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. In cell-based data the MEK inhibitors themselves showed no direct tubular or glomerular epithelial cytotoxicity at clinically relevant concentrations (only vemurafenib did), but the pharmacovigilance signal varies by agent and is not uniformly lower than for BRAF inhibitors — cobimetinib's FAERS acute-kidney-injury reporting-odds-ratio (~4.4) exceeds vemurafenib's (~3.3), in patients who receive the two agents together. 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 replete 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.