Avutometinib

Kidney injury is predominantly indirect and multi-pathway. (1) MEK/ERK inhibition disturbs skeletal-muscle homeostasis and causes CPK release; marked, sustained elevations reflect myonecrosis/rhabdomyolysis, releasing myoglobin that produces pigment (myoglobin-cast) nephropathy — intratubular cast obstruction, proximal tubular oxidative injury, and renal vasoconstriction culminating in acute tubular necrosis. (2) MEK-class gastrointestinal toxicity (grade >=3 diarrhea) causes volume depletion (prerenal azotemia) plus gastrointestinal and renal electrolyte wasting — hypokalemia, hypomagnesemia, and hyponatremia. (3) MEK-class fluid retention manifests as peripheral edema (an on-pathway MAPK effect on endothelial/fluid handling), generally not a primary nephron lesion. Direct tubular nephrotoxicity of MEK inhibitors themselves appears modest relative to BRAF inhibitors in pharmacovigilance and cell-based data. Within the co-packaged regimen the renal/electrolyte signal is attributable to the MEK arm (avutometinib): the companion FAK inhibitor defactinib is not nephrotoxic and FAK inhibition/loss is renoprotective in preclinical kidney-injury models.

Most commonly an asymptomatic CPK elevation detected on routine labs, sometimes with myalgia or muscle weakness. Grade >=3 diarrhea can produce volume depletion with prerenal azotemia and clinically significant electrolyte disturbances (hypokalemia, hypomagnesemia, hyponatremia). Peripheral edema/fluid retention is a common MEK-class finding. Rarely, sustained rhabdomyolysis-range CPK is accompanied by dark (pigmented) urine, myoglobinuria, and a disproportionate rise in serum creatinine indicating pigment-cast acute tubular injury.

For electrolyte loss from diarrhea: intensify antidiarrheal therapy, rehydrate, and rep+lete potassium and magnesium (magnesium repletion often needed to correct refractory hypokalemia). For marked CPK elevation: hold avutometinib, ensure generous hydration, monitor renal function and urine myoglobin, and resume at a reduced dose per the label's stepwise modifications once CPK recovers; permanently discontinue for recurrent severe or symptomatic rhabdomyolysis. For established rhabdomyolysis-associated AKI: aggressive isotonic IV fluids and supportive care, with renal-replacement therapy reserved for standard AKI indications. For peripheral edema/fluid retention: dose modification and cautious diuresis. Prerenal azotemia is treated with volume repletion and removal of contributing agents (diuretics, RAAS inhibitors, NSAIDs), not immunosuppression. Coordinate onco-nephrology co-management when creatinine rises or CPK is in the rhabdomyolysis range.Lesion-level management framework

No dedicated renal-impairment dosing has been established for this 2025 first-in-class agent; formal data in moderate-to-severe impairment and dialysis are lacking. Avutometinib is cleared mainly by hepatic (CYP3A4) metabolism with limited renal elimination, so dose modification is driven by toxicity — chiefly CPK elevation, diarrhea, and myopathy — rather than by eGFR. The approved schedule is avutometinib 3.2 mg orally twice weekly with defactinib 200 mg twice daily, dosed 3 weeks on / 1 week off; the label prescribes stepwise interruptions and reductions for grade >=3 CPK elevation, rhabdomyolysis, and severe diarrhea. Avoid strong CYP3A inhibitors/inducers.

Not characterized. As a small-molecule, predominantly hepatically cleared oral agent expected to be substantially protein-bound with a large volume of distribution, avutometinib is unlikely to be meaningfully removed by hemodialysis; specific dialysis-removal data are not available. Dialysis in this setting supports severe AKI rather than clearing the drug.

In a patient on avutometinib with a rising creatinine, separate: (1) prerenal azotemia from diarrheal volume depletion (responds to rehydration); (2) rhabdomyolysis-associated pigment-cast ATN (very high CPK, myoglobinuria, dark urine, disproportionate creatinine rise) — the reason CPK is tracked; (3) electrolyte disturbance from gastrointestinal versus renal wasting (hypokalemia, hypomagnesemia, hyponatremia); and (4) contribution from concomitant myotoxins (statins) or other nephrotoxins. Isolated asymptomatic CPK elevation — common and usually benign skeletal-muscle origin — must be distinguished from true rhabdomyolysis. Peripheral edema is generally MEK-class fluid retention rather than glomerular disease. Because the drug is given as a co-packaged regimen, the renal/electrolyte signal is attributable to the MEK arm (avutometinib); FAK inhibition by defactinib is not nephrotoxic and is renoprotective in preclinical models.