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Ayvakit (avapritinib)

Antineoplastic - Protein-Tyrosine Kinase Inhibitors Oral Tablet

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Last reviewed · Source: First Databank (FDB) drug data

Overview

Avapritinib, a potent and selective inhibitor of platelet-derived growth factor receptor alpha (PDGFR-alpha), PDGFR-alpha with D842 mutations, and c-Kit with exon 11, 11/17, and 17 mutations, is an antineoplastic agent.

Avapritinib, a potent and selective inhibitor of platelet-derived growth factor receptor alpha (PDGFR-alpha), PDGFR-alpha with D842 mutations, and c-Kit with exon 11, 11/17, and 17 mutations, is an antineoplastic agent. Some mutations in PDGFR-alpha and c-Kit increase autophosphorylation and activation, independent of ligand binding, of the tyrosine kinase receptor resulting in increased cell proliferation and survival in GI stromal tumors (GIST) harboring these mutations. In cellular assays, avapritinib inhibits autophosphorylation of PDGFR-alpha D842V and c-Kit D816V mutations associated with resistance to other tyrosine kinase inhibitors (e.g., imatinib, regorafenib, sunitinib).

In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines that included murine mastocytoma cell lines and human mast cell leukemia cell lines. In vivo, avapritinib demonstrated antitumor activity in patient-derived xenograft models of imatinib-resistant GIST harboring c-Kit exon 11/17 mutations.

Systemic exposure to avapritinib increases in a dose proportional manner over a dosage range of 25-400 mg daily. Following oral administration, the median time to peak plasma concentrations of avapritinib is 2-4 hours. Following repeated daily dosing, steady-state concentrations of the drug are attained in 15 days with a mean accumulation ratio of 3.82, 4.06, and 6.41 in GIST, ISM, and systemic mastocytosis, respectively.

Administration of avapritinib with a high-fat, high-calorie meal (i.e., approximately 909 calories, 56 g of fat) increases the area under the concentration-time curve (AUC) and peak plasma concentration of avapritinib by 29 and 59%, respectively, compared with administration in the fasted state. Avapritinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4, CYP3A5, and to a lesser extent by CYP2C9. The main circulating metabolites are M690 (a hydroxy glucuronide metabolite) and M499 (an oxidative metabolite).

Following administration of avapritinib 300 mg once daily, M499 accounts for approximately 80% of systemic exposure to the drug at steady state but is unlikely to contribute significantly to the activity of avapritinib at the recommended dose. Following oral administration of a single radiolabeled dose of avapritinib, 70% of the radioactivity was recovered in feces (11% of the dose as unchanged drug) and 18% was recovered in urine (0.23% of the dose as unchanged drug). In vitro, avapritinib is 98.8% bound to plasma proteins, and binding is independent of avapritinib concentration.

The mean elimination half-life of the drug is 32-57 hours in patients with GIST, 20-39 hours in patients with AdvSM, and 38-45 hours in patients with ISM.

The pharmacokinetics of avapritinib do not appear to be affected substantially by age (18-90 years), sex, race, and body weight (39.5-156.3 kg).

USES: This medication is used to treat a certain type of stomach, bowel, or esophagus cancer (gastrointestinal stromal tumor-GIST). Avapritinib is also used to treat certain immune system disorders (advanced systemic mastocytosis, indolent systemic mastocytosis). Avapritinib belongs to a class of drugs known as kinase inhibitors.

It works by slowing or stopping the growth of cancer cells and certain immune system cells (mast cells).

Generic name: avapritinib
Pronunciation: (A-va-PRI-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics

Reference product & biosimilars

No reference, biosimilar or interchangeable associated with this drug.

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Indications

The following indications are listed for Ayvakit:

  • Aggressive Systemic Mastocytosis
  • Mast Cell Leukemia
  • Platelet-Derived Growth Factor Receptor Alpha Exon 18 Mutation(+) Gastrointestinal Stromal Tumor
  • Systemic Mastocytosis With Associated Hematological Neoplasm

Also known as: Pdgfra Exon 18 Mut-Positive Gist, Pdgfra Exon 18 Mutation-Positive Gastrointestinal Stromal Tumor, Pdgfra Exon 18 Mutation-Positive Gist, Systemic Mastocytosis With An Associated Hematologic Non-Mast Cell Lineage Disease.

Dosing

If adverse reactions occur during avapritinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage reduction is required, the dosage of avapritinib should be reduced as described in Table 1.

Table 1: Recommended Dosage Reductions for Avapritinib after Recovery from Toxicity

Dosage Reduction GIST AdvSM First Dose Reduction 200 mg once daily 100 mg once daily Second Dose Reduction 100 mg once daily 50 mg once daily Third Dose Reduction Discontinue avapritinib 25 mg once daily

Permanently discontinue avapritinib in patients with GIST unable to tolerate a dose of 100 mg daily.

Permanently discontinue avapritinib in patients with AdvSM unable to tolerate a dose of 25 mg daily.

The following table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for adverse effects according to severity.

Table 2. Recommended Dosage Modifications for Avapritinib Toxicity

Adverse Reaction and Severity Dosage Modification Patients with GIST or AdvSM with Any grade: Permanently discontinue intracranial hemorrhage therapy Patients with GIST or AdvSM with Grade 1: Continue at same or reduced cognitive effects dosage, or withhold therapy until toxicity resolves or improves to baseline and then resume at same or reduced dosage Grade 2 or 3: Withhold therapy; when toxicity resolves or improves to baseline or grade 1, resume at same or reduced dosage Grade 4: Permanently discontinue therapy Patients with GIST or AdvSM with Grade 3 or 4: withhold therapy; when other toxicity toxicity improves to grade 2 or less, resume at same or reduced dosage Patients with AdvSM with Platelets <50,000/mm3: interrupt thrombocytopenia treatment until platelet count >=50,000/mm3, then resume at reduced dosage. If platelet counts do not recover to >=50,000/mm3, consider platelet support

Drug interactions

Avapritinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4, 3A5, and to a lesser extent by CYP2C9; the major circulating metabolites are a hydroxy glucuronide metabolite (M690) and an oxidative metabolite (M499). Formation of M690 is catalyzed by UDP-glucuronosyltransferase (UGT) 1A3.

In vitro, avapritinib demonstrates time-dependent inhibition and induction of CYP3A. In vitro, avapritinib inhibits CYP2C9, but does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C19, or 2D6 or induce CYP isoenzymes 1A2 or 2B6 at clinically relevant concentrations. In vitro, avapritinib is a substrate of CYP3A.

In vitro, M499 inhibits CYP isoenzymes 3A, 2C8, and 2C9, but does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, and 2D6 at clinically relevant concentrations.

In vitro studies indicate that avapritinib is an inhibitor of P-glycoprotein (P-gp), intestinal breast cancer resistance protein (BCRP), multidrug and toxic compound extrusion protein (MATE) 1, MATE2K, and bile salt export pump (BSEP). Avapritinib does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, and OCT2. Avapritinib also is not a substrate for P-gp or BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, and BSEP. The effect of M499 on transport systems is not known.

Contraindications

None.

Adverse reactions

The most common adverse reactions in clinical trials for GIST (occurring in >=20% of patients receiving avapritinib) include edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness.

The most common adverse reactions in clinical trials for AdvSM (occurring in >=20% of patients receiving avapritinib) include: edema, diarrhea, nausea, and fatigue/asthenia.

The most common adverse reactions in a clinical trial for ISM (occuring in >=10% of patients receiving avapritinib) include: eye edema, dizziness, peripheral edema, andflushing.

Precautions

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ICD codes

CodeTypeDescription
Aggressive systemic mastocytosis
C96.21ICD10CMAggressive systemic mastocytosis
Mast cell leukemia
C94.3ICD10CMMast cell leukemia
C94.30ICD10CMMast cell leukemia not having achieved remission
Platelet-derived growth factor receptor alpha exon 18 mutation(+) gastrointestinal stromal tumor
C49.AICD10CMGastrointestinal stromal tumor
C49.A0ICD10CMGastrointestinal stromal tumor, unspecified site
C49.A1ICD10CMGastrointestinal stromal tumor of esophagus
C49.A2ICD10CMGastrointestinal stromal tumor of stomach
C49.A3ICD10CMGastrointestinal stromal tumor of small intestine
C49.A4ICD10CMGastrointestinal stromal tumor of large intestine
C49.A5ICD10CMGastrointestinal stromal tumor of rectum
C49.A9ICD10CMGastrointestinal stromal tumor of other sites
Systemic mastocytosis with associated hematological neoplasm
C96.21ICD10CMAggressive systemic mastocytosis
D47.02ICD10CMSystemic mastocytosis

ICD code information from First Databank (FDB).

Formulary status

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Last reviewed · Source: First Databank (FDB) drug data