Avapritinib

Brand name: Ayvakit
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
VA class: AN900
Chemical name: (1S)-1-(4-Fluorophenyl)-1-(2-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl}pyrimidin-5-yl)ethan-1-amine.
Molecular formula: C₂₆H₂₇FN₁₀
CAS number: 1703793-34-3

Medically reviewed by Drugs.com on Sep 19, 2022. Written by ASHP.

Introduction

Antineoplastic agent; potent and selective inhibitor of platelet-derived growth factor receptor alpha (PDGFR-α), PDGFR-α with D842 mutations, and c-Kit with exon 11, 11/17, and 17 mutations.

Uses for Avapritinib

GI Stromal Tumor (GIST)

Treatment of unresectable or metastatic GIST harboring PDGFR-α exon 18 mutation, including PDGFR-α D842V mutations (designated an orphan drug by FDA for treatment of this cancer).

Confirmation of the presence of PDGFR-α exon 18 mutation is necessary prior to initiation of therapy. In clinical studies, presence of PDGFR-α exon 18 mutation was determined by polymerase chain reaction (PCR) or next-generation sequencing (NGS) assay.

Avapritinib Dosage and Administration

General

• Confirm presence of PDGFR-α exon 18 mutation prior to initiation of therapy. (See Uses: GI Stromal Tumors [GIST].)

Restricted Distribution

• Obtain through designated specialty pharmacies.

Administration

Oral Administration

Administer orally once daily on an empty stomach (i.e., ≥1 hour before or 2 hours after a meal).

Dosage

Adults

GIST

Oral

300 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

If concomitant use with moderate CYP3A inhibitors cannot be avoided, reduce avapritinib dosage. (See Interactions.)

Dosage Modification for Toxicity

Oral

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of drug may be necessary. When dosage reduction is required, reduce dosage of avapritinib as described in Table 1.

If an adverse reaction occurs, modify dosage accordingly (see Table 2).

Prescribing Limits

Adults

GIST

Oral

Dosage <100 mg once daily not recommended.

Special Populations

Hepatic Impairment

Mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding ULN, or total bilirubin concentration exceeding ULN, but not >1.5 times ULN, with any AST concentration) or moderate (total bilirubin concentration exceeding 1.5 times ULN , but not >3 times ULN, with any AST concentration) hepatic impairment: No dosage adjustment required.

Severe preexisting hepatic impairment (total bilirubin concentration >3 times ULN with any AST concentration): No specific dosage recommendations. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment required.

Severe renal impairment or end-stage renal disease (Cl_cr ≤29 mL/minute): No specific dosage recommendations. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions for Avapritinib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Intracranial Hemorrhage

Intracranial hemorrhage (e.g., subdural hematoma, intracranial or cerebral hemorrhage) reported within 1.7–19.3 months following initiation of therapy.

If intracranial hemorrhagic events occur, interruption of therapy, dosage reduction, and/or permanent discontinuance of avapritinib may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

CNS Effects

Avapritinib can cause a broad spectrum of adverse CNS effects (i.e., cognitive impairment; dizziness; hallucinations; sleep, speech, or mood disorder). Median time to initial onset was 6.1 weeks in clinical trials.

Inform patients and their caregivers of the risk of adverse CNS effects. Advise patients not to drive or operate hazardous machinery if they are experiencing adverse CNS effects. If adverse CNS effects occur, interruption of therapy, dosage reduction, and/or permanent discontinuance of avapritinib may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals.

Perform pregnancy test prior to initiating avapritinib therapy in women of reproductive potential.

Avoid pregnancy during therapy and for 6 weeks after the last dose of the drug. Advise women of reproductive potential and men who are partners of such women to use effective contraception while receiving the drug and for 6 weeks after the last dose of the drug.

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Impairment of Fertility

Results of animal studies suggest avapritinib may impair male and female fertility.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether avapritinib or its metabolites distribute into milk or affect milk production or the nursing infant.

Women should not breast-feed during therapy and for 2 weeks after the last dose of the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In NAVIGATOR study, 40% of patients were ≥65 years of age and 6% were ≥75 years of age. No overall differences in safety and efficacy were observed between geriatric patients and younger adults.

Hepatic Impairment

Pharmacokinetics not substantially altered by mild or moderate hepatic impairment; dosage adjustment not necessary in such patients. (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe hepatic impairment.

Renal Impairment

Pharmacokinetics not substantially altered by mild or moderate renal impairment; dosage adjustment not necessary in such patients. (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment or end-stage renal disease.

Common Adverse Effects

Edema, nausea, fatigue, asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, dizziness, decreased hemoglobin concentration, leukopenia, neutropenia, thrombocytopenia, elevated INR, elevated bilirubin concentration, elevated ALT and/or AST concentration, hypophosphatemia, hypokalemia, hypoalbuminemia, hypomagnesemia, elevated S_cr concentration, hyponatremia.

Interactions for Avapritinib

Metabolized principally by CYP3A4 and to a lesser extent by CYP2C9; major circulating metabolites are M690 and M499. Substrate of CYP3A.

Avapritinib: Time-dependent inhibitor and inducer of CYP3A. Inhibits 2C9 in vitro. Does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C19, or 2D6 or induce CYP isoenzymes 1A2 or 2B6 at clinically relevant concentrations.

M499: Inhibits CYP isoenzymes 3A, 2C8, and 2C9, but not CYP isoenzymes 1A2, 2B6, 2C19, and 2D6 at clinically relevant concentrations.

Avapritinib: Inhibits 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) in vitro. Does not inhibit organic anion-transporting polypeptides (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, and OCT2. Not a substrate for P-gp or BCRP.

M499: Effect on transporter systems not known.

Drugs Affecting Hepatic Microsomal Enzymes

Potent or moderate inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, avapritinib. Avoid concomitant use. If concomitant use of a moderate CYP3A inhibitor cannot be avoided, reduce avapritinib dosage to 100 mg once daily.

Potent or moderate inducers of CYP3A: Possible decreased systemic exposure to, and decreased therapeutic efficacy of, avapritinib. Avoid concomitant use.

Specific Drugs

Avapritinib Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma concentrations is 2–4.1 hours following oral administration.

Systemic exposure increases in a dose proportional manner over dosage range of 30–400 mg daily.

Steady-state concentrations achieved in 15 days; mean accumulation ratio is 3.1–4.6.

Food

Administration with a high-fat, high-calorie meal (i.e., approximately 909 calories, 56 g of fat) increased AUC and peak plasma concentration by 29 and 59%, respectively.

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding ULN, or total bilirubin concentration exceeding ULN, but not >1.5 times the ULN, with any AST concentration) or moderate hepatic impairment (total bilirubin concentration exceeding 1.5 times ULN , but not >3 times ULN, with any AST concentration) does not affect pharmacokinetics of avapritinib.

Severe hepatic impairment (total bilirubin concentrations >3 times ULN with any AST concentration): Pharmacokinetics not studied.

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute) does not affect pharmacokinetics of avapritinib.

Severe renal impairment (Cl_cr ≤29 mL/minute) or end-stage renal disease: Pharmacokinetics not studied.

Age (18–90 years), sex, race, and body weight (40–156 kg) do not substantially affect pharmacokinetics of avapritinib.

Distribution

Extent

Not known whether avapritinib or its metabolites are distributed into milk.

Plasma Protein Binding

99% (independent of avapritinib concentration).

Elimination

Metabolism

Principally metabolized by CYP3A4 and to a lesser extent by CYP2C9.

Main circulating metabolites are M690 (hydroxy glucuronide metabolite) and M499 (oxidative metabolite); M499 accounts for approximately 80% of systemic exposure to the drug at steady state.

Elimination Route

Eliminated in feces (70%; 11% as unchanged drug) and urine (18%; 0.23% as unchanged drug).

Half-life

32–57 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Potent and selective inhibitor of PDGFR-α, PDGFR-α with D842 mutations, and c-Kit with exon 11, 11/17 and 17 mutations.

• Some mutations in PDGFR-α and c-Kit increase autophosphorylation and activation, independent of ligand binding, of the tyrosine kinase receptor resulting in increased tumor cell proliferation and survival.

• Inhibits autophosphorylation of PDGFR-α D842V and c-Kit D816V mutations associated with resistance to other tyrosine kinase inhibitors (e.g., imatinib, regorafenib, sunitinib).

• Demonstrates antitumor activity in patient-derived xenograft models of imatinib-resistant GIST harboring c-Kit exon 11/17 mutations.

• M499 metabolite unlikely to contribute to activity of avapritinib at recommended dose.

Advice to Patients

• Importance of instructing patients to read the manufacturer-s patient information.

• Importance of advising patients to take avapritinib tablets once daily on an empty stomach at least 1 hour before or 2 hours after a meal.

• If a dose is missed, importance of advising patients to take it as soon as they remember unless the next dose is due in <8 hours.

• If vomiting occurs, a replacement dose should not be administered. Patients should be advised to resume dosing at the time of the next scheduled dose.

• Risk of intracranial hemorrhagic events. Importance of immediately informing clinician if severe headache, vision problems, severe drowsiness, or severe weakness on one side of the body occurs.

• Risk of adverse CNS effects. Importance of informing clinician if new or worsening manifestations of CNS symptoms (e.g., confusion, speech difficulty, dizziness, drowsiness, forgetfulness, trouble thinking, insomnia, hallucinations, changes in behavior or mood) occur. Necessity of advising patients to avoid driving or operating hazardous machinery if they experience adverse CNS effects.

• Risk of fetal harm. Necessity of advising women of reproductive potential and men who are partners of such women that they should use effective methods of contraception during therapy and for ≥6 weeks after the last dose of the drug. Importance of women informing their clinicians if they become pregnant during therapy or think they may be pregnant. Advise men and women of reproductive potential of potential risk to the fetus.

• Importance of advising women to avoid breast-feeding while receiving avapritinib and for ≥2 weeks after the last dose of the drug.

• Risk of impaired male and female fertility.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of avapritinib is restricted. (See Restricted Distribution under Dosage and Administration.)

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