PBPK modeling to predict drug‐drug interactions of ivosidenib as a perpetrator in cancer patients and qualification of the Simcyp platform for CYP3A4 induction

Abstract

Ivosidenib is a potent, targeted, orally active, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) that has been approved in the United States for the treatment of adults with newly diagnosed acute myeloid Leukemia (AML) who are ≥75 years of age or ineligible for intensive chemotherapy, and those with relapsed or refractory AML, with a susceptible IDH1 mutation. Accepted ArticleThis article is protected by copyright. All rights reserved Ivosidenib is an inducer of the CYP2B6, CYP2C8, CYP2C9, and CYP3A4 and an inhibitor of Pglycoprotein (P-gp), organic anion transporting polypeptide-1B1/1B3 (OATP1B1/1B3), and organic anion transporter-3 (OAT3) in vitro. A physiologically-based PK (PBPK) model was developed to predict DDIs of ivosidenib in patients with AML. The in vivo CYP3A4 induction effect of ivosidenib was quantified using 4β-hydroxycholesterol and was subsequently verified with the PK data from an ivosidenib and venetoclax combination study. The verified model was prospectively applied to assess the effect of multiple doses of ivosidenib on a sensitive CYP3A4 substrate, midazolam. The simulated midazolam geometric mean AUC and C max ratios were 0.18 and 0.27, respectively, suggesting ivosidenib is a strong inducer. The model was also used to predict the DDIs of ivosidenib with CYP2B6, CYP2C8, CYP2C9, P-gp, OATP1B1/1B3, and OAT3 substrates. The AUC ratios following multiple doses of ivosidenib and a single dose of CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 (warfarin), P-gp (digoxin), OATP1B1/1B3 (rosuvastatin), and OAT3 (methotrexate) substrates were 0.90, 0.52, 0.84, 1.01, 1.02, and 1.27, respectively. Finally, in accordance with regulatory guidelines, the Simcyp modeling platform was qualified to predict CYP3A4 induction using known inducers and sensitive substrates.

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

“…Ivosidenib is a substrate and an inducer of CYP3A4 and also induces CYP2B6, and CYP2C enzymes. PBPK modeling was used to predict magnitude of CYP2B6, CYP2C8, CYP2C9, and CYP3A4 induction of ivosidenib along with other DDI predictions in patients with cancer 51 . For CYP3A induction prediction, the in vivo induction parameters were optimized using 4β‐hydroxycholesterol (4‐OHC), an endogenous biomarker of CYP3A4 activity, data being obtained from patients.…”

Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy

“…According to the literature ( Upreti et al, 2011 ; Boulton, 2017 ), here, we assumed that all DPP-4 enzymes were located in the blood compartment in the present model. Across published studies ( Rowland Yeo et al, 2011 ; Bolleddula et al, 2021 ), k deg values of CYP3A4 ranged from 0.0077 –1 to 0.03 h −1 . However, a recent study has confirmed that it was a more reasonable value at 0.03 h −1 for the most accurate prediction ( Rowland Yeo et al, 2011 ); hence, the k deg value was set at 0.03 h −1 in this PBPK-DO model.…”

Unraveling pleiotropic effects of rifampicin by using physiologically based pharmacokinetic modeling: Assessing the induction magnitude of P‐glycoprotein–cytochrome P450 3A4 dual substrates

“…The CYP3A4 induction parameters of the default rifampicin model (maximal fold induction of CYP3A4 over vehicle [Ind max_CYP3A4 ] = 16, drug concentration that supports half maximal induction of CYP3A4 [IndC 50_CYP3A4 ] = 0.32, unbound fraction of drug in enterocytes [f u,gut ] = 1) have been validated extensively using clinical DDI studies with a large number of CYP3A4 substrates. 4,22,23 An alternative set of CYP3A4 induction parameters (Ind max_CYP3A4 = 30.6, IndC 50_CYP3A4 = 0.32, f u,gut = 0.116), which were previously used as a worst case assessment of DDI liability for metabolically stable CYP3A4 substrates, further improved the predictions for some compounds such as bosutinib by simulating a stronger induction of CYP3A4 (Figure S7). Although bosutinib is predominantly metabolized by CYP3A4 (f m,CYP3A4 ≈ 1), such improvement should be interpreted with caution as rifampicin is also shown to induce other proteins such as CYP1A2, CYP2B6, CYP2C8, CYP2C9, UDP glucuronosyltransferase (UGT)1A1, and possibly organic anion transporting polypeptide (OATP)1B1, 15,[43][44][45][46][47][48] which may account for the underestimation of DDIs with the default rifampicin model when their involvement, if any, is not considered in the substrate model.…”

“…was a 1.4-fold to 3.5-fold increase in P-gp protein levels in healthy subjects who received 600 mg rifampicin once daily for 10 days, as measured using immunohistochemistry and Western blot. 16 Although the application of PBPK in predicting CYP3A4 induction has been well established, 4,22,23 the use of PBPK in predicting P-gp induction is relatively less reported. The published PBPK models for rifampicin incorporated the measured fold increase in the P-gp protein level and reasonably recovered the clinically observed magnitudes of DDIs with a number of P-gp substrates (e.g., digoxin and talinolol) when coadministered with rifampicin.…”

“…[1][2][3] Although the prediction of competitive inhibition of cytochrome P450 (CYP) enzymes remains one of the most established areas of PBPK modeling, there has been an increase in the application and regulatory acceptance of the use of PBPK in predicting DDIs with other mechanisms such as CYP induction and competitive inhibition of drug transporters. 4,5 P-glycoprotein (P-gp), a well-studied adenosine triphosphate-binding cassette transporter, is an efflux pump expressed on the apical membranes of various types of cells, such as hepatocytes, renal proximal tubular cells, brain capillary endothelial cells, and gut enterocytes. [6][7][8] Given the localization of P-gp in these organs, it functions to facilitate biliary clearance and active renal secretion while limiting penetration of drugs across the blood-brain barrier and restricting absorption of drugs into gut enterocytes from the gut lumen.…”