Pralsetinib

Brand name: Gavreto
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- Rearranged During Transfection
- RET Inhibitor
Chemical name: N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide
Molecular formula: C₂₇H₃₂FN₉O₂
CAS number: 2097132-93-7

Medically reviewed by Drugs.com on Feb 25, 2022. 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.

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 JAK1/2-positive or TRKC-positive NSCLC.

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

Medullary Thyroid Cancer

Treatment of advanced or metastatic RET mutation-positive medullary thyroid cancer in adult and pediatric patients 12 years of age or older who require systemic therapy.

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

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 (iodine-131) (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 medullary thyroid cancer, confirm presence of specific RET mutations.

• In patients with NSCLC or thyroid cancer, confirm presence of a RET gene fusion.

• Assess serum ALT and AST concentrations.

• Assess BP. Do not initiate pralsetinib therapy in patients with uncontrolled hypertension.

• Pregnancy test 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 BP 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

Medullary Thyroid Cancer

Oral

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

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.

Medullary Thyroid Cancer

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, the dosage of pralsetinib should be reduced as described in Table 1.

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.

Concomitant Use with Combined P-glycoprotein and Strong CYP3A Inhibitors

Concomitant use of pralsetinib with combined P-glycoprotein (P-gp) and strong cytochrome P-450 (CYP) isoenzyme 3A inhibitors should be avoided. If concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of pralsetinib as described in Table 3. When concomitant use of the combined P-gp or strong CYP3A inhibitor is discontinued, the pralsetinib dosage should be returned (after 3–5 elimination half-lives of the combined P-gp or CYP3A inhibitor) to the dosage used prior to initiation of the combined P-gp and strong CYP3A inhibitor.

Concomitant Use with Strong CYP3A Inducers

Concomitant use of pralsetinib with strong CYP3A inducers should be avoided. If concomitant use cannot be avoided, double the current pralsetinib dosage starting on day 7 of concomitant use of pralsetinib with a strong CYP3A inducer. After the strong CYP3A inducer has been discontinued for at least 14 days, the pralsetinib dosage should be returned to the dosage used prior to initiation of the strong CYP3A inducer.

Prescribing Limits

Pediatric Patients

Medullary Thyroid Cancer

Oral

Dosage <100 mg once daily not recommended.

Thyroid Cancer

Oral

Dosage <100 mg once daily not recommended.

Adults

NSCLC

Oral

Dosage <100 mg once daily not recommended.

Medullary Thyroid Cancer

Oral

Dosage <100 mg once daily not recommended.

Thyroid Cancer

Oral

Dosage <100 mg once daily not recommended.

Special Populations

Hepatic Impairment

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

Moderate or severe hepatic impairment: No specific dosage recommendations at this time.

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. Pneumonitis occurred in 10% (grade 3 or 4 in 2.7%) of patients who received pralsetinib; 0.5% resulted in fatality.

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 BP 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 BP 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 1.5 years) or 22 days (range: 7 days to 1.7 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 nonhormonal 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 milk, affect milk production, or affect nursing infants. Women should not breast-feed during therapy and for 1 week following the final dose.

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 and RET mutation-positive medullary 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 (i.e., physeal hypertrophy) and tooth abnormalities (i.e., malocclusion, tooth discoloration, tooth dysplasia) 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 but not exceeding 1.5 times the ULN with any AST concentration): Pharmacokinetics not substantially altered; no dosage adjustment needed.

Moderate (total bilirubin concentration exceeding 1.5 but no more than 3 times the ULN and any AST concentration) or severe (total bilirubin concentration exceeding 3 times the ULN and any AST concentration) hepatic impairment: Not studied.

Renal Impairment

Population pharmacokinetic analysis suggests that mild or moderate renal impairment (Cl_cr 30–89 mL/minute) does not affect exposure of pralsetinib.

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

Common Adverse Effects

The most common adverse reactions (≥25%) were fatigue, constipation, musculoskeletal pain, and hypertension. The most common grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased neutrophils, decreased phosphate, decreased hemoglobin, decreased sodium, decreased calcium (corrected), increased ALT/AST concentrations, decreased platelets, increased alkaline phosphatase.

Interactions for Pralsetinib

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 CYP3A4/5 and an inhibitor of CYP isoenzymes 2C8, 2C9, and 3A4/5; inducer of CYP isoenzymes 2C8, 2C9, and 3A4/5. Does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, or 2D6.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

P-gp and/or Strong CYP3A Inhibitors: Potential increased pralsetinib exposure and increased risk or severity of adverse reactions to pralsetinib. Avoid concomitant use with strong CYP3A inhibitors, including combined P-gp and strong CYP3A inhibitors. If concomitant use with combined P-gp and strong CYP3A inhibitors cannot be avoided, reduce the dose of pralsetinib as described in Table 4. When concomitant use of the combined P-gp or strong CYP3A inhibitor is discontinued, return pralsetinib dosage (after 3–5 elimination half-lives of the combined P-gp or CYP3A inhibitor) to dosage used prior to initiation of the combined P-gp and strong CYP3A inhibitor.

Strong CYP3A Inducers: Potential decreased pralsetinib exposure and decreased efficacy of pralsetinib. Avoid concomitant use. If concomitant use cannot be avoided, double the current pralsetinib dosage starting on day 7 of concomitant use of pralsetinib with a strong CYP3A inducer. After the strong CYP3A inducer has been discontinued for at least 14 days, return pralsetinib dosage to dosage used prior to initiation of the strong CYP3A inducer.

Weak CYP3A Inducers: No clinically meaningful effect on pharmacokinetics of pralsetinib.

Specific Drugs

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 milk.

Plasma Protein Binding

97.1% 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: 15.7 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

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

• Importance of advising patients to take pralsetinib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by their clinician. Importance of advising 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. Importance of advising patients to notify their clinician of any new or worsening respiratory symptoms.

• Risk of hypertension. Importance of advising 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. Importance of advising 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. Importance of advising patients of the risk of bleeding and to notify their clinician immediately of signs or symptoms of bleeding.

• Risk of tumor lysis syndrome (TLS). Importance of educating patients on symptoms and to notify their clinician immediately of signs or symptoms of TLS.

• Risk of impaired wound healing. Importance of advising 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 nonhormonal 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.

• Importance of informing 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).

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.

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