Selpercatinib

Introduction Overview

Generic Name

selpercatinib

Brand Name

Retevmo

Dosage Form

oral capsule, oral tablet

Drug Class

Multikinase inhibitors

Pharmacokinetics

Absorption:
Selpercatinib, marketed as Retevmo, is administered orally and exhibits good bioavailability when taken by mouth. The pharmacokinetics indicate that the drug is absorbed efficiently with or without food, although co-administration with proton-pump inhibitors (PPIs) may require intake with food to optimize absorption. The pharmacokinetic profile shows consistent plasma concentration levels when administered twice daily approximately 12 hours apart. Factors affecting absorption include concomitant use of gastric pH-altering agents such as antacids, H2 blockers, and PPIs, which necessitate careful timing relative to Retevmo administration to avoid reduced drug bioavailability.

Distribution:
Following absorption, selpercatinib demonstrates extensive distribution within body tissues, attributable to its multikinase inhibitor properties targeting the RET proto-oncogene and its associated pathological protein expressions. Although specific volume of distribution values are not publicly detailed in the prescribing information, clinical studies confirm the drug’s ability to reach target tissues, including lung, thyroid, and other solid tumor sites. Protein binding is moderate to high, facilitating cellular uptake but also implicating interactions with plasma proteins during polypharmacy.

Metabolism:
Selpercatinib undergoes metabolic processing primarily via the cytochrome P450 system, predominantly by CYP3A isoenzymes. This metabolism results in multiple metabolites, some of which may retain pharmacologic activity, though generally at reduced potency. The metabolism pathway renders selpercatinib susceptible to drug-drug interactions, especially with strong CYP3A inducers or inhibitors, which can markedly alter plasma levels and efficacy. The metabolism is critical clinically, as dose adjustments or monitoring may be required when used concomitantly with agents affecting CYP3A.

Elimination:
The elimination of selpercatinib occurs via both hepatic and renal pathways, with the liver playing a predominant role in drug and metabolite clearance. Excretion is primarily through biliary-fecal routes, with a proportion eliminated via urine. The terminal elimination half-life supports twice-daily dosing schedules and is consistent with steady-state plasma concentrations achieved in clinical trials. Special considerations are warranted in patients with hepatic impairment due to potential for increased drug exposure. Routine monitoring liver function tests are recommended to preemptively detect hepatotoxicity.

Dosage Forms

Available Dosage Forms:
Retevmo is available in two primary oral dosage forms:
- Capsules: 40 mg and 80 mg
- Tablets: 40 mg, 80 mg, 120 mg, 160 mg
These formulations facilitate precise dose adjustments based on patient weight, body surface area, and clinical indication.

Dosages for Adults and Adolescents:
In adults and adolescents aged 12 years and older, dosing is weight-based:
- Patients weighing less than 50 kg: 120 mg orally twice daily (approximately every 12 hours).
- Patients weighing 50 kg or greater: 160 mg orally twice daily.

Specific Patient Populations:
For children aged 2 years to less than 12 years, dosing is based on body surface area (BSA):
- BSA 0.33 to 0.65 m2: 40 mg three times daily.
- BSA 0.66 to 1.08 m2: 80 mg twice daily.
- BSA 1.09 to 1.52 m2: 120 mg twice daily.
- BSA ≥ 1.53 m2: 160 mg twice daily.

Clinical guidelines highlight that dosing modifications may be warranted in patients with hepatic impairment or those experiencing adverse effects. Additionally, adherence to proper administration timing relative to gastric pH modifying agents is crucial to maintain therapeutic drug levels. Tablets should be swallowed whole without crushing or chewing; capsules must be swallowed whole as well, and not administered to children unable to swallow capsules.

Mechanism Of Action

Retevmo's active component, selpercatinib, is a potent and highly selective inhibitor of the RET tyrosine kinase receptor, a key driver of oncogenesis in RET fusion-positive tumors. The drug acts by binding to the ATP-binding site of the RET kinase domain, effectively preventing ATP from activating RET and subsequently halting downstream signaling cascades involved in cellular proliferation and survival.

By inhibiting the RET kinase activity, selpercatinib interrupts critical signaling pathways such as the RAS/MAPK and PI3K/AKT pathways, which are normally upregulated in tumors harboring RET alterations. This selective inhibition results in reduced tumor cell growth, induction of apoptosis, and decreased metastatic potential.

Unlike broader multikinase inhibitors that target multiple kinases and may cause significant off-target effects, selpercatinib offers improved specificity for RET-driven tumors, leading to a favorable therapeutic index. This selective targeting is supported by clinical evidence demonstrating efficacy across RET fusion-positive non-small cell lung cancer, medullary thyroid cancer, and other RET aberrant solid tumors.

Clinical studies confirm that selpercatinib’s ability to penetrate tumor tissues and selectively inhibit RET kinase correlates with substantial tumor shrinkage and prolonged progression-free survival, underscoring its importance in targeted cancer therapy regimens. Ongoing research continues to explore resistance mechanisms and combination therapies to enhance and sustain responses.

Pharmacological Actions

Selective inhibition of RET tyrosine kinase signaling pathways involved in tumor growth and progression.
Blocks ATP binding to RET kinase domain, preventing receptor activation.
Induces apoptosis and inhibits proliferation of RET-driven cancer cells.
Targets both RET fusion-positive and RET-mutant solid tumors.
Exhibits potent activity in non-small cell lung cancer with RET fusions.
Demonstrates efficacy in advanced thyroid cancers refractory to radioactive iodine.
Improves progression-free survival in RET-altered malignancies.
Reduces metastatic spread by inhibiting RET-mediated cellular motility.
Favorable safety profile due to high selectivity for RET kinase.
Minimal off-target kinase inhibition compared to previous multikinase inhibitors.
Potential to overcome resistance to prior kinase inhibitors targeting RET.
Affects tumor microenvironment by modulating RET signaling influenced pathways.

Therapeutic Or Clinical Uses

Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring RET gene fusions in adults.
Management of advanced or metastatic thyroid cancer including radioactive iodine-refractory differentiated thyroid cancer in adults and children aged 2 years and older.
Therapy for advanced or metastatic medullary thyroid cancer (MTC) requiring systemic treatment in adults and children aged 2 years and older.
Treatment of locally advanced or metastatic solid tumors driven by abnormal RET alterations in adults and children aged 2 years and older under accelerated approval.
Utilized in patients who have progressed after prior treatments or lack satisfactory alternative therapies.
Targeted treatment option in precision oncology for RET-driven malignancies.
Offered as oral therapy facilitating outpatient management and compliance.
Used in pediatric oncology settings for RET-positive thyroid cancers in children.
Incorporated into treatment regimens following molecular confirmation of RET gene status.
Recommended in clinical guidelines for RET fusion-positive NSCLC and thyroid cancers.

Side Or Adverse Effects

Peripheral edema including swelling of arms, legs, hands, and feet.
Gastrointestinal disturbances such as diarrhea, nausea, constipation, and abdominal pain.
Fatigue and general tiredness impacting quality of life during therapy.
Dry mouth (xerostomia) often reported throughout treatment.
Hypertension, ranging from mild to severe elevations in blood pressure.
Cutaneous rash with varying severity, occasionally requiring management.
Headache reported frequently among patients.
Laboratory abnormalities including leukopenia (decreased white blood cell count).
Electrolyte imbalances such as hyponatremia (low sodium) and hypocalcemia (low calcium).
Serious liver toxicity evidenced by elevated liver enzymes and symptoms such as jaundice.
Potential for serious bleeding events including gastrointestinal bleeding and hemorrhages.
Lung toxicities including severe interstitial lung disease or pneumonitis.
Cardiac effects such as QT interval prolongation and arrhythmias.
Allergic reactions manifesting as fever, rash, muscle or joint pain especially early in treatment.
Risks of tumor lysis syndrome leading to kidney failure, seizures, and related complications.

Precautions

Monitor liver function tests regularly due to risk of hepatotoxicity.
Monitor blood pressure frequently; manage hypertension proactively.
Assess cardiac status and monitor QT interval to detect arrhythmias early.
Avoid use during pregnancy; employ effective contraception for both females and males during treatment and for 1 week after last dose.
Evaluate bleeding risk prior to and during therapy, especially in patients with coagulopathies.
Avoid concomitant use of drugs that interact with CYP3A metabolism without dose adjustments.
Adhere to timing guidelines when administering gastric pH altering agents to avoid reduced drug absorption.
Discontinue Retevmo at least 7 days before planned surgeries to prevent wound healing complications.
Consider fertility risks; counsel patients on reproductive planning.
Use caution in pediatric patients, monitor for rare events such as slipped capital femoral epiphysis.
Avoid breastfeeding during treatment and for at least 1 week after last dose due to unknown lactation safety.
Withhold or adjust dosing in presence of serious adverse events including severe liver or lung toxicities.
Be vigilant for symptoms suggestive of tumor lysis syndrome and manage accordingly.
Educate patients regarding signs of bleeding, cardiac symptoms, and allergic reactions.
Ensure molecular testing confirming RET alterations prior to initiation.

Warnings

Risk of severe and potentially fatal hepatotoxicity necessitating frequent liver enzyme monitoring.
Possibility of life-threatening interstitial lung disease or pneumonitis.
Hypertension that can reach severe levels posing cardiovascular risk.
Serious cardiac rhythm disturbances including QT prolongation leading to arrhythmias, syncope, or death.
Major bleeding events including gastrointestinal, genitourinary, and intracranial hemorrhages.
Tumor lysis syndrome causing acute kidney injury, electrolyte abnormalities, and systemic complications.
Risk of impaired wound healing, requiring drug discontinuation ahead of surgical procedures.
Allergic reactions that may manifest with fever, rash, or musculoskeletal symptoms.
Potential teratogenic effects; contraindicated in pregnancy.
Possibility of slipped capital femoral epiphysis in adolescent and pediatric patients.
Severe adverse effects may necessitate treatment interruption or discontinuation.
Do not administer to children under 2 years due to lack of safety data.
Interactions with concomitant medications may enhance toxicity or reduce therapeutic efficacy.
Not all side effects are known; continuous monitoring during therapy is essential.
Patients should report immediately any symptoms of bleeding, shortness of breath, chest pain, or neurological changes.

Contraindication

Known hypersensitivity to selpercatinib or any formulation components.
Pregnancy due to teratogenic risk and potential harm to fetus.
Severe hepatic impairment without ability to monitor and adjust dosing appropriately.
Active uncontrolled bleeding disorders or severe coagulopathy.
Patients unable to swallow capsules (for capsule dosage form) with no alternative feasible administration.
Concomitant use of strong CYP3A inducers that cannot be discontinued or managed.
Pediatric patients under 2 years old due to insufficient safety and efficacy data.
Known severe cardiac arrhythmias that cannot be controlled prior to initiating therapy.
Concurrent use of drugs causing significant QT prolongation without careful monitoring.
History of radiation-induced liver disease or other severe liver comorbidities.
Severe pulmonary disease that may increase risk of pneumonitis or lung toxicity.
Patients with poor compliance who cannot adhere to dosing or monitoring schedules.
Use with other multikinase inhibitors without adequate clinical justification.
Presence of active infections posing risk of exacerbation under immunomodulatory therapy.
Known allergy to gelatin or capsule shell components in case of capsule usage.

Drug Interactions

Strong CYP3A inhibitors may increase selpercatinib plasma concentrations leading to toxicity.
Strong CYP3A inducers can decrease selpercatinib effectiveness by reducing plasma levels.
Proton pump inhibitors (PPIs) such as omeprazole and esomeprazole may reduce absorption if not administered with food and correct timing.
H2 receptor blockers (e.g., famotidine, nizatidine) require separation of dosing by at least 2 to 10 hours to prevent interaction.
Antacids containing aluminum, magnesium, calcium, or simethicone should be spaced at least 2 hours before or after Retevmo dose.
St. John’s wort is contraindicated due to significant induction of CYP3A and reduced therapeutic effect.
Co-administration with other QT-prolonging agents may potentiate cardiac risks.
Concomitant use with drugs affecting blood pressure may increase hypertensive events.
Potential interaction with anticoagulants may enhance bleeding risk; monitor coagulation parameters.
Medications inhibiting or inducing drug transporters involved in selpercatinib disposition may alter plasma exposure.
Use with caution alongside immunosuppressants which may modulate efficacy or toxicity.
Drug interactions affecting electrolyte balance (diuretics, corticosteroids) may compound adverse risks.
Herbal supplements and over-the-counter agents should be disclosed and evaluated for interactions.
Clinical monitoring and possible dose adjustments are required when combined with interacting drugs.
Patients should maintain updated medication records to assist healthcare providers in interaction management.

Preparations Of The Drug

Oral capsules available in 40 mg and 80 mg strengths with gelatin-based shells differing in colorants (black or blue ink).
Oral tablets provided in 40 mg, 80 mg, 120 mg, and 160 mg doses with film coatings containing titanium dioxide and various iron oxide pigments.
Inactive ingredients in capsules include colloidal silicon dioxide and microcrystalline cellulose.
Tablet excipients include croscarmellose sodium, hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate.
Tablet film coating components incorporate polyvinyl alcohol, polyethylene glycol, talc, and ferrosoferric or ferric oxide as pigmentation agents.
Capsule shells use gelatin with distinct pigment profiles to differentiate dosages.
Black ink used in capsules consists of shellac, potassium hydroxide, and ferric oxide black.
Formulation design aims to facilitate patient adherence via oral administration once or twice daily.
Manufactured and supplied by Eli Lilly and Company under strict pharmaceutical quality standards.
Packaging designed to maintain stability at recommended room temperature (20˚C to 25˚C).
Storage conditions emphasize protection from moisture and out-of-reach placement from children and pets.
Formulations are not designed to be opened, crushed, or chewed to maintain pharmacokinetic integrity.
Extended dosing options allow titration based on patient weight and surface area for pediatric and adult use.
Availability in multiple dosage strengths supports individualized therapy and dose adjustments.
Each preparation undergoes rigorous testing for purity, potency, and batch consistency.