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Brand Name :
Avmapki Fakzynja Co-Pack
Synonyms :
avutometinib and defactinib
Class :
Kinase inhibitors
Brand Name :
Avmapki Fakzynja Co-Pack
Synonyms :
avutometinib and defactinib
Class :
Kinase inhibitors
Dosage Forms & Strengths
Capsules
0.8 mg of avutometinib
Tablets
200 mg of defactinib
Dosage Forms & Strengths
Safety and efficacy not established
Dosage Forms & Strengths
Refer adult dosing
Actions and Spectrum:
Avutometinib functions as an inhibitor of MEK1, a key component of the MAPK signaling pathway. It works by promoting the formation of inactive complexes between RAF and MEK, thereby blocking RAF’s ability to phosphorylate MEK1/2. This disruption leads to decreased activation of downstream proteins MEK1/2 and ERK1/2, ultimately suppressing the growth of cancer cells, particularly those with KRAS mutations. Additionally, avutometinib has been shown to elevate levels of phosphorylated focal adhesion kinase (FAK), suggesting further involvement in tumor signaling regulation.
Defactinib targets focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), which are non-receptor tyrosine kinases involved in cellular adhesion and signaling. By inhibiting the autophosphorylation of FAK, defactinib impairs the growth and survival of cancer cells both in laboratory studies and animal models.
When avutometinib and defactinib are used together, they produce a synergistic effect that more effectively halts cancer cell proliferation and enhances antitumor activity, particularly in models of low-grade serous ovarian cancer (LGSOC).
Abdominal pain
Constipation
Cough
Decreased hemoglobin
Decreased lymphocyte count
Decreased neutrophil count
Decreased platelet count
Dermatitis acneiform
Diarrhea
Dry skin
Dyspepsia
Dyspnea
Edema
Fatigue
Increased alkaline phosphatase
Increased alanine aminotransferase
Increased aspartate aminotransferase
Increased blood bilirubin
Increased creatine phosphokinase
Increased triglycerides
Musculoskeletal pain
Nausea
Pruritus
Rash
Stomatitis
Urinary tract infection
Visual impairment
Vitreoretinal disorders
Vomiting
Black box warning:
None
Contraindications/caution:
Pregnancy warnings:
Pregnancy Category: N/A
Lactation:
Excretion of the drug in human breast milk is unknown
Pregnancy Categories:
Category A: Satisfactory and well-controlled studies show no evidence of risk to the fetus in the 1st trimester or in the 3rd trimester.
Category B: No evidence of risk to fetus found in animal reproduction studies and there are not enough studies on pregnant women.
Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women.
Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits.
Category X: Drugs listed in this category clearly outweigh risks over benefits. These category drugs should be prohibited for pregnant women.
Category N: There is no data available for the drug under this category.
Pharmacology:
AVMAPKI FAKZYNJA CO-PACK combines two oral kinase inhibitors: avutometinib and defactinib.
Avutometinib (in AVMAPKI capsules) inhibits specific kinases involved in cancer cell signaling. It is a potassium salt compound with poor solubility in aqueous solutions between pH 1–7 and a pKa of 7.02. Each capsule delivers 0.8 mg of avutometinib along with excipients like magnesium stearate and mannitol.
Defactinib (in FAKZYNJA tablets) targets kinases that regulate cell adhesion and survival. It is supplied as a hydrochloride salt, has limited solubility in acidic and near-neutral pH ranges, and a pKa of 3.81. Each tablet contains 200 mg of defactinib and standard oral tablet excipients.
Together, these agents work synergistically to inhibit key signaling pathways that promote tumor growth and survival.
Pharmacodynamics:
The exposure-response relationships and the time course of the pharmacodynamic response for both avutometinib and defactinib have not been fully defined.
Regarding cardiac electrophysiology, at the recommended doses of AVMAPKI FAKZYNJA CO-PACK, no significant mean increase in the QTc interval (greater than 20 msec) was observed. In a study with 88 patients, the mean PR interval increased by 16 msec from baseline to Cycle 1, Day 15, 4 hours after dosing.
Pharmacokinetics:
Absorption
Avutometinib: Tmax (time to peak plasma concentration) is approximately 2 hours under fasted conditions.
Defactinib: Tmax is approximately 4 hours under fed conditions.
Effect of Food:
Avutometinib: No significant changes in AUC when taken with a high-fat meal, but Cmax decreases by 29%.
Defactinib: AUC increases by 2.7-fold and Cmax increases by 1.9-fold when taken with a high-fat meal.
Distribution
Avutometinib: Steady-state apparent volume of distribution (Vd) is 25 L, with 99% plasma protein binding.
Defactinib: Steady-state apparent Vd is 1,560 L, with 90% plasma protein binding.
Metabolism
Avutometinib: Primarily metabolized by CYP3A4 and undergoes nonenzymatic degradation.
Defactinib: Metabolized by CYP3A4 and CYP2C9, forming two major metabolites: M2 (inactive) and M4 (equipotent). M2 and M4 account for 92% and 28% of defactinib exposure, respectively.
Elimination/Excretion
Avutometinib: Elimination half-life is 51 hours, and apparent oral clearance (CL/F) is 0.3 L/h.
After a single dose, 39% of the dose is recovered in feces (9.5% unchanged) and 52% in urine (3.2% unchanged).
Defactinib: Elimination half-life is 9 hours, and CL/F is 69 L/h. After a single dose, 87% of the dose is recovered in feces (52% unchanged) and 7.6% in urine (0.8% unchanged).
Administration:
avutometinib should be taken with food at the same time each day, and the capsules should be swallowed whole—do not chew, break, or open them. If a dose is missed by more than 24 hours, skip it and take the next scheduled dose. Do not take two doses at once.
defactinib -Each dose should be taken with food, and the tablets should be swallowed whole—do not chew, break, or crush them. If a dose is missed by more than 6 hours, skip it and take the next scheduled dose. Do not take two tablets at once.
Storage: AVMAPKI (avutometinib) 0.8 mg capsules are presented as white capsules with “6766” printed on the cap and “0.8 mg” marked on the body in black ink. These are packaged in bottles containing 24 capsules, with each bottle including a desiccant that should not be discarded.
FAKZYNJA (defactinib) 200 mg tablets are white to off-white, oval-shaped, and debossed with “VS2” on one side. These tablets come in bottles containing 42 tablets.
Both AVMAPKI capsules and FAKZYNJA tablets should be stored in the original bottles, refrigerated at temperatures between 2°C and 8°C (36°F to 46°F).
Patient information leaflet
Generic Name: avutometinib and defactinib
Why do we use avutometinib and defactinib?
AVMAPKI FAKZYNJA CO-PACK, a combination of avutometinib and defactinib, is indicated for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have previously received systemic therapy. This approval was granted under accelerated approval based on tumor response rate and duration of response. Continued approval may depend on the verification of clinical benefit in a confirmatory trial.
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