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Roxadustat

Evrenzo — FG-4592, a HIF prolyl-hydroxylase inhibitor

Performance & EnduranceOral✅ Clinically validated

Roxadustat (Evrenzo — FG-4592, a HIF prolyl-hydroxylase inhibitor) is a performance & endurance research compound. An inhibitor of the prolyl hydroxylase enzymes that tag hypoxia-inducible factor for destruction when oxygen is plentiful. Block them and HIF survives in a normally oxygenated cell, which is chemically the same signal a body reads at altitude: erythropoietin transcription rises from kidney and liver, hepcidin falls so stored iron is released, and iron-handling proteins are upregulated together rather than singly. That coordinated iron effect is the real difference from injected erythropoietin, which raises the demand for iron without doing anything about the supply.

Research & educational use only. The information below summarizes published research and mechanisms. It is not medical advice or a recommendation for human use. The protocol that uses it — dosing, sequence and what to retest — is inside Skool ($10/mo).

Roxadustat quick facts

RouteOral
Frequency3x weekly in the registration trials
Half-life~12 hrs; three-times-weekly dosing is what the trials used
FormsOral
Evidence levelApproved for anemia of chronic kidney disease in China, Japan, the EU and elsewhere; the FDA declined it in 2021. Prohibited in sport.
Coach Cam’s take

This is a prescription medicine for anemia of kidney disease and a prohibited substance in sport, and both of those facts are the page rather than a footnote. It is the closest thing in pharmacology to a pill that fakes altitude, which is exactly why the anti-doping literature has spent years building assays for it — including one that finds it in hair and nails, long after blood and urine are clean. The efficacy question is settled and the safety question is not: across more than twenty-seven thousand patients the hemoglobin response is not in doubt and the cardiovascular verdict still is.

How Roxadustat works

An inhibitor of the prolyl hydroxylase enzymes that tag hypoxia-inducible factor for destruction when oxygen is plentiful. Block them and HIF survives in a normally oxygenated cell, which is chemically the same signal a body reads at altitude: erythropoietin transcription rises from kidney and liver, hepcidin falls so stored iron is released, and iron-handling proteins are upregulated together rather than singly. That coordinated iron effect is the real difference from injected erythropoietin, which raises the demand for iron without doing anything about the supply.

⚠️ Good to know: Prescription-only. Approved for anemia of chronic kidney disease in China, Japan and the EU; the FDA declined it in 2021 over the cardiovascular safety question. Prohibited in sport, and detectable in hair and nails long after blood and urine clear.

Where to get Roxadustat

Buy Roxadustat at RUPharma →
Use code CAMERON at checkout
Before you run this, know your numbers

Approved for anemia of chronic kidney disease in China, Japan and the EU, declined by the FDA in 2021, and prohibited in sport. It works by making the body behave as though it is at altitude.

It raises red cell mass, so the number that matters is hemoglobin and hematocrit on a CBC — the trials targeted a hemoglobin ceiling precisely because overshooting it is where the thrombotic risk lives. Iron gets consumed building those cells, which is why iron studies belong beside it.

CBC →Iron panel →Ferritin →
Order these through my Marek link →

The evidence for Roxadustat

Graded by what exists behind each claim.

✅ Clinically validated

📊 Correlative data

🧪 Theoretical / extrapolated

How to read these tiers: they say how much human evidence exists, not how well something works — and ✗ flags harm, never a disappointing trial. How the evidence tiers work →

What Roxadustat actually does

The oxygen sensor, named. Hypoxia-inducible factor is a transcription factor built from an alpha subunit and a beta subunit. In a normally oxygenated cell the alpha subunit is hydroxylated on specific proline residues by prolyl hydroxylase domain enzymes, which uses molecular oxygen as a substrate. The hydroxylated proline is recognized by the von Hippel-Lindau protein, which tags it for destruction. Oxygen is therefore consumed by the enzyme that destroys the oxygen-response factor, which is what makes those hydroxylases a sensor rather than merely a switch. Roxadustat inhibits them, so the alpha subunit survives in a cell that is not short of oxygen at all.

What survives, and what it turns on. Stabilized HIF drives erythropoietin transcription in kidney and liver, and it does something injected erythropoietin cannot: it suppresses hepcidin, the liver peptide that locks iron inside macrophages and enterocytes, while upregulating the transporters and ferroxidases that move iron into plasma. That is why the meta-analysis comparing this class with erythropoiesis-stimulating agents finds a different iron picture rather than merely a different route Zheng 2023. Injected erythropoietin raises the demand for iron. A HIF stabilizer raises the demand and releases the supply.

Why the liver matters here and does not for an injection. Erythropoietin production shifts from liver to kidney during development and the hepatic capacity remains latent. An oral drug reaching the portal circulation hits hepatocytes at high concentration before systemic distribution, which is the mechanistic reason this class raises endogenous erythropoietin into a physiologic range rather than to the supraphysiologic peaks an injection produces. Peak concentration, not total exposure, is the variable that distinguishes them.

The part that is not about red cells at all. HIF is a master regulator, and its other targets include vascular endothelial growth factor and a large set of glycolytic enzymes. Stabilizing it systemically means turning on a program the body normally runs only where oxygen is low. That breadth is the mechanistic root of the safety debate this class has not settled: a review of 27,228 patients is titled around exactly that unresolved position Fishbane 2023.

Cell, rodent, human — and where it stops

The efficacy question is closed and the safety question is not. Sackeyfio 2024 is a network meta-analysis across dialysis-dependent and non-dialysis chronic kidney disease populations, comparing HIF prolyl hydroxylase inhibitors against each other and against erythropoiesis-stimulating agents. The hemoglobin response is established. What the same literature has not settled is the cardiovascular one: Tian 2024 is a systematic review and meta-analysis written specifically about cardiovascular and renal safety outcomes for this drug, which is not a question anyone publishes about a drug whose safety is agreed.

The regulatory split is the clearest single fact about it. It is approved for anemia of chronic kidney disease in China, Japan and the European Union, and the United States Food and Drug Administration declined it in 2021. Same molecule, same trial program, different verdicts — which is what a genuinely unresolved risk-benefit judgment looks like from the outside. Fishbane 2023 is a nephrology commentary on exactly that position.

Every patient in every one of those trials had failing kidneys. That is the transfer nobody makes explicit. The population studied is anemic because damaged kidneys make too little erythropoietin; the drug restores a deficient signal toward normal. A person with healthy kidneys and a normal blood count has no deficient signal to restore, so the same drug is not correcting anything — it is pushing a normal system past its set point. No trial has ever been run in that person.

The iron finding is the one worth carrying away. Zheng 2023 compares this class with erythropoiesis-stimulating agents specifically on iron metabolism and inflammation in dialysis patients. The direction of the difference is the mechanism showing up in people: hepcidin suppression mobilizes stored iron. In a person who is not iron replete, that means stores are being spent to make red cells, and ferritin is the number that shows it happening.

Roxadustat pharmacokinetics — how much of it actually gets in

What degrades it. Czock 2022 is a dedicated clinical pharmacokinetics and pharmacodynamics review. The drug is metabolized principally by CYP2C8 with glucuronidation by UGT1A9, and it is a substrate for the OATP1B1 hepatic uptake transporter and for BCRP. Each of those is a real interaction surface: gemfibrozil inhibits CYP2C8, and OATP1B1 inhibition is the route by which a statin's exposure can rise alongside it.

The oral barrier, and why the tablet is separated from other things by the clock. Oral bioavailability is high, but the molecule is chelated in the gut by polyvalent cations — iron salts, calcium, magnesium and phosphate binders — which is why its label separates them in time rather than forbidding them. That is an absorption interaction, not a pharmacodynamic one, and it is the single most common way the drug is accidentally underdosed.

The number that shapes the schedule. The elimination half-life is roughly 12 hours and the registration trials dosed it three times weekly rather than daily Czock 2022. That combination is deliberate: HIF stabilization is intended to be intermittent, producing a pulse of erythropoietin transcription and then allowing the signal to fall, which is closer to how the system behaves at altitude than a continuous drug level would be. A once-daily habit applied to this drug is not a small deviation from the studied regimen.

The injectable comparator, and the asymmetry that matters. Erythropoiesis-stimulating agents are given by injection and produce plasma erythropoietin far above anything the body makes. This drug raises endogenous erythropoietin into a physiologic range instead Zheng 2023. That is genuinely a better-looking profile on paper, and it is also why the class's cardiovascular safety has to be argued from outcome trials rather than assumed from the hormone level: a lower peak hormone with the same rise in red cell mass still raises viscosity by the same amount.

What would have to be true, and how you would know it was not

Four predictions. This is a prescription medicine and the first two are the monitoring a prescriber would already be doing.

1. CBC, and the rate of rise matters more than the destination. Hemoglobin and hematocrit from a standard blood count are the endpoint of every registration trial in this class. The prediction that distinguishes a safe response from an unsafe one is not the final number but the slope: the class's outcome debate Tian 2024 is about how far and how fast red cell mass is pushed. In a person who is not anemic there is no target at all, because that trial has never been run.

2. Ferritin should fall, and if it does not, the mechanism is not engaged. Hepcidin suppression is what separates this class from injected erythropoietin Zheng 2023. A rising hemoglobin with a stable ferritin would be evidence against the proposed mechanism operating in that person. A falling ferritin with an unchanged hemoglobin is stores being emptied for nothing.

3. Iron panel and reticulocyte count are where the mechanism is visible earliest. Reticulocytes are new red cells and they respond within days, long before hemoglobin moves; transferrin saturation shows whether the released iron is actually reaching the marrow. Together they falsify the mechanism faster and more cheaply than the endpoint does.

4. Against any performance use: it is detectable, and not only in blood. Saigusa 2018 identified a methylated metabolite by global metabolomics and notes it clears faster than the glucuronide conjugate. Checkouri 2024 then developed liquid chromatography-tandem mass spectrometry detection of this whole class in hair and nails, matrices that keep a record long after urine and blood are clean, and Thevis 2026 is the annual review of how sports testing keeps up with such compounds. The prediction is simple: assay development is ahead of the assumption that this is invisible.

What nobody has tested yet

Nobody has run it in a person with normal kidneys and a normal blood count. Every efficacy and safety estimate in this file comes from populations with chronic kidney disease. The endurance use this drug is discussed for has no trial, no dose, no duration and no safety estimate, and the reason is not that the trial failed — it is that no ethics committee would approve raising red cell mass in healthy volunteers for performance.

The cardiovascular question is open in the literature itself. Tian 2024 and Fishbane 2023 are both attempts to resolve it from pooled data, and both are published because it is not resolved. The specific unknown is whether events track the drug or track the hemoglobin it produces, and that distinction cannot be settled by any meta-analysis of trials that all targeted similar hemoglobin ranges.

Nobody has published what long-term HIF stabilization does to the rest of the program. HIF regulates vascular endothelial growth factor and glycolytic genes as well as erythropoietin. Whether years of intermittent stabilization changes tumor behavior, retinal vasculature or metabolism is a question the trial durations were never long enough to answer, and it is named in every review of the class as outstanding.

Extrapolation, labeled as such. If the benefit is the physiologic erythropoietin profile rather than the molecule, then any HIF stabilizer should behave alike and the choice between them is pharmacokinetic rather than pharmacodynamic. Sackeyfio 2024 compares them indirectly; no head-to-head trial powered on outcomes has been run, and until one is, class effects and molecule effects cannot be separated.

Roxadustat — its own safety story, not its class's

Prescription-only, and prohibited in sport. Both facts belong in the first sentence. This drug is licensed for anemia of chronic kidney disease in several jurisdictions and was declined by the FDA in 2021; it is a prohibited substance in competition; and the Vault carries no buy route for it. Nothing on this page is instruction for obtaining or using it.

The predicted hazard follows from the endpoint, not from the molecule. Raising red cell mass raises blood viscosity, and viscosity is the mechanism behind thrombotic risk. That is why the safety literature for this class is about cardiovascular and thromboembolic events Tian 2024 rather than about the ordinary side effects of a small molecule. Anyone with a personal or family history of clotting, an inherited thrombophilia, or an existing elevated hematocrit sits at the wrong end of that mechanism before taking anything.

Two interaction surfaces with names. CYP2C8 metabolism and OATP1B1 transport Czock 2022 mean a shared route with several commonly used drugs, most notably statins, whose exposure can rise. Separately, iron salts, calcium, magnesium and phosphate binders chelate it in the gut. Neither of those is exotic and both are the kind of thing a prescriber checks and a search box does not.

What an empty column would have meant here, and does not. Unlike most of what the RUPharma crawl found, this drug has a real pharmacovigilance record: tens of thousands of patients, published meta-analyses, and a regulator that said no. That is the opposite of the Khavinson pages in this same tranche, where the safety section is empty because nobody ever looked. Here somebody looked, at length, and disagreed with themselves across three continents.

Sources read for this page

Roxadustat — interference & stacking

Predicted from mechanism, not from an interaction study. How mechanism-predicted claims are made →

What Roxadustat moves on your bloodwork

Expected direction, not a measured one.

A prescription medicine for anemia of chronic kidney disease, and a prohibited substance in sport. The interference picture that matters most is not a drug interaction at all: raising red cell mass raises blood viscosity, and every published safety debate about this class is about thrombotic and cardiovascular events rather than about the hemoglobin it produces.

🔒
The dose is the easy part. Making Roxadustat actually work is what's behind Skool:
Running it
  • Dose range and how to work up to it
  • When to take it, and why that window
  • Cycle length
  • Time off between cycles
  • Fasted or fed, and when in the day
  • Coach Cam's personal notes
Stacking it
  • Which compounds push the same lever, and why the dose adds up faster than people count
  • What blunts it — the stacks that waste your money
  • What compounds the risk, so a side effect arrives sooner than any one of them suggests
  • Coach Cam's read on running it alongside the rest of your protocol

Everything above is free and stays free. Skool is where it becomes a plan — Roxadustat in an order, with the rest of what you're running.

Unlock in Skool — $10/mo →

Bloodwork to run alongside Roxadustat

Baseline first, then again at 8–12 weeks.

MarkerWhat it’s watching for
Comprehensive Metabolic Panel (CMP)Liver, kidney, electrolytes and glucose in one
Complete Blood Count (CBC) with DifferentialBroad screen for anything unexpected
hs-CRP (High-Sensitivity C-Reactive Protein)Inflammation baseline

The Basics — Start Here panel covers these in one order — 4 markers, $32.40 with the discount applied.

Check results you already have → · All 103 markers A–Z

Roxadustat — frequently asked questions

What is Roxadustat?

Roxadustat (Evrenzo — FG-4592, a HIF prolyl-hydroxylase inhibitor) is a performance & endurance research compound. An inhibitor of the prolyl hydroxylase enzymes that tag hypoxia-inducible factor for destruction when oxygen is plentiful. Block them and HIF survives in a normally oxygenated cell, which is chemically the same signal a body reads at altitude: erythropoietin transcription rises from kidney and liver, hepcidin falls so stored iron is released, and iron-handling proteins are upregulated together rather than singly. That coordinated iron effect is the real difference from injected erythropoietin, which raises the demand for iron without doing anything about the supply.

Where can I find Roxadustat dosing and protocols?

Dosing, the reconstitution calculator and Coach Cam's full Roxadustat protocol are available to members inside Skool. This public page covers what Roxadustat is, how it works and the evidence.

What is the half-life of Roxadustat?

Roxadustat has an approximate half-life of ~12 hrs; three-times-weekly dosing is what the trials used, which is part of what determines how often it's dosed.

What's the evidence behind Roxadustat?

Current evidence level: Approved for anemia of chronic kidney disease in China, Japan, the EU and elsewhere; the FDA declined it in 2021. Prohibited in sport.. Roxadustat is offered for research purposes only and is not an approved medicine.

What Roxadustat is used for

Roxadustat appears under 1 goal in the goal router.

🏃 Endurance & work capacityOxygen delivery & nitric oxide
BemethylCytoflavinHypoxen

Where this goes next

In contextOxygen delivery & nitric oxideThe endurance & work capacity pathway Roxadustat belongs to
Go deeper$10/mo

The pages here are the frameworks. The protocols — the dosing, the order to correct things in, the week-by-week schedule and what to retest — are inside Skool.

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