465265)
Biopharm Drug Dispos. 2020 Feb;41(1-2):3-31. (PMID: 31778578)
Clin Pharmacol Ther. 2017 Jul;102(1):98-105. (PMID: 27770430)
Mol Cancer. 2018 Feb 19;17(1):57. (PMID: 29455639)
J Med Chem. 2018 Mar 22;61(6):2227-2245. (PMID: 29457982)
Curr Opin Allergy Clin Immunol. 2018 Oct;18(5):425-431. (PMID: 30015639)
Pharmacol Ther. 2012 Nov;136(2):186-201. (PMID: 22884524)
Korean J Physiol Pharmacol. 2017 Jan;21(1):107-115. (PMID: 28066147)
Drug Metab Dispos. 2011 Feb;39(2):170-3. (PMID: 21036951)
J Allergy Clin Immunol. 2017 Sep;140(3):875-879.e1. (PMID: 28389390)
Clin Transl Sci. 2022 Jan;15(1):118-129. (PMID: 34432364)
Nat Rev Drug Discov. 2007 Feb;6(2):140-8. (PMID: 17268485)
Pharm Res. 1993 Jul;10(7):1093-5. (PMID: 8378254)
Drug Metab Pharmacokinet. 2011 Jun;26(3):220-7. (PMID: 21297316)
Pharm Res. 2016 Nov;33(11):2583-93. (PMID: 27439505)
J Med Chem. 2013 Feb 14;56(3):781-795. (PMID: 23241029)
Br J Clin Pharmacol. 1998 Aug;46(2):101-10. (PMID: 9723817)
Int J Rheum Dis. 2012 Apr;15(2):163-8. (PMID: 22462419)
Biopharm Drug Dispos. 2018 Mar;39(3):152-163. (PMID: 29451681)
Clin Pharmacol Drug Dev. 2018 Nov;7(8):844-859. (PMID: 30044899)
Clin Pharmacol Ther. 2015 Jul;98(1):76-86. (PMID: 25808023)
CPT Pharmacometrics Syst Pharmacol. 2016 Sep;5(9):475-83. (PMID: 27566992)
Biopharm Drug Dispos. 2013 Apr;34(3):141-54. (PMID: 23225350)
Clin Pharmacol Ther. 2015 Mar;97(3):247-62. (PMID: 25670209)

0 (Cytochrome P-450 CYP3A Inhibitors)
EC 2.7.10.1 (Protein-Tyrosine Kinases)

Date Created: 20210825 Date Completed: 20220303 Latest Revision: 20220303

20221213

PMC8742645

10.1111/cts.13126

34432364