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Tucatinib

Class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical Name: 6-N-(4,4-dimethyl-5H-1,3-oxazol-2-yl)-4-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazoline-4,6-diamine
Molecular Formula: C26H24N8O2
CAS Number: 937263-43-9
Brands: Tukysa

Medically reviewed by Drugs.com on Oct 4, 2021. Written by ASHP.

Introduction

Antineoplastic agent; a highly selective, reversible tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2).

Uses for Tucatinib

Breast Cancer

Used in combination with trastuzumab and capecitabine for the treatment of HER2-positive unresectable, locally advanced, or metastatic breast cancer in patients, including those with brain metastases, previously treated with ≥1 anti-HER2-based regimen in the metastatic setting (designated an orphan drug by FDA for this cancer).

Tucatinib Dosage and Administration

General

Pretreatment Screening

  • Serum ALT, AST, and bilirubin concentrations.

  • Verify pregnancy status in females of reproductive potential.

Patient Monitoring

  • Serum ALT, AST, and bilirubin concentrations every 3 weeks during therapy, and as clinically indicated.

Premedication and Prophylaxis

  • Prophylactic use of antidiarrheal agents not required in principal efficacy study (HER2CLIMB study).

Administration

Oral Administration

Administer twice daily, approximately 12 hours apart at the same time each day, without regard to meals.

Swallow tablets intact; do not chew, crush, crack, break, or split.

If a dose of tucatinib is missed or vomited, take the next dose at the regularly scheduled time.

Dosage

Adults

Breast Cancer
Oral

300 mg twice daily in combination with trastuzumab and capecitabine.

Consult respective manufacturers' labelings or published protocols for information on dosage and method and sequence of administration of other antineoplastic agents used in combination with tucatinib.

May administer capecitabine and tucatinib at the same time. In the HER2CLIMB study, capecitabine 1 g/m2 twice daily within 30 minutes after a meal was administered on days 1–14 and trastuzumab 8 mg/kg IV initially, followed by either 6 mg/kg IV or 600 mg by subcutaneous injection was administered on day 1 of each 21-day cycle.

Dosage Modification for Toxicity
Oral

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

Table 1. Dosage Reduction for Tucatinib Toxicity.1

Dose Reduction Level

Dosage Reduction after Recovery from Toxicity (Initial Dosage = 300 mg twice daily)

First

Restart at 250 mg twice daily

Second

Restart at 200 mg twice daily

Third

Restart at 150 mg twice daily

Fourth

Permanently discontinue tucatinib

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

Table 2. Dosage Modification for Tucatinib Toxicity1

Adverse Reaction and Severity

Modification

Diarrhea

Grade 3

Initiate appropriate medical therapy and withhold tucatinib therapy; when diarrhea improves to grade 1 or less, resume at same dosage

If grade 3 diarrhea occurs despite appropriate antidiarrheal therapy, intensify medical therapy and withhold tucatinib therapy; when diarrhea improves to grade 1 or less, resume at next lower dosage (see Table 1)

Grade 4

Permanently discontinue therapy

Hepatic Toxicity

Grade 2 elevations of serum bilirubin concentrations

Withhold therapy; when toxicity improves to grade 1 or less, resume at same dosage

Grade 3 elevations of serum ALT or AST concentrations

Withhold therapy; when toxicity improves to grade 1 or less, resume at next lower dosage (see Table 1)

Grade 3 elevations of serum bilirubin concentrations

Withhold therapy; when toxicity improves to grade 1 or less, resume at next lower dosage (see Table 1)

Grade 4 elevations of serum ALT, AST, or bilirubin concentrations

Permanently discontinue therapy

Elevations of serum ALT or AST >3 times the upper limit of normal (ULN) with concomitant elevations in serum bilirubin concentrations >2 times the ULN

Permanently discontinue therapy

Other Toxicity

Grade 3

Withhold therapy; when toxicity improves to grade 1 or less, resume at next lower dosage (see Table 1)

Grade 4

Permanently discontinue therapy

Special Populations

Hepatic Impairment

Oral

Severe hepatic impairment (Child-Pugh class C): Reduce tucatinib dosage to 200 mg twice daily.

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.

Renal Impairment

Oral

Mild or moderate renal impairment (Clcr 30–89 mL/minute using Cockcroft-Gault formula): No dosage adjustment required.

Severe renal impairment (Clcr <30 mL/minute using Cockcroft-Gault formula): Combination therapy with tucatinib, capecitabine, and trastuzumab not recommended.

Geriatric Patients

No specific dosage recommendations; however, in principal efficacy study, 26% of tucatinib-treated patients were ≥65 years of age and 2.5% were ≥75 years of age.

Cautions for Tucatinib

Contraindications

  • None.

Warnings/Precautions

Combination Therapy

When used in combination with capecitabine and trastuzumab, consider cautions, precautions, and contraindications of capecitabine and trastuzumab.

Diarrhea

Severe diarrhea associated with dehydration, hypotension, acute kidney injury, and death reported. Median time to initial onset of diarrhea was 12 days. Median time to resolution of diarrhea was 8 days.

Administer antidiarrheal therapy as clinically indicated if diarrhea occurs during therapy. Perform diagnostic tests to exclude other causes of diarrhea. If diarrhea occurs, temporary interruption, dosage reduction, or permanent discontinuance of therapy may be necessary.

Hepatic Toxicity

Severe hepatotoxicity (i.e., elevations in ALT and/or AST concentrations >5 times the ULN, elevations in serum bilirubin concentrations >3 times the ULN) reported.

Monitor liver function tests (i.e., ALT, AST, bilirubin concentrations) prior to initiation of therapy, every 3 weeks thereafter, and as clinically indicated. If hepatotoxicity occurs, temporary interruption, dosage reduction, or permanent discontinuance of therapy may be necessary.

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action and animal findings, tucatinib may cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiating tucatinib therapy in females of reproductive potential. Advise females of reproductive potential and men who are partners of such women to use effective contraception while receiving the drug and for ≥1 week after the last dose of the drug. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Impairment of Fertility

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

Specific Populations

Pregnancy

May cause fetal harm.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiating tucatinib therapy in females of reproductive potential.

Advise females of reproductive potential and men who are partners of such women to use effective contraception while receiving the drug and for ≥1 week after the last dose of the drug. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Lactation

Not known whether tucatinib or its metabolites distribute into milk, affect milk production, or affect breast-fed infants.

Women should not breast-feed during therapy and for ≥7 days after the last dose of the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

In the HER2CLIMB study, 26% of tucatinib-treated patients were ≥65 years of age and 2.5% were ≥75 years of age. No overall difference in efficacy relative to younger adults. Serious adverse reactions (e.g., diarrhea, vomiting, nausea) reported more frequently in geriatric patients.

Hepatic Impairment

Mild or moderate hepatic impairment: Systemic exposure not substantially altered. No dosage adjustment required.

Severe hepatic impairment: Systemic exposure increased by 1.6-fold. Reduce tucatinib dosage to 200 mg twice daily.

Renal Impairment

Mild or moderate renal impairment: Pharmacokinetics not substantially affected. No dosage adjustment required.

Severe renal impairment: Pharmacokinetics not studied.

Common Adverse Effects

Adverse effects occurring in ≥20% of patients: Diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, rash.

Tucatinib increases Scr by inhibiting tubular secretion of creatinine. Elevated Scr concentrations are reversible following discontinuance of therapy. Use of alternative markers for renal function may be necessary if elevated Scr concentrations persist.

Interactions for Tucatinib

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A.

In vitro, reversible inhibitor of CYP isoenzymes 2C8 and 3A. Time-dependent inhibitor of CYP3A, but does not inhibit CYP isoenzymes 1A2, 2B6, 2C9, 2C19, and 2D6, or uridine diphosphate-glucuronosyltransferase (UGT) 1A1.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, multidrug and toxin extrusion (MATE) 1, MATE2K, or bile salt export pump (BSEP).

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2C8 inhibitors: Possible increased systemic exposure to tucatinib and increased risk of adverse effects. Avoid concomitant use. If concomitant use cannot be avoided, reduce tucatinib dosage to 100 mg twice daily. If concomitant use of potent CYP2C8 inhibitor is discontinued, return tucatinib dosage (after 3 elimination half-lives of the CYP2C8 inhibitor) to dosage used prior to initiation of CYP2C8 inhibitor.

Moderate CYP2C8 inhibitors: Possible increased systemic exposure to tucatinib and increased risk of adverse effects. If used concomitantly, monitor for signs of tucatinib toxicity.

Potent CYP3A or moderate CYP2C8 inducers: Possible decreased systemic exposure to tucatinib and reduced efficacy of tucatinib. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible increased systemic exposure to the CYP3A substrate and increased risk of adverse effects of the substrate drug. Avoid concomitant use with CYP3A substrates that have a narrow therapeutic index. If concomitant use cannot be avoided, reduce dosage of the CYP3A substrate as appropriate.

Drugs Affected by Transport Systems

P-gp substrates: Possible increased systemic exposure of the P-gp substrate and increased risk of adverse effects of the substrate drug. If used concomitantly with a P-gp substrate that has a narrow therapeutic index, reduce dosage of the P-gp substrate as appropriate.

Specific Drugs

Drug

Interaction

Comments

Digoxin

Increased AUC and peak plasma concentrations of digoxin by 1.5- and 2.4-fold, respectively

Avoid concomitant use; if concomitant cannot be avoided, adjust dosage of digoxin as appropriate

Gemfibrozil

Increased AUC and peak plasma concentrations of tucatinib by 3- and 1.6-fold, respectively

Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of tucatinib to 100 mg twice daily

When gemfibrozil is discontinued, return tucatinib dosage (after 3 elimination half-lives of gemfibrozil) to prior dosage

Itraconazole

Increased both AUC and peak plasma concentrations of tucatinib by 1.3-fold.

Metformin

Reduced renal clearance of metformin without any effect on GFR

Increased AUC and peak plasma concentration of metformin by 1.4- and 1.1-fold, respectively

Midazolam

Increased AUC and peak plasma concentration of midazolam by 5.7- and 3-fold, respectively

Omeprazole

No clinically important effect on pharmacokinetics of tucatinib

Rifampin

Decreased AUC and peak plasma concentrations of tucatinib by 48 and 37%, respectively

Avoid concomitant use

Tolbutamide

No clinically important effect on pharmacokinetics of tucatinib

Tucatinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration and AUC of tucatinib are dose proportional over an oral dosage range of 50–300 mg.

Peak plasma concentrations attained in a median of 2 hours following oral administration.

Steady-state concentrations are achieved in approximately 4 days; accumulation based on AUC or peak plasma concentration is 1.7- or 1.5-fold, respectively.

Food

Administration of high-fat meal did not substantially affect pharmacokinetics of tucatinib.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): Systemic exposure not substantially altered.

Severe hepatic impairment (Child-Pugh class C): AUC increased by 1.6-fold.

Mild or moderate renal impairment (Clcr 30–89 mL/minute): Pharmacokinetics not substantially altered.

Severe renal impairment (Clcr <30 mL/minute): Pharmacokinetics not studied.

Age, serum albumin concentration (2.5–5.2 g/dL), body weight (41–138 kg), and race (White, Black, or Asian) do not affect pharmacokinetics of tucatinib.

Distribution

Extent

Not known whether tucatinib or its metabolites distribute into milk.

Plasma Protein Binding

97.1%.

Elimination

Metabolism

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A.

Elimination Route

Eliminated in feces (86% [16% as unchanged drug]) and urine (4.1%).

Half-life

8.5 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C) in original container to protect from moisture. Replace cap securely each time after opening. Do not discard desiccant. Discard after 3 months of first opening.

Actions

  • Highly selective and reversible tyrosine kinase inhibitor of HER2.

  • Inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt) pathways.

  • In vivo, inhibits cellular proliferation of HER2-expressing tumors.

  • Increased antitumor activity with combination of tucatinib and trastuzumab compared with either drug alone.

  • Demonstrates 500-fold greater selectivity for HER2 than for epidermal growth factor receptor (EGFR) , thereby potentially reducing the incidence of adverse effects associated with EGFR inhibition, such as adverse GI and dermatologic effects.

Advice to Patients

  • Advise the patient to read the FDA-approved patient labeling (Patient Information).

  • Inform patients that tucatinib has been associated with severe diarrhea. Instruct patients on how to manage diarrhea and to inform their healthcare provider immediately if there is any change in bowel patterns.

  • Inform patients that tucatinib has been associated with severe hepatotoxicity and that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately.

  • Inform pregnant women and females of reproductive potential of the risk to a fetus. Advise women to inform their healthcare provider of a known or suspected pregnancy.

  • Advise females of reproductive potential to use effective contraception during treatment with tucatinib and for at least 1 week after the last dose.

  • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with tucatinib and for at least 1 week after the last dose.

  • Advise women not to breastfeed during treatment with tucatinib and for at least 1 week after the last dose.

  • Advise males and females of reproductive potential that tucatinib may impair fertility.

  • Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Inform 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.

Available only from a designated specialty pharmacy. Contact manufacturer for additional information.

Tucatinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg

Tukysa

Seattle Genetics

150 mg

Tukysa

Seattle Genetics

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 4, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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