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BALVERSA(erdafitinib)tablets,(十)
ally insoluble, or insoluble in aqueous media over a widerange of pH values. The molecular formula is C25H30N6O2 and molecular weight is 446.56.
Chemical structure of erdafitinib is as follows:
N
MeO N N
OMe
N
N
Me
NH
BALVERSA (erdafitinib) is supplied as 3 mg, 4 mg or 5 mg film-coated tablets for oral administrationand contains the following inactive ingredients:
Tablet Core: Croscarmellose sodium, Magnesium stearate (from vegetable source), Mannitol,Meglumine, and Microcrystalline Cellulose.
Film Coating: (Opadry amb II): Glycerol monocaprylocaprate Type I, Polyvinyl alcohol-partiallyhydrolyzed, Sodium lauryl sulfate, Talc, Titanium dioxide, Iron oxide yellow, Iron oxide red (for theorange and brown tablets only), Ferrosoferric oxide/iron oxide black (for the brown tablets only).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Erdafitinib is a kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3and FGFR4 based on in vitro data. Erdafitinib also binds to RET, CSF1R, PDGFRA, PDGFRB, FLT4,KIT, and VEGFR2. Erdafitinib inhibited FGFR phosphorylation and signaling and decreased cellviability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, andfusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models
derived from tumor types, including bladder cancer.
12.2 Pharmacodynamics
Cardiac Electrophysiology
Based on eva luation of QTc interval in an open-label, dose escalation and dose expansion study in 187patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval.
Serum Phosphate
Erdafitinib increased serum phosphate level as a consequence of FGFR inhibition. BALVERSA shouldbe increased to the maximum recommended dose to achieve target serum phosphate levels of 5.5–7.0 mg/dL in early cycles with continuous daily dosing [see Dosage and Administration (2.3)].
In erdafitinib clinical trials, the use of drugs which can increase serum phosphate levels, such aspotassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas orlaxatives, and medications known to have phosphate as an excipient were prohibited unless noalternatives exist. To manage phosphate elevation, phosphate binders were permitted. Avoidconcomitant use with agents that can alter serum phosphate levels before the initial dose increase period
based on serum phosphate levels [see Drug Interactions (7.1)].
12.3 Pharmacokinetics
Following administration of 8 mg once daily, the mean (coefficient of variation [CV%]) erdafitinibsteady-state maximum observed plasma concentration (Cmax), area under the curve (AUCtau), andminimum observed plasma concentration (Cmin) were 1,399 ng/mL (51%), 29,268 ng·h/mL (60%), and936 ng/mL (65%), respectively.
Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasmaconcentration [Cmax] and area under the plasma concentration time curve [AUC]) increasedproportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approvedrecommended dose). Steady state was achieved after 2 weeks with once daily dosing and the meanaccumulation ratio was 4-fold.
Absorption
Median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours).
Effect of Food
No clinically meaningful dif |
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