Abstract CT125: Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs)

Abstract

Background Futibatinib is an oral, irreversible FGFR1-4 inhibitor with clinical activity in cholangiocarcinoma and other FGFR-aberrant tumors. The recommended futibatinib dosage is 20 mg once daily (QD). In vitro studies have shown that futibatinib is predominantly metabolized by and inhibits cytochrome p450 3A (CYP3A); futibatinib is also a P-glycoprotein substrate. Two phase 1 studies were performed in healthy volunteers to evaluate potential DDIs between futibatinib and CYP3A substrates (midazolam; study 1) or CYP3A inhibitors/inducers (itraconazole/rifampin; study 2). As the solubility of futibatinib is pH dependent, study 3 assessed the effect of PPI (lansoprazole) coadministration on futibatinib pharmacokinetics (PK). Methods All 3 studies, conducted in adult nonsmokers, were open-label, fixed-sequence, 2-period cross-over studies with a 1- or 2-d washout between each period. In study 1, midazolam 2 mg was given on d1 of period 1 (-futibatinib) and on d7 of period 2 (+futibatinib 20 mg QD d1-7). In study 2, futibatinib 20 mg was given on d1 of period 1 (alone) and on d5 (+itraconazole 200 mg QD d1-6) or d8 (+rifampin 600 mg QD d1-9) of period 2. In study 3, futibatinib 20 mg was given on d1 of period 1 (-lansoprazole) and d5 of period 2 (+lansoprazole 60 mg QD d1-5). Plasma samples for PK assessment were collected predose through 24 h post-midazolam dosing (study 1) and predose through 48 h post-futibatinib dosing (studies 2 and 3). Results In study 1 (N=24), coadministration of futibatinib did not result in clinically significant changes in midazolam PK, based on the area under the concentration curve extrapolated to the last measurable time (AUC0-t; -9%) or infinity (AUC0-inf; -9%) or maximum plasma concentration (Cmax; -5%), compared with midazolam alone. In study 2 (N=40), relative to futibatinib administered alone, coadministration with itraconazole increased futibatinib Cmax (+51%) and plasma exposure (AUC0-t and AUC0-inf +41% each), whereas coadministration with rifampin decreased futibatinib Cmax (-53%) and plasma exposure (AUC0-t and AUC0-inf -64% each). In study 3 (N=20), coadministration of lansoprazole did not result in clinically significant changes in futibatinib PK parameters vs futibatinib alone (AUC0-t +5%; AUC0-inf +5%; Cmax +8%). Agents were well tolerated, and all 3 studies were completed with no clinically relevant safety signals. Conclusions Futibatinib is not expected to affect the exposure of concomitant medications metabolized via CYP3A, the most common drug metabolism pathway. Caution should be exercised when coadministering strong CYP3A inducers or inhibitors with futibatinib, as significant DDIs were observed with itraconazole and rifampin. Futibatinib can be concomitantly administered with PPIs with no clinically relevant impact on futibatinib exposure. Citation Format: Ikuo Yamamiya, John Laabs, Allen Hunt, Toru Takenaka, Daryl Sonnichsen, Mark Mina, Yaohua He, Karim Benhadji. Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT125.

Evaluation of Potential Food Effects and Drug Interactions With Lansoprazole in Healthy Adult Volunteers Receiving Futibatinib

“…Based on in vitro data that showed futibatinib inhibits and is primarily metabolized by cytochrome p450 (CYP) 3A and is a substrate of p‐glycoprotein (P‐gp), phase 1 studies were conducted in healthy subjects to assess the involvement of futibatinib in the CYP and P‐gp pathways 12 . Findings from these studies suggested that futibatinib was not expected to affect the metabolism of concomitant medications metabolized by CYP3A (eg, midazolam) 12 .…”

“…Based on in vitro data that showed futibatinib inhibits and is primarily metabolized by cytochrome p450 (CYP) 3A and is a substrate of p‐glycoprotein (P‐gp), phase 1 studies were conducted in healthy subjects to assess the involvement of futibatinib in the CYP and P‐gp pathways 12 . Findings from these studies suggested that futibatinib was not expected to affect the metabolism of concomitant medications metabolized by CYP3A (eg, midazolam) 12 . However, strong CYP3A/P‐gp inhibitors and inducers (itraconazole and rifampin, respectively) significantly altered futibatinib plasma exposure: itraconazole increased futbatinib C max and AUC by approximately 51% and 41%, respectively, and rifampin decreased futibatinib C max and AUC by approximately 53% and 64%, respectively 12 …”

“…12 Findings from these studies suggested that futibatinib was not expected to affect the metabolism of concomitant medications metabolized by CYP3A (eg, midazolam). 12 However, strong CYP3A/P-gp inhibitors and inducers (itraconazole and rifampin, respectively) significantly altered futibatinib plasma exposure: itraconazole increased futbatinib C max and AUC by approximately 51% and 41%, respectively, and rifampin decreased futibatinib C max and AUC by approximately 53% and 64%, respectively. 12 As a poorly soluble, weak-base, oral drug, 13 futibatinib may interact with a variety of external factors that could alter its bioavailability.…”

Effect of Futibatinib on Cardiac Repolarization: Results of a Randomized, Controlled, Double‐Blind, QT/QTc, Phase 1 Study in Healthy Subjects

“…2 Similar PK outcomes were observed with futibatinib in phase 1 studies evaluating potential drug-drug interactions. 6 The safety profile of futibatinib in phase 1 and phase 2 studies in patients with advanced solid tumors was predictable and manageable [2][3][4] and similar to that of other FGFR inhibitors. [23][24][25][26] The most commonly reported AE with futibatinib was hyperphosphatemia.…”

“…Plasma futibatinib exposures with the 80-mg dose were expected to exceed those experienced at steady state in outlier patients receiving futibatinib 20 mg QD and under conditions of potential decreased elimination (eg, cytochrome P450 3A4 inhibition or hepatic impairment). 6 Cardiac safety is a major factor in drug development because some investigational agents can delay cardiac repolarization or prolong the heart-rate corrected QT (QTc) interval, potentially leading to life-threatening proarrhythmias such as torsades de pointes. 7 A number of cancer therapies, including tyrosine kinase inhibitors (TKIs), are associated with a prolongation of the QTc interval.…”