Pralsetinib (Monograph)

Brand name: Gavreto
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; inhibitor of multiple receptor tyrosine kinases, including wild-type and mutated rearranged during transfection (RET) isoforms.

Uses for Pralsetinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of adults with metastatic RET fusion-positive NSCLC.

Designated an orphan drug by FDA for the treatment JAK1/2-positive or TRKC-positive NSCLC.

Confirmation of RET fusion necessary prior to initiation of therapy by an FDA-approved test ([Web]). In clinical studies, presence of RET fusion was determined by next generation sequencing (NGS), fluorescence in situ hybridization (FISH), or other tests.

ASCO living guideline for stage IV NSCLC with driver alterations states that for patients with a RET rearrangement, clinicians should offer selpercatinib as a first-line treatment option. If selpercatinib is unavailable, then clinicians may offer pralsetinib. In the second-line and subsequent treatment option arena, clinicians should offer selpercatinib or pralsetinib to patients who have not received a RET inhibitor.

Thryoid Cancer

Treatment of advanced or metastatic RET fusion-positive thyroid cancer in adult and pediatric patients 12 years of age or older who require systemic therapy and are refractory to radioactive iodine (for whom such therapy is appropriate).

Accelerated approval based on objective response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Designated an orphan drug by FDA for the treatment of this cancer.

Confirmation of specific RET gene fusion or mutation necessary prior to initiation of therapy. In clinical studies, presence of RET fusion was determined by NGS, FISH, or other tests.

Pralsetinib Dosage and Administration

General

Pretreatment Screening

In patients with NSCLC or thyroid cancer, confirm presence of a RET gene fusion.
Assess serum ALT and AST concentrations.
Assess blood pressure. Do not initiate pralsetinib therapy in patients with uncontrolled hypertension.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Assess serum ALT and AST concentrations every 2 weeks for the first 3 months of therapy, monthly thereafter, and as clinically indicated.
Monitor blood pressure 1 week following initiation of pralsetinib therapy, at least monthly thereafter, and as clinically indicated.
Skeletal and tooth abnormalities observed in immature animals receiving pralsetinib; monitor growth plates in adolescents with open growth plates.
Closely monitor patients at risk for tumor lysis syndrome (e.g., high tumor burden, rapidly growing tumors, renal dysfunction, dehydration).
Monitor for manifestations of interstitial lung disease or pneumonitis (e.g., dyspnea, cough, fever).

Administration

Oral Administration

Administer orally once daily on an empty stomach (i.e., at least 2 hours after and at least 1 hour before food).

If a dose is missed, administer the missed dose as soon as it is remembered on the same day. Take the next dose at the regularly scheduled time.

If a dose is vomited following administration, do not administer an additional dose to make up for the vomited dose; administer the next dose at the regularly scheduled time.

Dosage

Pediatric Patients

Thyroid Cancer

Oral

≥12 years of age: 400 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Adults

NSCLC

Oral

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

Thyroid Cancer

Oral

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

Dosage Modification

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

Table 1. Dosage Reduction for Pralsetinib Toxicity.1
Dose Reduction Level	Recommended Dosage Reduction
First	300 mg once daily
Second	200 mg once daily
Third	100 mg once daily
Fourth	Permanently discontinue pralsetinib

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

Table 2. Dosage Modification for Pralsetinib Toxicity1
Adverse Reaction and Severity	Modification
Pulmonary Effects
Grade 1 or 2 interstitial lung disease or pneumonitis	Withhold therapy; when interstitial lung disease or pneumonitis resolves, resume at reduced dosage (see Table 1)
	If grade 1 or 2 interstitial lung disease or pneumonitis recurs, permanently discontinue therapy
Grade 3 or 4 interstitial lung disease or pneumonitis	Permanently discontinue therapy
Hepatotoxicity
Grade 3 or 4	Withhold therapy and monitor AST and ALT concentrations once weekly
	When the toxicity resolves to baseline or grade 1, resume at reduced dosage (see Table 1)
	If toxicity recurs at grade 3 or higher, discontinue therapy
Hypertension
Grade 3	Withhold therapy if grade 3 hypertension occurs despite optimal antihypertensive therapy
	When hypertension is controlled, resume at reduced dosage (see Table 1)
Grade 4	Discontinue therapy
Hemorrhagic Events
Grade 3 or 4	Withhold therapy until toxicity improves to baseline or grade 1 or less
	If severe or life-threatening hemorrhagic events occur, discontinue therapy
Growth Plate Abnormality
Any grade	Consider interrupting or discontinuing therapy based on severity and individual risk-benefit assessment (see Pediatric Use under Cautions)
Other Toxicity
Grade 3 or 4	Withhold therapy until toxicity improves to baseline or grade 2 or less; resume at reduced dosage (see Table 1)
	If grade 4 toxicity recurs, permanently discontinue therapy

Concomitant Use with P-glycoprotein and/or CYP3A Inhibitors

Avoid concomitant use of pralsetinib with any of the following: strong or moderate CYP3A inhibitors, P-gp inhibitors, combined P-gp and strong CYP3A inhibitors, or combined P-gp and moderate CYP3A inhibitors. If concomitant use cannot be avoided, reduce the dosage of pralsetinib as described in Table 3. When concomitant use of the P-gp and/or CYP3A inhibitor is discontinued, return the pralsetinib dosage (after 3–5 elimination half-lives) to the dosage used prior to initiation of the P-gp and/or CYP3A inhibitor.

Table 3: Recommended Dosage Modification for Concomitant Use with P-gp and/or CYP3A Inhibitors1
Current Dosage	Recommended Pralsetinib Dosage when Coadministered with:	Recommended Pralsetinib Dosage when Coadministered with:
	Combined P-gp and Strong CYP3A Inhibitors	Strong CYP3A Inhibitors, Moderate CYP3A Inhibitors, P-gp Inhibitors, Combined P-gp and Moderate CYP3A Inhibitors
400 mg once daily	200 mg once daily	300 mg once daily
300 mg once daily	200 mg once daily	200 mg once daily
200 mg once daily	100 mg once daily	100 mg once daily

Concomitant Use with Moderate or Strong CYP3A Inducers

Avoid concomitant use of pralsetinib with moderate or strong CYP3A inducers. If concomitant use cannot be avoided, increase the dose of pralsetinib as described in Table 4, starting on day 7 of concomitant use of pralsetinib with a moderate or strong CYP3A inducer. After the moderate or strong CYP3A inducer has been discontinued for at least 14 days, return the pralsetinib dosage to the dosage used prior to initiation of the moderate or strong CYP3A inducer.

Table 4: Recommended Dosage Modification for Concomitant Use with Moderate or Strong CYP3A Inducers1
Current Dosage	Recommended Pralsetinib Dosage when Coadministered with:	Recommended Pralsetinib Dosage when Coadministered with:
	Strong CYP3A Inducers	Moderate CYP3A Inducers
400 mg once daily	800 mg once daily	600 mg once daily
300 mg once daily	600 mg once daily	500 mg once daily
200 mg once daily	400 mg once daily	300 mg once daily

Special Populations

Hepatic Impairment

Mild (total bilirubin concentrations not exceeding the ULN with AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding 1 to 1.5 times the ULN with any AST concentration), moderate (total bilirubin concentration exceeding 1.5 to 3 times the ULN and any AST concentration), or severe (total bilirubin concentration exceeding 3 times the ULN and any AST concentration) hepatic impairment: No dosage adjustment necessary.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Pralsetinib

Contraindications

None.

Warnings/Precautions

Interstitial Lung Disease (ILD)/Pneumonitis

Severe, life-threatening, and fatal ILD or pneumonitis reported.

Monitor for pulmonary symptoms indicative of ILD or pneumonitis such as cough, dyspnea, and fever. Withhold pralsetinib and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms suggestive of ILD (e.g., dyspnea, cough, and fever). If ILD is confirmed, temporary interruption of pralsetinib therapy, dosage reduction, or discontinuance of therapy may be necessary.

Hypertension

Hypertension, including grade 3 and 4 hypertension, reported. Treatment-emergent hypertension commonly managed with antihypertensive therapy.

Do not initiate pralsetinib in patients with uncontrolled hypertension. Assess blood pressure prior to initiation of therapy, and monitor after 1 week of therapy, at least monthly thereafter, and as clinically indicated. Initiate antihypertensive therapy or adjust as appropriate to control blood pressure during therapy. If hypertension occurs, interruption of drug therapy, dosage reduction, or permanent discontinuance of therapy may be necessary.

Hepatotoxicity

Serious hepatic adverse reactions reported. Median time to onset of increased AST or ALT concentration is 15 (range: 5 days to 2.5 years) or 24 days (range: 7 days to 3.7 years), respectively.

Monitor ALT and AST concentrations prior to initiating pralsetinib, every 2 weeks during the first 3 months of therapy, monthly thereafter, and as clinically indicated. If hepatotoxicity occurs, interruption of drug therapy, dosage reduction, or permanent discontinuance of therapy may be necessary.

Hemorrhagic Events

Serious, including fatal, hemorrhagic events reported.

Permanently discontinue therapy in patients with severe or life-threatening hemorrhage.

Tumor Lysis Syndrome

Tumor lysis syndrome reported in patients with medullary thyroid carcinoma receiving pralsetinib.

Closely monitor patients at risk for tumor lysis syndrome (e.g., those with rapidly growing tumors, high tumor burden, renal dysfunction, dehydration). Consider appropriate prophylaxis (e.g., adequate hydration). If tumor lysis syndrome occurs, treat patients as clinically indicated.

Wound Healing Complications

Inhibitors of vascular endothelial growth factor (VEGF) signaling pathway, such as pralsetinib, may impair wound healing.

Withhold pralsetinib therapy for ≥5 days prior to elective surgery. Do not administer pralsetinib for ≥2 weeks following major surgery and until adequate wound healing has occurred. Safety of resuming pralsetinib therapy following resolution of wound healing complications not established.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryotoxicity and malformations observed in animals.

Verify pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Females of reproductive potential should use effective non-hormonal methods of contraception while receiving pralsetinib and for 2 weeks after the final dose. Advise males who are partners of such females to use effective methods of contraception while receiving the drug and for 1 week after the final dose. If used during pregnancy, apprise patient of the potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status prior to initiating therapy. If used during pregnancy, apprise patient of the potential fetal hazard.

Lactation

Not known whether pralsetinib or its metabolites are distributed into human milk, affect milk production, or affect nursing infants. Women should not breast-feed during therapy and for 1 week following the final dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to initiating pralsetinib. Advise females of reproductive potential to use effective non-hormonal contraception during therapy and for 2 weeks after the last dose. Advise males with females partners of reproductive potential to use effective contraception during therapy and for 1 week after the last dose.

May impair fertility based on histopathological findings in reproductive tissues of male and female rats and a fertility study in which animals of both sexes were treated and mated to each other.

Pediatric Use

Safety and efficacy not established for treatment of metastatic RET fusion-positive NSCLC.

Safety and efficacy in pediatric patients ≥12 years of age with RET fusion-positive thyroid cancer supported by extrapolation of data from clinical studies evaluating pralsetinib in adults and pharmacokinetic data in pediatric patients ≥12 years of age.

Skeletal and tooth abnormalities observed in immature animals receiving pralsetinib. Monitor growth plates in adolescents with open growth plates. If growth plate abnormalities occur, consider interrupting or discontinuing therapy based on severity of the abnormality and individual risk-benefit assessment.

Geriatric Use

No overall differences in safety relative to younger adults observed.

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentrations not exceeding the ULN with AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding 1 to 1.5 times the ULN with any AST concentration), moderate (total bilirubin concentration exceeding 1.5 to 3 times the ULN and any AST concentration), or severe (total bilirubin concentration exceeding 3 times the ULN and any AST concentration) hepatic impairment : Pharmacokinetics not substantially altered; no dosage adjustment needed.

Renal Impairment

Population pharmacokinetic analysis suggests that mild or moderate renal impairment (Cl_cr30–89 mL/minute) does not affect exposure of pralsetinib.

Severe renal impairment (Cl_cr <15 mL/minute): Not studied.

Common Adverse Effects

Most common adverse reactions (≥25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, cough. Most common grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased leukocytes, decreased sodium, decreased calcium (corrected), increased ALT/AST concentrations, decreased platelets, increased alkaline phosphatase, increased or decreased potassium, increased bilirubin.

Drug Interactions

Metabolized principally by CYP3A4; lesser extent by CYP isoenzymes 2D6 and 1A2. In vitro, drug is a substrate and inhibitor of P-gp and breast cancer resistance protein (BCRP). Also, inhibits organic anion transporting peptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, multidrug and toxin extrusion (MATE) 1, MATE2-K, and bile salt efflux pump (BSEP). Does not inhibit organic cation transporter (OCT) 1, OCT2, and OAT1A3.

In vitro, a time-dependent inhibitor of CYP3A and an inhibitor of CYP isoenzymes 2C8, 2C9, and 3A; inducer of CYP isoenzymes 2C8, 2C9, and 3A. Does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, or 2D6 and does not induce 1A2, 2B6, or 2C19.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Strong or moderate CYP3A Inhibitors and/or P-gp inhibitors: Potential increased pralsetinib exposure and increased risk or severity of adverse reactions to pralsetinib. Avoid concomitant use of pralsetinib with a strong or moderate CYP3A inhibitor and/or P-gp inhibitor. If concomitant use with a strong or moderate CYP3A and/or P-gp inhibitor cannot be avoided, reduce the dose of pralsetinib as described in Table 3. When concomitant use of the P-gp and/or CYP3A inhibitor is discontinued, return the pralsetinib dosage (after 3–5 elimination half-lives) to the dosage used prior to initiation of the P-gp and/or CYP3A inhibitor.

Strong or moderate CYP3A Inducers: Potential decreased pralsetinib exposure and decreased efficacy of pralsetinib. Avoid concomitant use of pralsetinib with strong or moderate CYP3A inducers. If concomitant use with strong or moderate CYP3A inducers cannot be avoided, increase the dose of praseltinib as described in Table 4, starting on day 7 of concomitant use. After the moderate or strong CYP3A inducer has been discontinued for at least 14 days, return the pralsetinib dosage to the dosage used prior to initiation of the moderate or strong CYP3A inducer.

Specific Drugs

Drug	Interaction	Comments
Antacids	No clinically meaningful effect on pralsetinib absorption
Cyclosporine	Increased pralsetinib AUC and peak plasma concentration by 1.8- and 1.5-fold, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce the dose of pralsetinib as described in Table 3 When concomitant use is discontinued, return pralsetinib dosage (after 3–5 elimination half-lives of the P-gp and/or CYP3A inhibitor) to dosage used prior to initiation of the P-gp and/or CYP3A inhibitor
Histamine H₂-receptor antagonists	No clinically meaningful effect on pralsetinib absorption
Efavirenz	Decreased predicted pralsetinib AUC and peak plasma concentration decreased by 45 and 18%, respectively	Avoid concomitant use; if concomitant use cannot be avoided, increase the dose of praseltinib as decribed in Table 4, starting on day 7 of concomitant use After the CYP3A inducer has been discontinued for ≥14 days, return pralsetinib dosage to dosage used prior to initiation of the CYP3A inducer
Fluconazole	Increased prediected pralsetinib AUC and peak plasma concentration by 1.7- and 1.2-fold, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce the dose of pralsetinib as described in Table 3 When concomitant use is discontinued, return pralsetinib dosage (after 3–5 elimination half-lives of the P-gp and/or CYP3A inhibitor) to dosage used prior to initiation of the P-gp and/or CYP3A inhibitor
Itraconazole	Increased pralsetinib AUC and peak plasma concentration by 3.5- and 1.8-fold, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce the dose of pralsetinib as described in Table 3 When concomitant use is discontinued, return pralsetinib dosage (after 3–5 elimination half-lives of the P-gp and/or CYP3A inhibitor) to dosage used prior to initiation of the P-gp and/or CYP3A inhibitor
Proton-pump inhibitors	No clinically meaningful effect on pralsetinib absorption Esomeprazole: No clinically significant differences in pharmacokinetics of pralsetinib observed
Rifampin	Decreased pralsetinib AUC and peak plasma concentration decreased by 68 and 30%, respectively	Avoid concomitant use; if concomitant use cannot be avoided, increase the dose of praseltinib as decribed in Table 4, starting on day 7 of concomitant use After the CYP3A inducer has been discontinued for ≥14 days, return pralsetinib dosage to dosage used prior to initiation of the CYP3A inducer
Verapamil	Increased predicted pralsetinib AUC and peak plasma concentration by 2.1- and 1.6-fold, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce the dose of pralsetinib as described in Table 3 When concomitant use is discontinued, return pralsetinib dosage (after 3–5 elimination half-lives of the P-gp and/or CYP3A inhibitor) to dosage used prior to initiation of the P-gp and/or CYP3A inhibitor
Voriconazole	Increased predicted pralsetinib AUC and peak plasma concentration by 2.2- and 1.2-fold, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce the dose of pralsetinib as described in Table 3 When concomitant use is discontinued, return pralsetinib dosage (after 3–5 elimination half-lives of the P-gp and/or CYP3A inhibitor) to dosage used prior to initiation of the P-gp and/or CYP3A inhibitor

Pralsetinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved at a median of 2–4 hours.

Food

High-fat meal increased peak plasma concentration and AUC, and delayed median time to peak concentration.

Special Populations

Age, sex, body weight, and race/ethnicity: No clinically important effects on pharmacokinetics.

Distribution

Extent

Not known whether pralsetinib or its metabolites are distributed into human milk.

Plasma Protein Binding

97% bound to plasma proteins (independent of pralsetinib concentration).

Elimination

Metabolism

Metabolized principally by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Minor pathways: oxidation and glucuronidation.

Elimination Route

Eliminated in feces (73%; 66% as unchanged drug) and urine (6%; 4.8% as unchanged drug).

Half-life

Single dose: 16 hours.

Repeated dosing: 20 hours.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C).

Actions

An inhibitor of multiple tyrosine kinases, including wild-type and mutated RET isoforms.
Antitumor activity in cultured cells and animal models with RET fusions and mutations including KIF5B-RET, CCDC6-RET, RET-M918T, RET-C634W, V804E, V804L, and V804M.
In cellular assays, inhibits RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.

Advice to Patients

Advise patients to read the manufacturer's patient information.
Advise patients to take pralsetinib exactly as prescribed and to not alter the dosage or discontinue therapy unless advised to do so by their clinician. Advise patients to take pralsetinib on an empty stomach which is defined as no food intake for at least 2 hours before and at least 1 hour after taking pralsetinib. If a dose is missed, pralsetinib can be taken as soon as possible on the same day. The regular scheduled dose can be taken the next day. If vomiting occurs after taking a dose, the next dose should be taken at the regularly scheduled time; an additional dose should not be taken.
Risk of interstitial lung disease (ILD)/pneumonitis. Advise patients to notify their clinician of any new or worsening respiratory symptoms.
Risk of hypertension. Advise patients about the need to monitor blood pressure regularly and to inform clinicians of any increase in blood pressure or symptoms of high blood pressure.
Risk of hepatotoxicity. Advise patients about the risk of hepatotoxicity and associated symptoms and to notify their clinician immediately if any signs or symptom occur.
Risk of hemorrhagic events. Advise patients of the risk of bleeding and to notify their clinician immediately of signs or symptoms of bleeding.
Risk of tumor lysis syndrome. Educate patients on symptoms and to notify their clinician immediately of signs or symptoms of tumor lysis syndrome.
Risk of impaired wound healing. Advise patients to inform their clinician of any planned surgery as pralsetinib will need to be held before elective surgery.
Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise females of reproductive potential to use an effective non-hormonal contraceptive during treatment with pralsetinib and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use an effective contraceptive during treatment with pralsetinib and for 1 week after the last dose.
Advise females not to breast-feed during treatment with pralsetinib and for 1 week after the last dose.
Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., liver disease, hypertension).
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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 pralsetinib is restricted. Contact manufacturer for additional information.