orbitex
Iron
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Before I say anything more, I also uploaded this on tiktok so please check it out this took me 5 hours of dedicated studying to make.
Erdafitinib is an oral tyrosine kinase inhibitor used as a targeted therapy for cancer. It functions by blocking the activity of fibroblast growth factor receptors (FGFRs) 1-4. Commonly FGFR 2 & 3 are mutated or overactive in certain tumors therefore inhibiting tumor cell growth and survival.
These are the following IC50 (substances potency inhibiting a specific biological or biochemical function by 50%) values
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/erdafitinib
FGFR1 is a transmembrane receptor tyrosine kinase that regulates critical biological processes including cell proliferation, differentiation, angiogenesis, and embryonic development. It functions by binding to fibroblast growth factors (FGFs), which triggers receptor dimerization and activates downstream signaling pathways such as RAS-MAPK, PI3k-AKT, and STAT.
TLDR: FGFR1 plays essential roles in:
FGFR2 gene provides instructions for making fibroblast growth factor receptor 2, a protein that spans the cell membrane and plays a critical role in embryonic development, bone growth, and tissue repair. This receptor tyrosine kinase binds to fibroblast growth factors (FGFs), triggering intracellular signaling cascades such as MAPK and PI3K-AKT pathways that regulate cell proliferation, differentiation, and angiogenesis (formation of blood vessels). FGFR2 activity is tightly regulated to maintain tissue homeostasis however activation due to mutations, amplifications, or fusions can drive cancer progression in tissues like the breast, stomach, and bile ducts. Conversely, loss of function mutations are associated with congenital skeletal disorders, such as Apert syndrome and Crouzon syndrome, which involve abnormal skull and limb development
FGFR3 gene provides instructions for making a protein that acts as a negative regulator of endochondral bone growth, particularly in the long bones of the limbs and the skull.
This transmembrane receptor tyrosine kinase functions by:
binding to FGF's on cell surface -> inhibiting proliferation and differentiation of chondrocytes in growth plates -> slowing conversation of cartilage to bone
This means it essentially acts as one of the stopping forces of your skeletal growth, meaning theoretically inhibiting this would allow you to surpass your EAH (expected adult height). We see the reverse affect with FGFR3 gain of function mutations specifically Achondroplasia which is the most common form of dwarfism accounting for 90% of cases.
"Achondroplasia represents the most common genetic cause of dwarfism and the most prevalent skeletal dysplasia, characterized by severe, disproportionate short stature. This condition accounts for more than 90% of cases of disproportionate short stature (ie, dwarfism)." Source: https://www.ncbi.nlm.nih.gov/books/NBK559263/)
FGFR4 is a cell surface receptor tyrosine kinase that regulates cell proliferation, differentiation, migration, and metabolic homeostasis.
Primary Functions:
FGFR-1:
FGFR-2:
FGFR-3:
FGFR-4:
Shared risks across all FGFRs:
SOURCE
A huge question is: How much am I inhibiting my FGFR1-4 at average dosages? We will do a break down of different thresholds and how they affect the body.
The process to calculate:
Because we mainly have data at 8mg lets convert total -> free molar concentration (a good average):
Cavg total = 1,219.5 ng/mL x (1000/446.56) = 2,731nM
Cavg free = 2,731 nM x 0..002 = 5.46
Scale to 2mg and 4mg:
Dose | Free Cavg
2mg | 1.37 nM
4mg | 2.73 nM
6mg | 5.46 nM
Apply % Inhibition via following formula: C / (C+ Ic50) x 100:
Dose | FGFR1 | FGFR2 | FGFR3 | FGFR4
2mg | 53.3% | 35.4% | 31.4% | 19.4%
4mg | 69.5% | 52.2% | 47.6% | 32.4%
8mg | 82.0% | 68.6% | 64.5% | 48.9%
Now many of you I believe have seen the incidence rates of symptoms on erdafitinib which I will include. Please note inhibition response relationships are often non linear especially at the high end (80-100% inhibition approaching complete shutdown) Side effects can become disproportionately worse as you approach near or complete shutdown of FGFR signaling because the body loses its ability to maintain homeostasis
is it
Here are all the symptoms according too:
SOURCE
Now because I can't go on forever, I will go over the most important symptoms that was also went over:
SOURCE
Now although this isn't the best source, here are the different grades and what they mean:
Hyperphosphatemia is the most common laboratory abnormality with erdafitinib, occurring in 76% of patients. The large majority of these cases are defined as mild (Grade 1-2) Thankfully mild (grade 1) hyperphosphatemia is typically considered harmless in the short to medium term. Doctors usually only intervene (with phosphate binders or dose adjustment) when it reaches Grade 2 or higher or if it stays elevated for a long time. As for the phosphate decrease occurring 15% of the time this can either be attributed to homeostasis or by the fact that the target demographic on erdafitinib are likely experiencing minor Rhabdomyolysis (skeletal muscle breaking down releasing myoglobin into the bloodstream) as they have already when through chemotherapy & the average age is 67.
According to https://www.ema.europa.eu/en/documents/product-information/balversa-epar-product-information_en.pdf "Hypophosphataemia can occur during treatment with Balversa. Serum phosphate level should be monitored during erdafitinib treatment and erdafitinib treatment breaks. If the serum phosphate level falls below normal, phosphate-lowering therapy and dietary phosphate restrictions (if applicable) should be discontinued. Severe hypophosphataemia may present with confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and 8 haemolytic anaemia. For dose modifications see section 4.2. Hypophosphataemia reactions were Grade 3-4 in 1.0% of patients."
Now as for the eye issues this part is a bit more nuanced, as I mentioned 4mg vs 8mg is a HUGE difference so the notion that the incidence rate would be the same isn't logical at all, on top of this again, these people's average age was 67 and have already taken chemo therapy which has failed. I'm not saying there's a non-zero risk, just claiming it needs to be looked into more. Grade 1-2 Dry eyes can easily be mitigated with basic eyedrops and if you experience grade 1 vision blurring is generally considered okay, while grade 2 requires more attention (dosage reeducation).
Central serous retinopathy (CSR) / retinal pigment epithelial detachment is the more serious ocular toxicity associated with FGFR inhibitors. While the I'm not claiming the overall risk in non zero even at lower doses it is clearly exposure dependent. Regular eye exams are recommended in clinical use, and this risk needs further study in non cancer populations using lower doses.
Going back to the question at the start of this threadI believe you can reduce the risk with a low dose + careful monitoring. The sides that people previously fearmonger don't seem that extreme especially because we are taking 50% less then the therapeutic window. The only thing I'd add is that there are zero long term studies on what this drug can do so its 100% plausible that there can be long term ramifications. With that being said, yes, erdafitinib can be mitigated.
Can you truly mitigate erdafitinib? an in-depth explanation
What even is erdafitinib?
Erdafitinib is an oral tyrosine kinase inhibitor used as a targeted therapy for cancer. It functions by blocking the activity of fibroblast growth factor receptors (FGFRs) 1-4. Commonly FGFR 2 & 3 are mutated or overactive in certain tumors therefore inhibiting tumor cell growth and survival.
These are the following IC50 (substances potency inhibiting a specific biological or biochemical function by 50%) values
- FFR-1 - 1.2nM
- FGFR-2 - 2.5nM
- FGFR-3 - 3.0nM
- FGFR-4 - 5.7nM
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/erdafitinib
What even is Tyrosine Kinase?
Tyrosine kinase is an enzyme that transfers a phosphate group from ATP to the amino acid tyrosine on specific proteins acting as an "on" or "off" switch for various cellular functions. In the context of erdafitinib this means pan inhibition of FGFR 1-4.What does FGFR 1 do?
FGFR1 is a transmembrane receptor tyrosine kinase that regulates critical biological processes including cell proliferation, differentiation, angiogenesis, and embryonic development. It functions by binding to fibroblast growth factors (FGFs), which triggers receptor dimerization and activates downstream signaling pathways such as RAS-MAPK, PI3k-AKT, and STAT.
TLDR: FGFR1 plays essential roles in:
- Skeletal and Organ Development as it's required for normal skeletogenesis, axial organization, and the development of various organs during embryogenesis
- Neural Function: It is critical for the formation, survival, and migration of neurons, particularly those producing gonadotropin-releasing hormone (GnRH), which directs sexual development
- Sensory Processing: It contributes to the processing of smells by olfactory neurons and the development of the inner ear
- Cancer Progression: Aberrations in FGFR1, such as amplifications of mutations, are linked to various cancers by promoting tumor cell survival, invasion, and metastasis
What does FGFR 2 do?
FGFR2 gene provides instructions for making fibroblast growth factor receptor 2, a protein that spans the cell membrane and plays a critical role in embryonic development, bone growth, and tissue repair. This receptor tyrosine kinase binds to fibroblast growth factors (FGFs), triggering intracellular signaling cascades such as MAPK and PI3K-AKT pathways that regulate cell proliferation, differentiation, and angiogenesis (formation of blood vessels). FGFR2 activity is tightly regulated to maintain tissue homeostasis however activation due to mutations, amplifications, or fusions can drive cancer progression in tissues like the breast, stomach, and bile ducts. Conversely, loss of function mutations are associated with congenital skeletal disorders, such as Apert syndrome and Crouzon syndrome, which involve abnormal skull and limb development
What does FGFR 3 do?
FGFR3 gene provides instructions for making a protein that acts as a negative regulator of endochondral bone growth, particularly in the long bones of the limbs and the skull.
This transmembrane receptor tyrosine kinase functions by:
binding to FGF's on cell surface -> inhibiting proliferation and differentiation of chondrocytes in growth plates -> slowing conversation of cartilage to bone
This means it essentially acts as one of the stopping forces of your skeletal growth, meaning theoretically inhibiting this would allow you to surpass your EAH (expected adult height). We see the reverse affect with FGFR3 gain of function mutations specifically Achondroplasia which is the most common form of dwarfism accounting for 90% of cases.
"Achondroplasia represents the most common genetic cause of dwarfism and the most prevalent skeletal dysplasia, characterized by severe, disproportionate short stature. This condition accounts for more than 90% of cases of disproportionate short stature (ie, dwarfism)." Source: https://www.ncbi.nlm.nih.gov/books/NBK559263/)
What does FGFR 4 do?
FGFR4 is a cell surface receptor tyrosine kinase that regulates cell proliferation, differentiation, migration, and metabolic homeostasis.
Primary Functions:
- Metabolic Regulation: Highly expressed in mature hepatocytes, binds primarily to FGF19 to suppress CYP7A1 and regulates bile acid biosynthesis and cholesterol homeostasis. FGF19 signaling through FGFR4 also has secondary effects on glucose uptake and hepatic glycogen synthesis.
- Developmental Processes: Plays a role in embryonic development and skeletal muscle progenitor cell differentiation (myoblast maturation)
- Cell Signaling: Upon ligand binding, FGFR4 undergoes autophosphorylation, activating downstream cascades RAS-MAPK, PI3K-AKT, and PLCγ which drive cell survival and growth.
- Tumor Progression: In cancer, aberrant FGFR4 signaling (often via FGF19/FGFR4/KLB amplification) promotes tumor growth and proliferation, most notably in hepatocellular carcinoma, making it a therapeutic target.
Wow that's a lot of information, TLDR why do people use it for height?
- As mentioned people use erdafitinib for height because of it's effect on FGFR3 (a gene that acts as a negative regulator of endochondral bone growth, i.e. limbs & skull) FGFR3 acts through the following process:
Out of everything you listed about FGFR1-4, what's actually to be of concern when inhibiting them?
FGFR-1:
- Drives hyperphosphatemia (high blood phosphate, seen in ~70-80% of patients) This can cause soft tissue and vascular calcification
FGFR-2:
- Leads to skin and nail problems (onycholysis, paronychia, hand-foot syndrome, dry skin, mouth sores) These are very common and can be painful or does limiting
FGFR-3:
- Inhibiting it can accelerate bone growth by removing the brake on chondrocytes. However, this has caused abnormal overgrowth, kyphoscoliosis (spinal curvature), and slipped capital femoral epiphysis (hip problems requiring surgery) in children on the drug.
FGFR-4:
- Causes diarrhea and disrupts bile acid/cholesterol metabolism
Shared risks across all FGFRs:
- Eye toxicity: CSR (Central serous retinopathy) and vision changes
- Fatigue, elevated liver/kidney markers, and electrolyte issues.
Estimated % inhibition of FGFR1-4 2mg vs 4mg vs 8mg
SOURCE
A huge question is: How much am I inhibiting my FGFR1-4 at average dosages? We will do a break down of different thresholds and how they affect the body.
The process to calculate:
Because we mainly have data at 8mg lets convert total -> free molar concentration (a good average):
Cavg total = 1,219.5 ng/mL x (1000/446.56) = 2,731nM
Cavg free = 2,731 nM x 0..002 = 5.46
Scale to 2mg and 4mg:
Dose | Free Cavg
2mg | 1.37 nM
4mg | 2.73 nM
6mg | 5.46 nM
Apply % Inhibition via following formula: C / (C+ Ic50) x 100:
Dose | FGFR1 | FGFR2 | FGFR3 | FGFR4
2mg | 53.3% | 35.4% | 31.4% | 19.4%
4mg | 69.5% | 52.2% | 47.6% | 32.4%
8mg | 82.0% | 68.6% | 64.5% | 48.9%
% Inhibition nuance explained
Now many of you I believe have seen the incidence rates of symptoms on erdafitinib which I will include. Please note inhibition response relationships are often non linear especially at the high end (80-100% inhibition approaching complete shutdown) Side effects can become disproportionately worse as you approach near or complete shutdown of FGFR signaling because the body loses its ability to maintain homeostasis
is it
Symptoms and adverse reactions
Here are all the symptoms according too:
SOURCE
Symptoms and adverse reactions explained
Now because I can't go on forever, I will go over the most important symptoms that was also went over:
- Dry eye | All grades 28% | Grades 3-4 6%
- Vision Blurred | All grades 17% | Grades 3-4 0%
- Phosphate increases | All grades 76% | Grades 3-4 1%
- Phosphate decrease | All grades 24% | Grades 3-4 9%
- Dry eye: 22%
- Vision Blurred: 17%
- Phosphate increases: 75%
- Phosphate decrease: 15%
SOURCE
Now although this isn't the best source, here are the different grades and what they mean:
- Mild
- Moderate
- Severe
- Life-threatening
- Death
Symptoms and adverse reactions explained pt2
Hyperphosphatemia is the most common laboratory abnormality with erdafitinib, occurring in 76% of patients. The large majority of these cases are defined as mild (Grade 1-2) Thankfully mild (grade 1) hyperphosphatemia is typically considered harmless in the short to medium term. Doctors usually only intervene (with phosphate binders or dose adjustment) when it reaches Grade 2 or higher or if it stays elevated for a long time. As for the phosphate decrease occurring 15% of the time this can either be attributed to homeostasis or by the fact that the target demographic on erdafitinib are likely experiencing minor Rhabdomyolysis (skeletal muscle breaking down releasing myoglobin into the bloodstream) as they have already when through chemotherapy & the average age is 67.
According to https://www.ema.europa.eu/en/documents/product-information/balversa-epar-product-information_en.pdf "Hypophosphataemia can occur during treatment with Balversa. Serum phosphate level should be monitored during erdafitinib treatment and erdafitinib treatment breaks. If the serum phosphate level falls below normal, phosphate-lowering therapy and dietary phosphate restrictions (if applicable) should be discontinued. Severe hypophosphataemia may present with confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and 8 haemolytic anaemia. For dose modifications see section 4.2. Hypophosphataemia reactions were Grade 3-4 in 1.0% of patients."
Symptoms and adverse reactions explained pt3
Now as for the eye issues this part is a bit more nuanced, as I mentioned 4mg vs 8mg is a HUGE difference so the notion that the incidence rate would be the same isn't logical at all, on top of this again, these people's average age was 67 and have already taken chemo therapy which has failed. I'm not saying there's a non-zero risk, just claiming it needs to be looked into more. Grade 1-2 Dry eyes can easily be mitigated with basic eyedrops and if you experience grade 1 vision blurring is generally considered okay, while grade 2 requires more attention (dosage reeducation).
Central serous retinopathy (CSR) / retinal pigment epithelial detachment is the more serious ocular toxicity associated with FGFR inhibitors. While the I'm not claiming the overall risk in non zero even at lower doses it is clearly exposure dependent. Regular eye exams are recommended in clinical use, and this risk needs further study in non cancer populations using lower doses.
Final verdict
Going back to the question at the start of this threadI believe you can reduce the risk with a low dose + careful monitoring. The sides that people previously fearmonger don't seem that extreme especially because we are taking 50% less then the therapeutic window. The only thing I'd add is that there are zero long term studies on what this drug can do so its 100% plausible that there can be long term ramifications. With that being said, yes, erdafitinib can be mitigated.
