Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection and related morbidity and mortality in infants. Passive immunization with an RSV-neutralizing antibody can provide rapid protection to this vulnerable population. Proof-of-concept for this approach has been demonstrated by palivizumab; however, the use of this antibody is generally restricted to the highest-risk infants due to monthly dosing requirements and its cost.To address the large unmet medical need for most infants, we are evaluating MK-1654, a fully human RSV-neutralizing antibody with half-life extending mutations targeting site IV of the fusion protein. In this 2-part, placebo-controlled, double-blind, first-inhuman study, 152 healthy adults were randomized 3:1 to receive a single dose of MK-1654 or placebo in 5 cohorts (100 or 300 mg as an intramuscular dose or 300, 1000, or 3000 mg as an intravenous dose). Safety, pharmacokinetics, antidrug antibodies, and RSV serum-neutralizing antibody titers were evaluated through 1 year. MK-1654 serum concentrations increased proportionally with dose and resulted in corresponding elevations in RSV serum-neutralizing antibody titers. The antibody displayed a half-life of 73 to 88 days and an estimated bioavailability of 69% at the 300-mg dose. The overall safety profile of MK-1654 was similar to placebo, and treatment-emergent antidrug antibodies were low (2.6%) with no associated adverse events. These data support the continued development of MK-1654 for the prevention of RSV disease in infants.
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.
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.
Futibatinib, a selective, irreversible fibroblast growth factor receptor 1–4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement‐positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P‐glycoprotein (P‐gp) substrate and inhibitor. Futibatinib also showed time‐dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug‐drug interactions of futibatinib with itraconazole (a dual P‐gp and strong CYP3A inhibitor), rifampin (a dual P‐gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration–time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration–time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P‐gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug‐drug interaction studies with P‐gp–specific substrates and inhibitors are planned.
Futibatinib, a selective, irreversible fibroblast growth factor receptor 1–4 inhibitor, was recently approved for FGFR2 rearrangement–positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14C‐futibatinib single oral 20‐mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half‐life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine‐conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14C‐futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1‐aminobenzotriazole (a pan‐cytochrome P450 inhibitor), and glutathione‐ and cysteine‐conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O‐desmethylation and glutathione conjugation, with cytochrome P450 enzyme‐mediated desmethylation as the main oxidation pathway. 14C‐futibatinib was well tolerated in this Phase 1 study.
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