Erdafitinib - Dosage, Indications, and Side Effects

What Is Erdafitinib?

Erdafitinib is a prescription targeted anticancer drug used for treating urothelial carcinoma (a type of bladder cancer) in adult patients. It is used when there is a specific change in the FGFR (fibroblast growth factor receptor) gene and surgery is not an option for treating the cancer. It is also given to patients who have had at least one unsuccessful platinum-containing chemotherapy treatment.

Is Erdafitinib FDA Approved?

Based on the tumor response rate, the United States Food and Drug Administration (USFDA) granted it accelerated approval on April 12th, 2019.

How Effective Is Erdafitinib?

Erdafitinib belongs to a class of kinase inhibitors (drugs that inhibit the kinase enzyme, which promotes cell growth) and works by blocking the abnormal proteins that signal cancer cells to multiply, preventing or slowing the spread of cancer cells. It targets the susceptible FGFR genetic alterations in patients with metastatic bladder cancer. The introduction of Erdafitinib is a new option in treating such malignant conditions.

What Are the Indications of Erdafitinib?

This treatment is advised for people who have advanced bladder cancer that has spread to other parts of the body as well. It is used when the cancer has not improved or gotten worse even after treatment

with platinum-based chemotherapy (a type of treatment that kills cancer cells by damaging their DNA). It can also help patients who have received platinum chemotherapy before or after surgery to lower the chances of cancer relapse.

What Is the Recommended Dosage of Erdafitinib?

Patients who have advanced or metastatic urothelial carcinoma are selected for treatment with Erdafitinib based on the presence of susceptible FGFR gene differentiation in tumor specimens, which is diagnosed by an FDA-approved companion diagnostic test. Erdafitinib is readily available as 3 mg, 4 mg, and 5 mg tablets. An initial dose of two 4mg tablets should be taken orally once daily.

A gradual increase in dose is done based on the tolerance achieved at 14 to 21 days, with serum phosphate levels (PO4) less than 5.5 milligrams per deciliter (mg/dL), with no ocular disorders or grade 2 or severe adverse reactions. Phosphate levels are checked monthly for hyperphosphatemia.

What Precautions Should Be Taken While Taking Erdafitinib?

1. Embryo-fetal Toxicity:

Based on animal studies, Erdafitinib may result in fetal damage when given to pregnant women. For that reason, pregnant women are informed of the risk to the fetus. Female patients with reproductive potential should apply effective birth control methods while taking Erdafitinib and for one month following the last dose.

2. Eye Disorders:

Erdafitinib may cause ocular disorders, including central serous retinopathy (CSR) (a medical condition in which fluid builds up under the retina, causing blurred or distorted vision) or retinal pigment epithelial detachment (RPED) (retinal layer separation), which can lead to visual field defects. It was reported in approximately 25 percent of patients treated with Erdafitinib, with the first onset occurring at 50 days.

Some patients may develop dry eyes during treatment, so all patients should use moisturizing eye drops as a preventive measure. Regular eye checkups are required during the first 4 months of treatment and then every 3 months, or immediately if any vision problems occur. If central serous retinopathy develops, Erdafitinib should be stopped, and it must be permanently discontinued if the condition is severe (Grade IV) or does not improve within 4 weeks.

3. Hyperphosphatemia:

Treatment with Erdafitinib can cause an increase in phosphate levels, which onsets approximately 20 days after treatment initiation. The patient is therefore frequently monitored for hyperphosphatemia, and doses may be adjusted as needed.

What Are the Side Effects of Erdafitinib?

Serious side effects of Erdafitinib include:

• Vision changes such as blurred vision, loss of vision, etc.
• Muscle cramps, numbness, and tingling sensations around the mouth.
• Skin peel on the palms and soles, along with nail changes.
• Itchy, painful, dry, or cracked skin and rash.
• Swelling, pain, and redness of the hands and feet.
• Increased blood phosphate levels.

Some of the common side effects include:

• Nausea and vomiting.
• Dry mouth, sore lips, throat, and mouth.
• Change in taste perception.
• Decreased appetite.
• Fever.
• Diarrhea (loose or watery stools).
• Hair loss or thinning of hair.
• Fatigue.
• Constipation.
• Stomach pain.
• Shortness of breath.
• Burning sensation during urination.
• Muscle and joint pain.
• Anemia.

How Should Erdafitinib Be Stored?

Erdafitinib must be stored at room temperature between 20 and 25 degrees Celsius (68 and 77 degrees Fahrenheit), out of the reach of children.

How Should Erdafitinib Be Taken?

• Erdafitinib must be taken exactly as prescribed by the healthcare provider. It must be taken once a day, and the tablets must be swallowed whole, with or without food. It must not be crushed, dissolved, or chewed.
• If a dose is missed, it must be taken as soon as possible on the same day, and the next dose must be taken on the next day at the regularly scheduled time. In case of vomiting, another dose must not be taken; the regular dose should be taken the next day.
• Erdafitinib dose must not be modified, skipped, or stopped without consultation with a healthcare professional.
• The doctor may modify the dose or temporarily or permanently discontinue it in the presence of specific side effects.

What Are the Important Instructions About Erdafitinib?

• The healthcare provider will test for specific gene mutations to ensure the patient's treatment is effective.
• Females must not become pregnant during the period of treatment with Erdafitinib and, hence, must follow effective contraception methods during the treatment and for one month after the last dose. A pregnancy test may be advised before beginning therapy with Erdafitinib.
• Breastfeeding must not be done during the treatment with Erdafitinib and for one month after the final dose.
• Phosphate levels are periodically monitored during the treatment, and dose changes may be made if needed.

What Should Patients Tell Their Doctor Before Taking Erdafitinib?

• Tell your doctor if you have any vision or eye problems.
• Before starting Erdafitinib, tell your doctor if you are pregnant or breastfeeding (or plan to be), as this medication can cause harm to an unborn baby.
• Tell your doctor about all medicines you take, including prescription drugs, over-the-counter medicines, vitamins, and herbal supplements.

For Doctors

Clinical Pharmacology

Mechanism of Action

Erdafitinib acts by binding to and inhibiting FGFR enzyme activity, thereby blocking FGFR-mediated phosphorylation and signaling pathways that drive cell variability in cell lines with FGFR gene alterations. It thus prevents tumor cell proliferation and leads to cell death in tumor cells that overexpress FGFR.

Pharmacokinetics

Following an 8 mg oral dose, steady state was achieved at a plasma concentration of 1399 nanograms per milliliter (ng/mL), the area under the curve (AUC) was 29,268 ng h/mL, and the minimum plasma concentration was 936 ng/mL. Following multiple daily doses, Erdafitinib exposure exhibited a peak plasma concentration, and AUC was proportional to dose (dose range of 0.5 to 12 mg). A steady state was achieved after two weeks following a single daily dose.

• Absorption:

No major differences in the pharmacokinetics of Erdafitinib were observed following a high-fat meal containing approximately 800 to 1000 calories. A peak plasma concentration was achieved in 2.5 hours (approximately 2 to 6 hours).

• Distribution:

The protein binding capacity of Erdafitinib was 99.8% (primarily to alpha-1-acid glycoprotein), and the mean apparent volume of distribution in patients was approximately 29 Litres.

• Metabolism:

Erdafitinib is mainly metabolized by the enzymes CYP2C9 AND CYP3A4, and the total clearance is 39 percent and 20 percent, respectively. No circulating metabolites were detected; however, the major drug-related moiety, unchanged Erdafitinib, was present in plasma.

• Excretion:

Erdafitinib has a total apparent clearance of 0.362 L/h (liters per hour), and the mean effective half-life was 59 hours in patients. After a single dose, 69 percent was recovered in feces and 19 percent in urine.

Pharmacodynamics

After administration of Erdafitinib, serum phosphate levels increased due to FGFR inhibition. To manage this, phosphate binders were used, and the concomitant use of agents that alter serum phosphate levels was avoided. Based on QTc interval evaluation, a dose-expansion study of Erdafitinib in 187 patients showed no significant effects.

Results of Clinical Studies

• An open-label, multicenter, single-arm study determined Erdafitinib's safety and efficacy in patients with locally advanced or metastatic urothelial carcinoma. The testing group was a cohort of 87 patients with a disease that progressed following at least one previous chemotherapy regimen, as well as at least one genetic alteration.
• Tumor samples from 69 patients were tested based on an FDA-approved test. Patients received an initial dose of 8 mg Erdafitinib once daily, gradually increasing to 9 mg once daily in patients whose serum phosphate levels were below 5.5 mg/dL, between 14 and 17 days, until disease progression or unacceptable toxicity.
• Three percent of patients had disease progression following prior platinum-based therapy, and partial response was noted in 29.9 percent of patients.

Non-Clinical Toxicology

Erdafitinib has not been evaluated for carcinogenicity or fertility in animals. The drug was not mutagenic (causes changes in genetic material) in the bacterial reverse mutation assay (Ames test). However, a three-month toxicity study at exposure levels below the maximum recommended human dose showed some effects on the female reproductive organs of rats.

Drug Interactions

Some drugs that interact with Erdafitinib include:

• Atorvastatin.
• Butabarbital.
• Alpelisib.
• Calcium acetate.
• Calcium carbonate.
• Cetirizine.
• Chloramphenicol.
• Carbamazepine.
• Clarithromycin.
• Cyclosporin.
• Dexamethasone.
• Digoxin.
• Erythromycin.
• Fluconazole.
• Ibuprofen.
• Itraconazole.
• Methotrexate.
• Omeprazole.
• Verapamil.
• Voriconazole.

Use of Erdafitinib in Specific Populations

• Pregnancy:

There are no available data on Erdafitinib use in pregnant women. Animal studies show that Erdafitinib causes fetal malformations and embryo-fetal death when administered during organogenesis at exposures below the maximum recommended human dose (based on AUC). Therefore, Erdafitinib may cause fetal harm, and pregnant women should be advised of the potential risk to the fetus.

• Nursing Mothers:

There are no data on the presence of Erdafitinib in human milk, its effects on breastfed children, or milk production. Erdafitinib carries risks for unborn and nursing infants. Patients should notify their healthcare provider of any pregnancy or breastfeeding status. Note that breastfeeding is not recommended during treatment and should be avoided for at least 1 month following the final dose.

• Infertility:

According to animal studies, Erdafitinib can impair fertility in females of reproductive potential.

• Pediatric Use:

The safety and effectiveness of Erdafitinib have not been established in pediatric patients.

• Geriatric Use:

In clinical studies, among the 416 patients (45 percent aged 65+ and 12 percent aged 75+), no significant differences were observed compared with younger patients.

• CYP2C9 Genotype:

Plasma concentrations of Erdafitinib were higher in patients with the CYP2C9 genotype, and patients suspected to have such genotypes are frequently monitored due to an increased risk of adverse reactions.

What Are the Alternatives to Erdafitinib?

• Enfortumab vedotin and Sacituzumab govitecan.
• Immunotherapy drugs like Pembrolizumab and Atezolizumab.
• Chemotherapy with platinum drugs such as Cisplatin and Carboplatin.

Conclusion

Erdafitinib is a breakthrough in precision oncology for patients with advanced bladder cancer who have particular genetic changes related to the fibroblast growth factor receptor (FGFR). It provides a crucial alternative when conventional therapies are ineffective by targeting specific mutations.

But because it has special hazards, such as eye toxicity, and its effectiveness is dependent on specific genetic markers, it should only be used after consulting a cancer specialist.