Avapritinib

BRAND NAMES 

Avapritinib was marketed under different names by region:

• Ayvakit in the United States

• Ayvakyt in the European Union

MECHANISM OF ACTION 

Avapritinib inhibited tyrosine kinases, including mutated forms of KIT and PDGFRA. Its targets included KIT D816V, PDGFRA D842V, and other activating KIT and PDGFRA mutations. These mutations could keep the receptors continuously active, encouraging abnormal mast-cell or tumor-cell growth. Avapritinib reduced this activity by blocking the kinases. 

PHARMACOKINETICS 

Absorption

After a single dose, avapritinib reached its peak blood concentration in a median of 2–4 hours. With daily dosing, steady-state concentrations were reached before day 15. Compared with fasting, a high-fat, high-calorie meal increased peak concentration by 59% and total exposure (AUC) by 29%. The U.S. prescribing information advised taking the medicine on an empty stomach, at least 1 hour before or 2 hours after a meal

Distribution

The reported apparent volume of distribution ranged from 1,310 to 1,900 L, depending on the patient group and dose. In laboratory testing, 98.8% of avapritinib was bound to plasma proteins. Its blood-to-plasma ratio was 0.95. 

Metabolism

Avapritinib was metabolized mainly by CYP3A4 and CYP3A5, and to a lesser extent by CYP2C9. The main circulating metabolites after a radiolabeled dose included M690, a hydroxy-glucuronide formed mainly through UGT1A3, and M499, produced through oxidative deamination. The prescribing information reported that M499 was unlikely to contribute to the medicine’s effect at the recommended dose. 

Elimination

The average plasma half-life varied by patient group: 32–57 hours in GIST, 20–39 hours in advanced systemic mastocytosis, and 38–45 hours in indolent systemic mastocytosis. After a single radiolabeled dose, about 70% of the radioactivity was recovered in feces and 18% in urine. Only small amounts of unchanged avapritinib were found in either. 

PHARMACODYNAMICS

Avapritinib acted by blocking tyrosine kinases, including mutated KIT and PDGFRA proteins. Some KIT and PDGFRA mutations kept these proteins active and supported the growth of mast cells or tumor cells. Avapritinib inhibited that signaling, including activity linked to KIT D816V and PDGFRA D842V.

In studies of GIST and advanced systemic mastocytosis, greater avapritinib exposure was associated with higher rates of certain serious side effects, cognitive effects, and edema. A small study did not find a large average increase in the QTc interval at daily doses of 300 or 400 mg. 

ADMINISTRATION

Avapritinib was taken by mouth once a day, without food: at least one hour before eating or two hours afterward. If fewer than eight hours remained before the next scheduled dose, the missed dose was skipped. After vomiting, patients were advised not to take a replacement dose and to resume at the next scheduled time.

DOSAGE AND STRENGTHS

Tablets were supplied in 25 mg, 50 mg, 100 mg, 200 mg, and 300 mg strengths. The dose could have been adjusted for side effects, interacting medicines, or severe liver impairment. 

DRUG INTERACTIONS

• Strong and moderate CYP3A inhibitors could have raised avapritinib levels and increased side-effect risk, so the label advised avoiding them. If a moderate inhibitor could not have been avoided, the reduced starting doses were 100 mg daily for GIST and 50 mg daily for AdvSM. The combination was to be avoided for ISM.

• Strong and moderate CYP3A inducers could have lowered avapritinib levels and reduced its effect; the label advised avoiding them.

• Avapritinib could have increased exposure to ethinyl estradiol in some hormonal contraceptives. The label provided additional guidance on contraceptive choices.

• At GIST doses, avapritinib could have raised levels of CYP3A medicines with a narrow therapeutic range. The prescribing guidance for those medicines was to be checked.

• Medicines that reduced stomach acid were not found to cause clinically meaningful changes in avapritinib exposure in the studies described in the label.

FOOD INTERACTIONS

Avapritinib was taken on an empty stomach, at least 1 hour before or 2 hours after eating. A high-fat meal increased the medicine’s peak level and overall exposure. Patients were advised to ask their doctor or pharmacist about grapefruit and grapefruit juice, and to report all medicines, vitamins, and herbal supplements they used. Some medicines could raise or lower avapritinib levels. 

CONTRAINDICATIONS

The U.S. prescribing information listed no formal contraindications. Patients were advised to tell their clinician if they had a history of brain bleeding, an aneurysm, a recent stroke, low platelets, or liver problems. Avapritinib carried risks of serious bleeding and fetal harm. 

SIDE EFFECTS

Common side effects varied by condition:

• GIST: swelling or fluid retention, nausea, fatigue, memory or thinking problems, vomiting, reduced appetite, diarrhea, abdominal pain, constipation, rash, and dizziness.

Serious risks included bleeding in the brain, changes in thinking or alertness, low platelet counts—especially in advanced systemic mastocytosis—and sensitivity to sunlight. Avapritinib could also harm an unborn baby. 

OVERDOSE

The current U.S. prescribing information did not include a dedicated overdose treatment protocol or antidote. Anyone who took more than prescribed was advised to contact a poison service or emergency department promptly. Patients were told not to take an extra dose after vomiting or double a missed dose. 

TOXICITY

Avapritinib toxicity included the serious effects described above, along with possible changes in blood counts and laboratory results. Risk could increase when drug levels rose, including through interactions with certain medicines or taking it with a high-fat meal. In animal studies, high exposures were linked to tremors, bleeding in the brain or spinal cord, and fetal harm; those findings did not predict exactly what would happen in an individual patient.