DESCRIPTION Erdafitinib is an investigational compound which is a pan inhibitor of the fibroblast growth factor receptor tyrosine kinases, FGFR1-4 .

HALF-LIFE The mean effective half-life documented for erdafitinib is 59 hours [FDA Label], although it has also been observed between 50 to 60 hours [A177115].

PHARMACODYNAMICS Upon administration, it was observed that erdafitinib increased serum phosphate level as a consequence of FGFR inhibition [FDA Label][A177109, A177115]. Erdafitinib should be 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 [FDA Label][A177109, A177115].; ; Subsequently, in erfatinib clinical trials, the use of drugs which could increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and medications known to have phosphate as an excipient were prohibited unless no alternatives existed [FDA Label][A177109, A177115]. To manage phosphate elevation, phosphate binders were utilized [FDA Label][A177109, A177115]. Additionally, the concomitant use of agents that can alter serum phosphate levels before the initial erfatinib dose increase period based on serum phosphate levels was also avoided [FDA Label][A177109, A177115].; ; Furthermore, based on the evaluation of QTc interval in an open-label, dose escalation, and dose expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., > 20 ms) on the QTc interval [FDA Label].

MOA Urothelial cancer is statistically the fourth most common kind of cancer in the world [F4372]. In general, such urothelial cancers originate in the urothelium - or the transitional epithelium - a membrane that covers the renal pelvis to the ureter, the bladder, and the proximal two-thirds of the urethra [F4372]. While 90 to 95% of urothelial cancers are bladder cancers and the other 5 to 10% are upper tract urothelial cancers, the bladder cancers can also be either superficial or invasive (either not having or having invaded the deeper layers of the bladder) [F4372].; ; Moreover, fibroblast growth factor receptor (FGFR) is a transmembrane protein that is expressed ubiquitously in normal tissues and is involved in various endogenous bio-physiological processes including the homeostasis of phosphate and vitamin D, cell proliferation, cell anti-apoptotic signaling, and cell migration in a variety of cell types [A177109]. Concurrently, genetic mutations or changes like deregulation of FGFR pathways and FGFR aberrations such as gene amplification, point mutations, and chromosomal translocations have been implicated in the pathogenesis of urothelial cancer, including the possibility of such changes to all four FGFR genes (FGFR1, FGFR2, FGFR3, and FGFR4) [A177109, F4372]. Changes to the FGFR genes are consequently thought to promote cell proliferation, migration, angiogenesis, and anti-apoptosis in many cancers including urothelial cancer [A177109, F4372].; ; Erdafitinib is subsequently an oral selective pan-FGFR kinase inhibitor that binds to and inhibits the enzymatic activity of expressed FGFR1, FGFR2, FGFR3, and FGFR4 based on in vitro data [FDA Label][A177109, A177115]. In particular, erdafitinib demonstrates inhibition of FGFR phosphorylation and signaling as well as decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions [FDA Label][A177109, A177115]. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer [FDA Label][A177109, A177115].

INDICATION Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor [FDA Label][A177109, A177112, A177115] that is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has:; i) susceptible FGFR3 or FGFR2 genetic alterations and has [FDA Label],; ii) progressed during or following at least one line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy [FDA Label].; ; The selection of patients for the treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib should be based on the presence of susceptible FGFR genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic like the FDA approved therascreen FGFR RGQ RT-PCR Kit as developed by QIAGEN [FDA Label].; ; This above indication is approved under accelerated approval by the US FDA based on tumor response rate [FDA Label]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [FDA Label].

ROE After administering a single oral dose of radiolabeled erdafitinib, about 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged) [FDA Label].

METABOLISM It has been determined that erdafitinib is primarily metabolized by the cytochrome CYP2C9 and CYP3A4 isoenzymes [FDA Label]. The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively [FDA Label]. Unchanged erdafitinib was ultimately the predominant drug-related moiety found in the plasma - there were no circulating metabolites observed [FDA Label].

ABSORPTION Following administration of erdafitinib 8 mg once daily, the mean (coefficient of variation [CV%]) steady-state maximum observed plasma concentration (Cmax), area under the curve (AUCtau), and minimum observed plasma concentration (Cmin) were 1,399 ng/mL (51%), 29,268 ng·h/mL (60%), and 936 ng/mL (65%), respectively [FDA Label].; ; Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration [Cmax] and area under the plasma concentration time curve [AUC]) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose) [FDA Label]. Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold [FDA Label].; ; The median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours) [FDA Label]. And finally, no clinically meaningful differences with erdafitinib pharmacokinetics were observed following administration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in healthy subjects [FDA Label].

DESCRIPTION Erdafitinib (JNJ-42756493) is a potent and orally available FGFR family inhibitor; inhibits FGFR1/2/3/4 with IC50s of 1.2, 2.5, 3.0 and 5.7 nM, respectively.

PRICE 58

DESCRIPTION Erdafitinib is a pan-fibroblast growth factor receptor (FGFRs 1-4) tyrosine kinase inhibitor . It is the first targeted drug to be approved for advanced bladder cancer. (GtoPdb)

DESCRIPTION On april 2019, FDA approved erdafitinib to treat adult patients with locally advanced or metastatic bladder cancer (PKIDB)

DESCRIPTION Erdafitinib (JNJ-42756493), a quinoxaline derivative, targets FGFR1/2/3/4. (TargetMol Bioactive Compound Library)