Gavreto

Gavreto Uses, Dosage, Side Effects, Food Interaction and all others data.

Gavreto, similar to the previously approved selpercatinib, is a kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs) over other RTK classes. Enhanced RET (Rearranged during transfection) oncogene expression is a hallmark of many cancers, including non-small cell lung cancer. Although multikinase inhibitors, including cabozantinib, ponatinib, sorafenib, sunitinib, and vandetanib, have shown efficacy in RET-driven cancers, their lack of specificity is generally associated with substantial toxicity. Gavreto (BLU-667) and selpercatinib (LOXO-292) represent the first generation of specific RET RTK inhibitors for the treatment of RET-driven cancers.

Although a phase 1/2 trial of pralsetinib termed ARROW (NCT03037385) is still ongoing, pralsetinib was granted accelerated FDA approval on September 4, 2020, for the treatment of metastatic RET-fusion positive non-small cell lung cancer. It is currently marketed under the brand name GAVRETO™ by Blueprint Medicines.

Gavreto exerts an anti-tumour effect through specific inhibition of the rearranged during transfection (RET) tyrosine kinase, including multiple distinct oncogenic RET fusions, mutated RET kinase domains harbouring gatekeeper mutations, and in RET kinases with a variety of activating single point mutations. Due to pralsetinib's high selectivity for RET over other kinases, both in vitro and in vivo, pralsetinib has been described as having a better safety profile compared to previously used multi-kinase inhibitors. Despite this, pralsetinib use may increase the risk of hypertension, hemorrhagic events, impaired wound healing, hepatotoxicity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

Gavreto
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Gavreto
Availability	Prescription only
Generic	Pralsetinib
Pralsetinib Other Names	Pralsetinib
Related Drugs	Gavreto, Opdivo, methotrexate, Keytruda, Armour Thyroid, pembrolizumab, doxorubicin, cisplatin, Tagrisso, Avastin
Weight	100mg,
Type	Oral capsule
Formula	C₂₇H₃₂FN₉O₂
Weight	Average: 533.612 Monoisotopic: 533.266299469
Protein binding	Pralsetinib is 97.1% bound to plasma proteins regardless of concentration.
Groups	Approved, Investigational
Therapeutic Class
Manufacturer
Available Country	United States,
Last Updated:	September 19, 2023 at 7:00 am

Uses

Gavreto is a RET receptor tyrosine kinase inhibitor for the treatment of metastatic RET-driven non-small cell lung cancer.

Gavreto is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) in adult patients who are confirmed to possess a rearranged during transfection (RET) gene fusion, as determined by an FDA approved test.

Gavreto is currently approved for this indication under an accelerated approval scheme and continued approval may be contingent on future confirmatory trials.

Gavreto is also used to associated treatment for these conditions: Metastatic RET-fusion Non Small Cell Lung Cancer

How Gavreto works

Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase containing extracellular, transmembrane, and intracellular domains whose activity is required for normal kidney and nervous system development. Constitutive RET activation is achieved through chromosomal rearrangements producing 5' fusions of dimerizable domains to the 3' RET tyrosine kinase domain leading to constitutive dimerization and subsequent autophosphorylation; the most common fusions are KIF5B-RET and CCDC6-RET, although more than 35 genes have been reported to fuse with RET. Constitutive activation leads to increased downstream signalling and is associated with tumour invasion, migration, and proliferation.

Gavreto (formerly referred to as BLU-667) was developed through screening more than 10,000 agnostically designed kinase inhibitors followed by extensive chemical modification to improve its properties. Gavreto displays in vitro IC₅₀ values for both WT RET as well as several mutant forms, including CCDC6-RET, in the range of 0.3-0.4 nmol/L, and is 100-fold more selective for RET kinase over 96% of 371 kinases tested. It is this specific inhibition of RET kinase that is associated with anti-tumour activity and clinical benefit in patients.

Despite increased selectivity for RET over other kinases, pralsetinib has been reported to inhibit DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRb, and FGFR1-2 at clinically relevant concentrations. The significance of these findings remains uncertain.

Toxicity

Gavreto administered to rats at 20 mg/kg (roughly 2.5-3.6 times the recommended human exposure) resulted in resorption of litters in pregnant female mice in 92% of pregnancies (82% complete resorption); resorption occurred at doses as low as 5 mg/kg (0.3 times the recommended human exposure). Both male and female rats given 10 mg/kg pralsetinib or more had observable degeneration within the testis/ovaries. In 28-day rat and monkey studies, once-daily pralsetinib resulted in histological necrosis at doses 1.1 or more times the recommended human dose and myocardial hemorrhage at doses 2.6 or more times the recommended human dose. Also, pralsetinib induced hyperphosphatemia (rats only, dose 2.4-3.5 times the recommended human dose) and multi-organ mineralization (dose 0.11 or more times the recommended human dose).

Food Interaction

Take on an empty stomach. Food affects the absorption of pralsetinib. Patients should take pralsetinib either at least one hour before or at least two hours after a meal.

[Major] ADJUST DOSING INTERVAL: Food significantly increases the oral bioavailability of pralsetinib.

According to the product labeling, administration of pralsetinib with a high-fat meal (approximately 800 to 1000 calories; 50% to 60% from fat) increased mean pralsetinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 104% and 122%, respectively.

The median time to maximum concentration (Tmax) was delayed from 4 to 8.5 hours.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pralsetinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to pralsetinib may increase the risk of adverse effects such as musculoskeletal toxicity, fatigue, constipation, hypertension, and pneumonia.

MANAGEMENT: Gavreto should be administered on an empty stomach, at least 2 hours before or 1 hour after a meal.

Patients should avoid consumption of grapefruit or grapefruit juice during treatment with pralsetinib.

Volume of Distribution

Gavreto has a mean apparent volume of distribution of 228 L (CV 75%).

Elimination Route

Gavreto given at 400 mg once daily resulted in a mean steady-state C_max of 2830 ng/mL (coefficient of variation, CV, 52.5%) and AUC_0-24h of 43900 ng*h/mL (CV 60.2%). The C_max and AUC of pralsetinib increased inconsistently with increasing doses between 60 and 600 mg once daily, with a median T_max across this range of between two and four hours. At 400 mg once daily, pralsetinib reached steady-state plasma concentration by three to five days.

Gavreto absorption is affected by food. A single dose of 400 mg given with a high-fat meal (800 to 1000 calories with 50 to 60% of calories coming from fat) increased the mean C_max by 104% (95% CI 65-153%), mean AUC_0-∞ by 122% (95% CI 96-152%), and the median T_max from four to 8.5 hours.