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JAK2 inhibitor

Fedratinib

Inrebic · FED

JAK2 inhibitor · approved 2019 · 7 references

A selective JAK2 inhibitor for myelofibrosis that is not a direct nephrotoxin — its kidney relevance is a renally-influenced exposure that rises in kidney impairment (mandating dose reduction) compounded by heavy GI fluid-and-electrolyte loss.

Signature injury
Electrolyte Disturbance
Severity
Mild
Reversibility
Reversible
Onset
GI adverse events appear early — typically within the first one to two treatment cycles — and tend to diminish over time with supportive care and dose management; the associated electrolyte and creatinine changes track these early GI events. Reduced clearance in renal impairment is present from the first dose (higher exposure independent of time on drug).

Signature kidney injury & incidence

Electrolyte Disturbance.

There is no established incidence of direct fedratinib-induced kidney injury; the renal story is pharmacokinetic and GI-driven rather than a discrete nephrotoxic lesion. In the pivotal placebo-controlled JAKARTA phase 3 trial, gastrointestinal symptoms were among the most common adverse events and "increased levels of serum creatinine" was reported as a common laboratory abnormality — but neither a rate of clinically significant AKI nor a discrete electrolyte-depletion incidence was separately quantified, so a headline nephrotoxicity percentage cannot be stated without overstating the evidence. The dedicated phase 1 renal-impairment study found systemic exposure (AUC) roughly 1.9-fold higher in severe renal impairment, which is the basis for a mandated dose reduction rather than an injury rate.

Source: Pardanani et al., JAMA Oncol 2015 (JAKARTA)

Reported injury signatures: Electrolyte Disturbance, Prerenal / Hemodynamic AKI.

Renal toxicity profile

  1. Electrolyte DisturbancePrimary
  2. Prerenal / Hemodynamic AKISecondary

Onset timing & rechallenge

Subacute (~1–6 weeks) — GI adverse events appear early — within the first one to two treatment cycles — and the associated electrolyte and creatinine changes track those early GI events.

Mechanism of kidney injury

Two intertwined, indirect mechanisms rather than a primary tubular or glomerular toxin. (1) Renally-influenced clearance: population pharmacokinetics identify creatinine clearance as a statistically significant covariate on fedratinib apparent clearance, so reduced kidney function raises drug exposure (AUC ~1.5-fold in moderate and ~1.9-fold in severe impairment), amplifying downstream toxicity unless the dose is cut. (2) GI-mediated fluid and electrolyte loss: frequent nausea, vomiting and diarrhea reduce intake and drive volume contraction with potassium and magnesium loss, which can precipitate prerenal/hemodynamic AKI. Serum-creatinine rises observed in trials may partly reflect this hemodynamic effect (and possibly altered tubular creatinine handling) rather than proven structural GFR loss. A separate, non-renal but thematically linked concern is thiamine (vitamin B1) deficiency and Wernicke encephalopathy, plausibly aggravated by the same GI losses/reduced intake — the drug's black-box warning.

Clinical presentation

Rather than a classic nephrotoxic syndrome, the picture is an at-risk patient: gastrointestinal upset (nausea, vomiting, diarrhea) with reduced oral intake and volume contraction, whose biochemical footprint is hypokalemia, hypomagnesemia and a rising serum creatinine (often modest and reversible with rehydration). In kidney impairment the higher fedratinib exposure can manifest as more pronounced GI and hematologic (anemia, thrombocytopenia) toxicity. The most feared associated event is Wernicke-type encephalopathy (confusion, ophthalmoplegia, ataxia) from thiamine deficiency — a neurologic emergency, not a renal one, but part of the same GI-loss theme.

Management

Manage GI toxicity aggressively with antiemetics and antidiarrheals and by taking the dose with food; replete potassium and magnesium and restore intravascular volume for prerenal creatinine rises. Dose-interrupt or reduce for severe/persistent GI events, significant creatinine elevation, or cytopenias per label thresholds. For any encephalopathy, hold fedratinib immediately and give parenteral thiamine. In renal impairment, use the reduced dose and monitor exposure-driven toxicity (GI, hematologic); there is no specific antidote and no established renal-replacement removal strategy. Re-escalate cautiously once toxicity resolves.

Risk factors

  • Moderate-to-severe renal impairment (higher fedratinib exposure; severe impairment mandates dose reduction)
  • Uncontrolled nausea, vomiting or diarrhea causing ongoing fluid and electrolyte loss
  • Baseline thiamine deficiency or poor nutritional status / reduced oral intake
  • Concomitant diuretics or other drugs that deplete potassium or magnesium
  • Elderly or low-body-weight patients
  • Co-administration of strong CYP3A4 inhibitors (raise exposure) or inducers (lower it)

Prevention

  • Assess thiamine (vitamin B1) at baseline and periodically, and supplement/correct deficiency before and during therapy
  • Prophylactic and early antiemetic/antidiarrheal therapy to limit GI fluid and electrolyte loss
  • Check and normalize kidney function and electrolytes (potassium, magnesium, sodium) at baseline and during treatment
  • Reduce the starting dose to 200 mg once daily in severe renal impairment (CrCl 15-29 mL/min)
  • Encourage adequate hydration and oral intake; take doses with food to improve GI tolerability

Renal dose adjustment

Mild renal impairment (CrCl 60-89 mL/min): no dose adjustment. Moderate impairment (CrCl 30-59 mL/min): the standard 400 mg once-daily dose may be used but with monitoring and dose reduction as needed, since exposure is ~37% higher on population PK. Severe impairment (CrCl 15-29 mL/min): reduce to 200 mg once daily — a dedicated phase 1 study found ~1.9-fold higher AUC. Not studied in end-stage renal disease/dialysis. Separately, reduce the dose (or avoid) with concomitant strong CYP3A4 inhibitors.

Dialyzability & ESKD dosing

Not established and unlikely to be meaningfully dialyzable. Fedratinib is extensively protein-bound with a large volume of distribution and a long (~41 h) effective half-life; the dedicated impairment study did not identify hemodialysis as a clearance route, and no dosing recommendation exists for dialysis patients. Dosing is driven by exposure and tolerability, not by dialytic removal.

Differential diagnosis

Distinguish a prerenal/hemodynamic creatinine rise from GI volume loss (improves promptly with rehydration) from true intrinsic AKI. Consider that fedratinib's reported serum-creatinine elevations may be a laboratory or hemodynamic signal rather than a fall in true GFR — confirm with cystatin C or the trajectory if the clinical picture does not fit. Separate thiamine-deficiency Wernicke encephalopathy from other causes of altered mental status (hepatic encephalopathy, sepsis, CNS disease). Attribute electrolyte disturbances to GI losses and concomitant drugs rather than to a specific tubulopathy, since fedratinib is not a recognized direct tubular toxin. Anemia and thrombocytopenia are usually disease- or exposure-related cytopenias, not a renal process.

Monitoring

  • Thiamine (vitamin B1) level at baseline and periodically; reassess in at-risk or symptomatic patients
  • Serum creatinine / eGFR and electrolytes (potassium, magnesium, sodium) at baseline and during treatment
  • CBC for anemia and thrombocytopenia (exposure-driven in renal impairment)
  • Liver transaminases, bilirubin and amylase/lipase (label-recommended labs)
  • Clinical assessment of GI symptoms and hydration status, plus neurologic assessment for encephalopathy

Key trials & series

  • JAKARTA (phase 3, Pardanani, JAMA Oncol 2015): double-blind, placebo-controlled; 400 mg once daily achieved a 36% spleen response vs 1% with placebo; common adverse events were anemia, gastrointestinal symptoms and increased serum creatinine/transaminases; encephalopathy occurred in 4 women on 500 mg.
  • JAKARTA-2 (phase 2, Harrison, Lancet Haematol 2017): single-arm study in ruxolitinib-relapsed/intolerant myelofibrosis; 55% spleen response; suspected Wernicke encephalopathy cases contributed to a clinical hold on development.
  • Dedicated phase 1 renal/hepatic impairment PK study (Ogasawara, Cancer Chemother Pharmacol 2020): AUC 1.9- and 1.5-fold higher in severe and moderate renal impairment; basis for the 200 mg dose in severe impairment.
  • Population PK analysis (Ogasawara, Cancer Chemother Pharmacol 2019): creatinine clearance a significant covariate on clearance; mild and moderate renal impairment associated with 10% and 37% higher exposure.

Clinical pearls

  • Fedratinib is not a classic nephrotoxin — its kidney relevance is dosing (renally-influenced clearance) plus GI-driven electrolyte and volume loss, not a discrete tubular or glomerular lesion.
  • The one hard renal rule: severe renal impairment (CrCl 15-29) mandates cutting the dose to 200 mg because exposure runs ~1.9-fold higher; moderate impairment warrants monitoring with reduction as needed.
  • Check thiamine before and during therapy and give parenteral thiamine (and hold the drug) at any hint of encephalopathy — the black-box Wernicke risk is the defining safety issue and is plausibly compounded by GI losses.
  • A modest, reversible creatinine bump reported in trials may be hemodynamic or a laboratory signal rather than true GFR loss — rehydrate and recheck before abandoning an effective therapy.
  • GI toxicity is early and usually wanes; proactive antiemetics/antidiarrheals and electrolyte (K/Mg) repletion prevent the downstream prerenal AKI and electrolyte depletion.

Anticancer mechanism

Oral, selective small-molecule inhibitor of Janus kinase 2 (JAK2), including the JAK2V617F mutant that drives constitutive JAK/STAT signaling in myeloproliferative neoplasms. Blocking JAK2-mediated phosphorylation of STAT5 curbs malignant myeloid proliferation, reduces splenomegaly and improves constitutional symptoms; it also has secondary off-target activity against FLT3 and BRD4.

Note

Educational reference — not medical advice. Fedratinib has no established direct nephrotoxic lesion, so the kidney narrative here is pharmacokinetic (renally-influenced clearance → dose reduction) and indirect (GI fluid/electrolyte loss → prerenal AKI, plus thiamine-deficiency/Wernicke risk). FDA approval was August 2019. Claims are hedged to the available evidence.

Guidelines & consensus

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525

References

7 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Pharmacokinetics and tolerability of fedratinib, an oral, selective Janus kinase 2 inhibitor, in subjects with renal or hepatic impairment.Ogasawara K, et al. · Cancer Chemother Pharmacol · 2020 · PMID 32449142
  2. 2.Population pharmacokinetics of fedratinib in patients with myelofibrosis, polycythemia vera, and essential thrombocythemia.Ogasawara K, et al. · Cancer Chemother Pharmacol · 2019 · PMID 31444617
  3. 3.Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial.Pardanani A, et al. · JAMA Oncol · 2015 · PMID 26181658
  4. 4.Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study.Harrison CN, et al. · Lancet Haematol · 2017 · PMID 28602585
  5. 5.Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis.Talpaz M, Kiladjian JJ · Leukemia · 2020 · PMID 32647323
  6. 6.Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis.Bewersdorf JP, et al. · Cancer Manag Res · 2019 · PMID 31920387
  7. 7.Fedratinib hydrochloride to treat intermediate-2 or high-risk primary or secondary myelofibrosis.Schiffer M, et al. · Drugs Today (Barc) · 2020 · PMID 33332482
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.