Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
CSF1R inhibitor
Pexidartinib
Turalio · PEX
CSF1R inhibitor for tenosynovial giant cell tumor with boxed hepatotoxicity — renal effects are secondary (cholestatic illness, dehydration), not a direct nephropathy.
MildCSF1R-targeted era · approved 2019
Symptomatic tenosynovial giant cell tumor not amenable to surgery
Signature kidney injury
Prerenal / Hemodynamic AKI
The defining toxicity is serious, sometimes cholestatic, hepatotoxicity (boxed warning, REMS program); hair-color change, fatigue and GI effects are common. Direct nephrotoxicity is not a recognized signal, and renal effects are secondary (dehydration during illness, hepatorenal physiology in severe liver injury).
Source: Tap et al., Lancet 2019 (ENLIVEN); Lewis et al., Oncologist 2020
Mechanism of kidney injury
Pexidartinib has no characteristic direct renal lesion. Its renal relevance is indirect: severe hepatotoxicity (mixed/cholestatic, occasionally with ductopenia) can cause systemic illness, reduced intake and, in the most severe cases, hepatorenal-type physiology with prerenal azotemia and functional AKI. Routine GI toxicity and anorexia contribute to volume depletion. CSF1R inhibition also affects tissue macrophages broadly, but a specific renal injury is not established.
Clinical presentation
Rising transaminases and bilirubin (cholestatic pattern), fatigue, hair-color change, nausea; renally, a prerenal creatinine rise during severe hepatobiliary illness or dehydration rather than an acute structural lesion.
Onset
Hepatotoxicity can occur early (often within the first 1-2 months) or later; secondary renal effects track the severity of the systemic/hepatic illness.
Reversibility
Reversible
Anticancer mechanism
Oral inhibitor of colony-stimulating-factor-1 receptor (CSF1R), with activity against KIT and FLT3-ITD. In tenosynovial giant cell tumor (TGCT), CSF1 overexpression recruits CSF1R-bearing macrophage-lineage cells that form the tumor; CSF1R blockade depletes this population.
Management
Manage hepatotoxicity per REMS: interrupt/discontinue for protocol-defined liver-test elevations and treat supportively. For secondary prerenal AKI, restore volume and treat the underlying illness; in severe cholestatic liver injury, manage hepatorenal physiology with volume expansion and specialist input. Renal effects generally reverse as the hepatic/systemic illness resolves.
Risk factors
- Baseline hepatic dysfunction
- Concurrent hepatotoxic or nephrotoxic drugs
- Volume depletion from GI toxicity
- Pre-existing CKD
Prevention
- Strict hepatic monitoring under the REMS program (frequent LFTs)
- Avoid concurrent hepatotoxins; maintain hydration
- Prompt drug interruption for transaminase/bilirubin elevations per thresholds
- Early evaluation of any jaundice
Note · The renal link is indirect: there is no direct pexidartinib nephrotoxicity. AKI, when it occurs, is secondary to severe (cholestatic) hepatotoxicity and dehydration. No pexidartinib-specific renal paper exists; class/onconephrology context is cited.
Clinical depth
Renal dose adjustment
No specific renal dose adjustment defined; the critical modifications are for hepatotoxicity. Use general caution in CKD; hepatic metabolism predominates.
Dialyzability & ESKD dosing
Highly protein-bound; not expected to be dialyzable. No established ESKD dosing.
Differential diagnosis
Distinguish secondary prerenal/hepatorenal AKI (volume-responsive, in the setting of severe liver injury) from intrinsic renal causes and from other drug nephrotoxicity. The dominant clinical event is hepatic, not renal.
Monitoring
- Liver tests (AST, ALT, bilirubin) frequently per REMS schedule
- Volume status and serum creatinine during hepatic/systemic illness
- Electrolytes with GI toxicity
- Signs of jaundice/cholestasis
Key trials & series
- ENLIVEN (Tap, Lancet 2019) — registrational RCT defining efficacy and the boxed hepatotoxicity
- Lewis et al. (Oncologist 2020) — characterization of pexidartinib hepatic toxicity
Clinical pearls
- The story here is the liver — a boxed hepatotoxicity warning with a REMS program; the kidney is collateral.
- Severe cholestatic injury can produce hepatorenal-type prerenal AKI; treat with volume and source control.
- No characteristic direct pexidartinib nephropathy exists.
- Hair-color change (depigmentation) is a benign but characteristic on-target effect.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKI
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkPexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial.Tap WD et al. · Lancet 2019 · PMID 31229240Registrational RCT establishing efficacy and the hepatotoxicity that drives secondary renal effects.PMIDPexidartinib long-term hepatic safety and the management of hepatotoxicity.Lewis JH et al. · Oncologist 2020 · PMID 33289960Detailed characterization and management of the cholestatic hepatotoxicity.PMIDPexidartinib: First Approval and clinical profile.Gelderblom H et al. · Future Oncol 2020 · PMID 32700568Drug profile summarizing pharmacology and the REMS-managed hepatic risk.PMIDPexidartinib for tenosynovial giant cell tumor: clinical experience and safety.Tap WD et al. · Cancer 2020 · PMID 32755241Additional safety/efficacy context for the agent.PMIDPexidartinib REMS program and real-world hepatic safety monitoring.McCabe M et al. · Future Oncol 2023 · PMID 37805596Real-world REMS-based monitoring underscoring hepatic (not renal) primacy.PMIDOnco-nephrology: Core Curriculum 2020.Rosner MH et al. · Am J Kidney Dis 2020 · PMID 33276867Onconephrology framework for hepatorenal/secondary AKI in cancer therapeutics.
Related agents
Other agents sharing the same signature kidney injury.