Erdafitinib API Manufacturers

General Description:

Erdafitinib, identified by CAS number 1346242-81-6, is a notable compound with significant therapeutic applications. In early April of 2019, the US FDA approved Janssen Pharmaceutical Companies' brand name Balversa (erdafitinib) as the first-ever fibroblast growth factor receptor (FGFR) kinase inhibitor indicated for patients with locally advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy . At the same time, the FDA also approved the therascreen FGFR RGQ RT-PCR Kit (Qiagen) for utilization as a companion diagnostic with erdafitinib for selecting patients for the indicated therapy . Erdafitinib's innovation lies in the fact that it is the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer, which demonstrates the design of erdafitinib in developing more personalized and precision medicines with the capacity to target cancer treatment to a patient's specific genetic mutation . Considering urothelial cancer is statistically the fourth most common kind of cancer in the world , the introduction of erdafitinib offers a welcome new option in the ever-expanding therapeutic tool kit to treat such prevalent medical conditions. Nevertheless, although erdafitinib was granted Breakthrough Therapy designation and Accelerated Approval from the FDA so as to allow the agency to focus on and expedite the approval process for a medication indicated for a serious condition that fills an unmet medical need using clinical trial data that is believed to predict a genuine clinical benefit for patients with the given condition, such designations mean further ongoing clinical trials are necessary to confirm the clinical benefit of erdafitinib going forward .

Indications:

This drug is primarily indicated for: Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor 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 , 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 . 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 . This above indication is approved under accelerated approval by the US FDA based on tumor response rate . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Erdafitinib undergoes metabolic processing primarily in: It has been determined that erdafitinib is primarily metabolized by the cytochrome CYP2C9 and CYP3A4 isoenzymes . The contribution of CYP2C9 and CYP3A4 in the total clearance of erdafitinib is estimated to be 39% and 20% respectively . Unchanged erdafitinib was ultimately the predominant drug-related moiety found in the plasma - there were no circulating metabolites observed . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Erdafitinib are crucial for its therapeutic efficacy: Following administration of erdafitinib 8 mg once daily, the mean (coefficient of variation ) 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 . Following single and repeat once daily dosing, erdafitinib exposure (maximum observed plasma concentration and area under the plasma concentration time curve ) increased proportionally across the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose) . Steady state was achieved after 2 weeks with once daily dosing and the mean accumulation ratio was 4-fold . The median time to achieve peak plasma concentration (tmax) was 2.5 hours (range: 2 to 6 hours) . 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Erdafitinib is an important consideration for its dosing schedule: The mean effective half-life documented for erdafitinib is 59 hours , although it has also been observed between 50 to 60 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Erdafitinib exhibits a strong affinity for binding with plasma proteins: The protein binding recorded for erdafitinib is approximately 99.8%, and it was determined to be primarily bound to alpha-1-acid glycoprotein . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Erdafitinib from the body primarily occurs through: 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) . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Erdafitinib is distributed throughout the body with a volume of distribution of: The mean apparent volume of distribution determined for erdafitinib is about 26 to 29 L in patients . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Erdafitinib is a critical factor in determining its safe and effective dosage: The mean total apparent clearance (CL/F) documented for erdafitinib is about 0.362 L/h , while the oral clearance has been observed to be approximately 0.26 L/h . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Erdafitinib exerts its therapeutic effects through: Upon administration, it was observed that erdafitinib increased serum phosphate level as a consequence of FGFR inhibition . 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 . 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 . To manage phosphate elevation, phosphate binders were utilized . 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 . 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Erdafitinib functions by: Urothelial cancer is statistically the fourth most common kind of cancer in the world . 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 . 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) . 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 . 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) . Changes to the FGFR genes are consequently thought to promote cell proliferation, migration, angiogenesis, and anti-apoptosis in many cancers including urothelial cancer . 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 . 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 . Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Erdafitinib belongs to the class of organic compounds known as alkyldiarylamines. These are tertiary alkylarylamines having two aryl and one alkyl groups attached to the amino group, classified under the direct parent group Alkyldiarylamines. This compound is a part of the Organic compounds, falling under the Organic nitrogen compounds superclass, and categorized within the Organonitrogen compounds class, specifically within the Amines subclass.

Categories:

Erdafitinib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP2C9 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 Substrates, Fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors, Heterocyclic Compounds, Fused-Ring, Kinase Inhibitor, Narrow Therapeutic Index Drugs, OCT2 Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, P-glycoprotein substrates with a Narrow Therapeutic Index, Protein Kinase Inhibitors, Receptors, Fibroblast Growth Factor, antagonists & inhibitors, Tumor Suppressor Proteins, Tyrosine Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Erdafitinib include:

• Water Solubility:<1 mg/mL