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

Abstract

Futibatinib, an oral, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being evaluated for FGFRaberrant tumors. Two open-label phase 1 studies evaluated the effects of high-fat, high-calorie food and concomitant proton pump inhibitors (PPIs; lansoprazole) on single-dose futibatinib (20 mg) pharmacokinetics and safety in healthy adults. In the food effect study (N = 17), subjects received futibatinib under fed and fasted conditions, separated by a 7-day washout. In the PPI study (N = 20), subjects received futibatinib alone, underwent a 2-day washout, and then received lansoprazole 60 mg once daily for 5 days, with futibatinib also administered on day 5. Under fed versus fasted conditions, futibatinib bioavailability was 11.2% lower (area under the plasma concentration-time curve from time 0 to infinity geometric mean ratio 88.8%; 90% confidence interval, 79.8%-98.9%), and median time to maximum plasma concentration was significantly delayed (4.0 vs 1.5 hours; P < .0001). There were no significant differences in futibatinib exposure between futibatinib plus lansoprazole and futibatinib alone. No serious adverse events occurred in either study. These findings suggest that food and PPIs are unlikely to have clinically meaningful impacts on futibatinib bioavailability. Thus, futibatinib may be used with or without food and concomitantly with acid-reducing agents.

Evaluation of the Mass Balance and Metabolic Profile of Futibatinib in Healthy Participants

“…The pharmacokinetic analysis showed that oral 14 C-futibatinib was rapidly absorbed and metabolized to several compounds. The pharmacokinetic parameters of the 14 C-futibatinib solution in plasma were consistent with that of oral futibatinib 20-mg tablets (5 × 4 mg) in healthy participants from another Phase I study, 13 indicating that the absorption of tablets was similar to that of the solution formulation. The mean total exposure (AUC inf ) of futibatinib was only 41% of plasma radioactivity total exposure suggesting that metabolites contributed to plasma TRA exposures (given that there was complete recovery of radioactivity from plasma).…”

“…Plasma and urine were directly analyzed using liquid scintillation counting. Futibatinib concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as previously reported 13 ; the analytic range (lower limit of quantitation to upper limit of quantitation) was 0.5-250 ng/mL.…”

“…Futibatinib 20 mg once daily was identified as the maximum tolerated dose and determined as the recommended Phase II dose. 6 Although the pharmacokinetic properties of futibatinib have been previously reported in Phase I studies, 6,[11][12][13] the metabolite profiling and elimination routes of futibatinib have yet to be characterized. Mass balance studies using 14 C-radiolabeled drugs provided valuable information on the absorption, distribution, metabolism, and excretion of drug candidates.…”

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

“…The analytical range (lower limit of quantitation to upper limit of quantitation) for futibatinib was 0.500-250 ng/mL. 20 Safety was monitored throughout the study by repeated adverse event (AE) monitoring, vital sign measurements, physical examinations, and clinical laboratory tests. Single 12-lead ECG recordings were used for immediate assessment of safety at the clinical site.…”

“…Plasma futibatinib concentrations were determined using high‐performance liquid chromatography–tandem mass spectrometry methods validated with respect to accuracy, precision, linearity, sensitivity, and specificity. The analytical range (lower limit of quantitation to upper limit of quantitation) for futibatinib was 0.500–250 ng/mL 20 …”