Alpelisib
Piqray · PI3Kα inhibitor
Severe hyperglycemia (on-target) → osmotic diuresis and prerenal AKI risk.
PRELYTE
Moderate89% phenotype match
JAK2/ACVR1 inhibitor
Pacritinib
Vonjo · PAC
JAK2/ACVR1 inhibitor · approved 2022 · 7 citations
Up to date· through 2025
Well-established evidence7/9 · 7 signals▾
- 7 citations
- Deep literature (12+ refs)
- Accrued over 10+ years
- Beyond single case reports
- High-impact journal
- Landmark reference
- Registrational / key trials
- Current through 2025
- Real-world FAERS signal
Grades the strength of the evidence base (volume, journal quality, landmark trials, recency, real-world corroboration) — not the drug's severity. A rule-based summary, not a formal certainty appraisal.
A JAK2/IRAK1/ACVR1 inhibitor for cytopenic myelofibrosis whose kidney risk is indirect — severe diarrhea drives volume and electrolyte depletion into prerenal azotemia, not intrinsic nephrotoxicity.
ModerateJAK2/IRAK1 inhibitor
Intermediate- or high-risk primary myelofibrosis in adults with platelet count below 50 x 10^9/L (US accelerated approval, Feb 2022)Intermediate- or high-risk secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with platelets below 50 x 10^9/LSecond-line myelofibrosis after ruxolitinib, particularly in the setting of treatment-limiting thrombocytopenia
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Signature kidney injury
Signature lesion
Pacritinib has no established intrinsic nephrotoxicity; its renal risk is a downstream consequence of its dominant gastrointestinal toxicity. Diarrhea is the signature adverse effect — in the phase 2 study grade 1/2 diarrhea occurred in ~69% of patients and nausea in ~49% (Komrokji 2015), and in the PERSIST-1 phase 3 trial grade 3-4 diarrhea occurred in ~5%. In real-world FAERS pharmacovigilance, gastrointestinal disorders were the top disproportionality system-organ-class and diarrhea the most-reported preferred term (Zhang 2025). High-volume diarrhea (often with nausea/vomiting) can precipitate volume depletion, hypokalemia/hypomagnesemia, and prerenal azotemia, but a specific incidence of pacritinib-attributable acute kidney injury has not been separately quantified — so no headline AKI rate is reported here (incidencePct null).Source: 25762180
Onset & rechallenge
Time to injurySubacute (~1–6 weeks)
Diarrhea (and the prerenal azotemia/electrolyte loss that tracks it) emerges within the first days-to-weeks and is most pronounced over roughly the first 8 weeks — early and episodic, not cumulative.
Distilled from: “Diarrhea is an early effect, typically emerging within the first days-to-weeks of therapy and most pronounced over roughly the first 8 weeks; it tends to be self-limited and to improve with continued treatment, antidiarrheals, and dose management. Any prerenal azotemia and electrolyte disturbance tracks the diarrhea temporally and is therefore early and episodic rather than cumulative or delayed.” · PMID 25762180
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Renal toxicities, ranked
This agent's kidney lesions ordered by prominence — the #1 signature lesion first, then secondary and rare patterns. Cited incidence is shown where a citable figure exists; otherwise the tier stands qualitatively.
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Renal electrolyte derangement — magnesium/potassium/calcium wasting (cisplatin, anti-EGFR antibodies) or retention (FGFR-inhibitor hyperphosphatemia, tumor-lysis hyperkalemia/hyperphosphatemia).
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Kidney injury
Mechanism of kidney injury
Indirect and hemodynamic/volume-mediated rather than a direct nephron lesion. Pacritinib's JAK2/IRAK1/ACVR1 inhibition drives frequent, sometimes high-volume diarrhea (with nausea and vomiting), producing gastrointestinal fluid and electrolyte losses. The resulting extracellular volume depletion lowers renal perfusion and glomerular filtration, yielding prerenal (functional) azotemia; compensatory renin-angiotensin-aldosterone activation then enhances distal-nephron potassium secretion, compounding the direct GI losses of potassium and magnesium to produce hypokalemia and hypomagnesemia. If hypoperfusion is severe or prolonged, prerenal azotemia can progress to ischemic acute tubular necrosis. No direct tubular, glomerular, interstitial, or crystal-forming renal toxicity has been characterized for pacritinib.
Clinical presentation
Rising creatinine and BUN with a bland urine sediment and a low fractional excretion of sodium in a patient with frequent watery stools, weight loss, orthostatic symptoms, and clinical signs of volume depletion. Laboratory hypokalemia and hypomagnesemia are common and clinically important because pacritinib prolongs the QT interval, so electrolyte depletion compounds arrhythmia risk. Severe cases show oliguria and overt hypovolemia; the BUN:creatinine ratio is often elevated, consistent with a prerenal state.
Management
Largely supportive and directed at the gastrointestinal driver: control diarrhea with antidiarrheals, restore intravascular volume with oral or IV fluids, and aggressively replete potassium and magnesium (important given concurrent QT prolongation). Hold pacritinib for severe (grade 3-4) or refractory diarrhea and resume at a reduced dose once it resolves, per the prescribing information. Correcting the prerenal physiology typically lets the creatinine recover, because the injury is functional rather than structural — there is no drug-specific renal therapy. If creatinine does not improve with volume repletion, evaluate for additive or alternative causes of AKI (sepsis in an immunocompromised/thrombocytopenic host, other nephrotoxins, ischemic ATN).Lesion-level management framework
Risk factors
- Severe or persistent diarrhea (grade 3-4) and concurrent nausea/vomiting limiting oral rehydration
- Baseline volume depletion or poor oral intake
- Concomitant diuretics, ACE inhibitors/ARBs, or other nephrotoxins
- Older age and pre-existing chronic kidney disease
- Co-administration of other QT-prolonging drugs (electrolyte-arrhythmia interplay)
- Advanced myelofibrosis with poor performance status
Prevention
- Start proactive antidiarrheal therapy (e.g., loperamide) at the first onset of diarrhea
- Encourage oral hydration and actively maintain volume status
- Check electrolytes (especially potassium and magnesium) and renal function at baseline and periodically, repleting promptly
- Review and minimize concomitant diuretics, RAAS blockers, and other nephrotoxins
- Interrupt or reduce the pacritinib dose per label for severe or refractory diarrhea before prerenal injury develops
- Avoid strong CYP3A4 inhibitors/inducers that alter pacritinib exposure
Anticancer mechanism· how it treats cancer
Oral small-molecule kinase inhibitor with activity against JAK2 (including the JAK2 V617F mutant), FLT3, IRAK1, and ACVR1 (ALK2), while notably sparing JAK1. By dampening constitutive JAK2-STAT signaling it reduces splenomegaly and constitutional symptoms of myelofibrosis; because it spares JAK1, it can be dosed in patients with severe thrombocytopenia in whom ruxolitinib and fedratinib worsen cytopenias. Potent ACVR1 inhibition suppresses hepcidin production, contributing an anemia/transfusion-independence benefit, and IRAK1 inhibition attenuates NF-kB-driven inflammatory signaling.
Note · Educational content, not medical advice. Renal risk is inferred from pacritinib's well-documented gastrointestinal (diarrhea) toxicity and its predictable volume/electrolyte sequelae; a pacritinib-specific AKI incidence has not been directly quantified in the literature, so incidence is hedged and incidencePct is left null. Confirm dosing, renal, and QT guidance against the current Vonjo prescribing information.
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Clinical depth
Renal dose adjustment
There is no filtration-based renal dose rule for the kidney injury itself — the actionable lever is holding or reducing pacritinib for severe diarrhea (grade 3-4) or clinically significant volume/electrolyte depletion, then resuming at a reduced dose per the label. Pharmacokinetically, pacritinib is cleared predominantly by hepatic CYP3A4 metabolism with limited renal excretion, so a dose reduction for mild-to-moderate renal impairment is generally not required; data in severe renal impairment and ESKD are limited, so use caution and monitor closely. Avoid strong CYP3A4 inhibitors and inducers. Confirm all thresholds against the current prescribing information.
Dialyzability & ESKD dosing
Not established. Pacritinib is a highly protein-bound, hepatically (CYP3A4) metabolized small molecule, so meaningful removal by hemodialysis is unlikely and no formal dialysis-clearance or ESKD dosing data are available. In a dialysis patient, manage the toxicity by treating the diarrhea and the volume/electrolyte disturbance rather than by timing doses around dialysis sessions.
Differential diagnosis
The picture is prerenal/functional AKI from GI volume loss: bland sediment, low FENa (<1%), an elevated BUN:creatinine ratio, and creatinine that corrects with volume repletion distinguish it from intrinsic tubular injury. Suspect ischemic ATN if hypoperfusion was severe or prolonged (muddy-brown granular casts, FENa >2%, slower recovery despite volume). Unlike some myeloproliferative-neoplasm therapies, tumor-lysis-related urate/phosphate nephropathy is not a typical pacritinib effect. Also exclude concurrent nephrotoxins, sepsis in a thrombocytopenic/immunocompromised host, and contrast exposure, and separate diarrhea-driven hypokalemia from diuretic effect or other potassium-wasting causes.
Monitoring
- Serum electrolytes — especially potassium and magnesium — at baseline and regularly, with prompt repletion (heightened importance because pacritinib prolongs the QT interval)
- Serum creatinine/BUN and volume/orthostatic status during and after diarrhea episodes
- Stool frequency and severity, plus body weight, as an early marker of impending volume loss
- ECG/QTc, particularly when electrolytes are deranged or with concomitant QT-prolonging drugs
- Complete blood count (thrombocytopenia and anemia are the on-target hematologic effects)
Key trials & series
- PERSIST-2 (Mascarenhas 2018, JAMA Oncol) — registrational phase 3 in myelofibrosis with platelets <=100 x 10^9/L; basis for the 200 mg twice-daily accelerated approval, with diarrhea among the most common adverse events.
- PERSIST-1 (Mesa 2017, Lancet Haematol) — phase 3 versus best available therapy irrespective of baseline cytopenias; grade 3-4 diarrhea ~5%, with diarrhea the most common non-hematologic toxicity.
- Phase 2 study (Komrokji 2015, Blood) — grade 1/2 diarrhea ~69% and nausea ~49%, establishing GI toxicity as the dominant adverse effect and the driver of volume/electrolyte loss.
- FAERS disproportionality analysis (Zhang 2025, Front Oncol) — real-world post-marketing signal with gastrointestinal disorders as the leading system-organ-class and diarrhea the top reported term.
Clinical pearls
- The kidney injury is a downstream, functional consequence of pacritinib's dominant toxicity — diarrhea — not intrinsic nephrotoxicity; treat the gut and the volume/electrolyte deficit and the creatinine follows.
- Mind the QT-electrolyte loop: pacritinib prolongs the QT interval, and diarrhea-induced hypokalemia and hypomagnesemia amplify that risk — replete potassium and magnesium aggressively and check an ECG.
- Diarrhea is usually early (first weeks) and self-limited/manageable — pre-emptive loperamide and hydration prevent most prerenal events, so counsel patients before they start.
- Pacritinib's niche is myelofibrosis with severe thrombocytopenia (platelets <50 x 10^9/L) where ruxolitinib/fedratinib cannot be safely dosed; expect thrombocytopenia and anemia as on-target effects, with diarrhea as the manageable GI/renal-relevant toxicity.
- A FENa/urine-electrolyte check helps triage: a prerenal signature supports volume repletion over an expensive hunt for intrinsic renal disease.
Where it strikes· nephron segments & injury signatures
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Injury signatures
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References
7 peer-reviewed references. Citation metadata via PubMed / NLM.
Evidence accrual
7 references · 2015–2025 · 2 since 2023Citations per year in this profile — a proxy for how actively the agent's renal literature is accruing. Recent years are highlighted. Reflects curation depth, not a systematic bibliometric count.
- 1.LandmarkResults of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis.Komrokji RS, et al. · Blood · 2015 · PMID 25762180Phase 2 trial establishing the dominant GI toxicity profile: grade 1/2 diarrhea in ~69% and nausea in ~49% — the primary driver of volume and electrolyte depletion behind prerenal azotemia.
- 2.LandmarkDisproportionality analysis of adverse events associated with pacritinib: a real-world study based on FDA Adverse Event Reporting System (FAERS) database.Zhang H, et al. · Front Oncol · 2025 · PMID 40792279Real-world pharmacovigilance (1,940 pacritinib primary-suspect reports): gastrointestinal disorders were the top system-organ-class disproportionality signal and diarrhea the leading reported term, corroborating the GI-driven renal risk.
- 3.LandmarkPacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial.Mascarenhas J, et al. · JAMA Oncol · 2018 · PMID 29522138PERSIST-2 registrational phase 3 supporting the 200 mg twice-daily accelerated approval; diarrhea among the most common adverse events in the thrombocytopenic population that defines pacritinib's niche.
- 4.LandmarkPacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial.Mesa RA, et al. · Lancet Haematol · 2017 · PMID 28336242PERSIST-1 phase 3: diarrhea was the most common non-hematologic toxicity with grade 3-4 diarrhea in ~5%, quantifying the severity end of the GI toxicity that precipitates volume/electrolyte loss.
- 5.LandmarkPacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis.Oh ST, et al. · Blood Adv · 2023 · PMID 37552106Mechanistic paper defining pacritinib as a JAK2/IRAK1 inhibitor and potent ACVR1 inhibitor (hepcidin suppression), grounding the anticancerMechanism and the drug's distinct target profile.
- 6.Pacritinib: First Approval.Lamb YN · Drugs · 2022 · PMID 35567653Documents the February 2022 US accelerated approval, the platelets <50 x 10^9/L myelofibrosis indication, and the 200 mg twice-daily dosing regimen.
- 7.The odyssey of pacritinib in myelofibrosis.Venugopal S, Mascarenhas J · Blood Adv · 2022 · PMID 35622972Development/context review (PERSIST-1, PERSIST-2, PAC203 dose-finding) confirming pacritinib as a selective JAK2/FLT3/IRAK1 multikinase inhibitor and the 200 mg BID dose selection.
Guidelines & consensus· 12
General onco-nephrology references
ADQIThe nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupNat Rev Nephrol 2026 · PMID 41361704Provides 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.SIRMSIRM-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)Radiol Med 2022 · PMID 35303246Recommends 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.KDIGOKDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerKidney Int 2020 · PMID 33126977Identifies 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.KDIGOKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationKidney Int 2020 · PMID 33276867Addresses 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.ADDIKDIntegrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceEClinicalMedicine 2025 · PMID 40290844Provides 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.ADDIKDAligning kidney function assessment in patients with cancer to global practices in internal medicineEClinicalMedicine 2025 · PMID 40290845Three 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.ADDIKDA methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEClinicalMedicine 2025 · PMID 40290846Establishes 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.KDIGODiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Crit Care 2013 · PMID 23394211Defines/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.KDIGOExecutive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesKidney Int 2021 · PMID 34556300Provides 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.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisKidney Int 2024 · PMID 38388147Updates 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.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisKidney Int 2024 · PMID 38182299Updates 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.KDIGOExecutive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Kidney Int 2025 · PMID 40975525Encourages 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.
Where Pacritinib sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype.
Phenotype-similar agents· nearest neighbors in nephrotoxicity space
Profile
Neratinib
Nerlynx · HER2 / pan-EGFR TKI
Severe diarrhea → prerenal AKI; loperamide prophylaxis.
PRELYTE
Moderate89% phenotype match
Gilteritinib
Xospata · FLT3 inhibitor
Differentiation syndrome, tumor lysis and PRES in AML.
PRELYTE
Moderate84% phenotype match
Darolutamide
Nubeqa · Androgen receptor inhibitor (ARSI)
Not nephrotoxic; exposure rises in severe renal impairment, so consider dose adaptation.
LYTEPRE
Mild83% phenotype match
Glasdegib
Daurismo · Hedgehog (SMO) inhibitor
QT prolongation and muscle spasms; AML.
PRELYTE
Mild83% phenotype match
Quizartinib
Vanflyta · FLT3 inhibitor
2023 AML FLT3 inhibitor; tumor lysis and QT.
PRELYTE
Mild83% phenotype match
Nearest agents by kidney-injury phenotype (shared injuries, nephron target, severity, class) — a similarity approximation, not a claim of shared drug identity or mechanism.