Koselugo
Koselugo Uses, Dosage, Side Effects, Food Interaction and all others data.
Activation of the Raf-MEK-ERK signaling pathway is known to be implemented in several types of malignancies, thus, mitogen-activated protein kinase kinase (MEK) inhibitors such as selumetinib are important tools that can target the problematic overactivity of this pathway.Results from clinical trials investigating earlier developed MEK inhibitors were underwhelming. However, selumetinib demonstrated impressive efficacy and tolerability in Phase I trials, leading to its continued investigation for the treatment of various types of tumors in Phase II trials.
Currently, the novel MEK 1 / 2 inhibitor, selumetinib, is approved solely for the treatment of Neurofibromatosis type 1 (NF-1) in a limited age group. NF-1 is considered rare with an estimated incidence of 1/3000 individuals. It is a genetic, autosomal dominant condition resulting from mutations of the NF1 gene, which can lead to various complications including the development of multiple tumors in the nervous system. Some patients with this disorder develop plexiform neurofibromas (PN); however, this is considered to be relatively uncommon compared to other variants of NF-1. Luckily, the use of selumetinib in patients with NF-1 has shown efficacy in shrinking associated tumors and is linked to other positive clinical outcomes.
Koselugo is a non-ATP-competitive mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) inhibitor. By selectively targeting MEK1 and MEK2, selumetinib is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often overactive in certain types of cancer. Indeed, a study investigating the effects of selumetinib in children with NF-1 found that treatment with the anti-neoplastic resulted in reduced tumor size. Decreases in tumor-associated pain and improvements in overall function were also subjectively reported.
| Trade Name | Koselugo |
| Availability | Prescription only |
| Generic | Selumetinib |
| Selumetinib Other Names | Selumetinib, Sélumétinib, Selumetinibum |
| Related Drugs | Koselugo |
| Weight | 10mg, 25mg, |
| Type | Oral capsule |
| Formula | C17H15BrClFN4O3 |
| Weight | Average: 457.68 Monoisotopic: 456.000009 |
| Protein binding | Separate studies investigating selumetinib protein binding found that 96% of selumetinib was bound to serum albumin, while 13 Overall, approximately 98.4% of selumetinib is plasma protein bound. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States, |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Koselugo is a MEK 1/2 inhibitor used in pediatric patients to treat neurofibromatosis type 1 (NF1) accompanied by symptomatic, inoperable plexiform neurofibromas (PN).
Although selumetinib has been investigated for the treatment of several types of cancer, it is currently only indicated for the treatment of neurofibromatosis type 1 (NF1) in patients ≥2 years who have symptomatic, inoperable plexiform neurofibromas (PN).
Koselugo is also used to associated treatment for these conditions: Neurofibromatosis Type 1 (NF1)
How Koselugo works
The Ras-Raf-MEK-ERK signaling cascade is known to be activated in several types of cancer, and regulates the transcription of proteins involved in apoptosis. In addition, studies have shown that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance.
Ras as well as several kinases and phosphatases are responsible for regulating the Raf-MEK-ERK pathway. Often in cancers, Ras (a G-protein coupled receptor) is deregulated, allowing downstream signalling to proceed unchecked. Through several complex steps, Raf phosphorylates and activates MEK, which then phosphorylates and activates ERK. ERK is then able to exert its effects on several downstream targets.
As such, therapies inhibiting upstream components of this pathway have become attractive targets for cancer treatment. Koselugo exerts its effects by selectively inhibiting MEK1 and MEK2 which can effectively blunt the pleiotropic effects of the Ras-Raf-MEK-ERK cascade. By inhibiting this oncogenic pathway, selumetinib reduces cell proliferation, and promotes pro-apoptotic signal transduction.
Toxicity
Toxicity information regarding selumetinib is not readily available. Patients experiencing an overdose are at an increased risk of adverse effects such as cardiomyopathy, ocular toxicity, and diarrhea. It is generally thought that since selumetinib is extensively protein-bound, dialysis is unlikely to be helpful in situations of overdose.
Food Interaction
- Take on an empty stomach. Avoid consuming food 2 hours before and 1 hour after each dose.
[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of selumetinib, which undergoes metabolism primarily by CYP450 3A4 and to a lesser extent by CYP450 2C19, 1A2, 2C9, 2E1 and 3A5, as well as glucuronidation by UGT1A1 and UGT1A3.
The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.
Inhibition of hepatic CYP450 3A4 may also contribute.
The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors.
When coadministered with itraconazole, a potent CYP450 3A4 inhibitor, selumetinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 19% and 49%, respectively.
When coadministered with fluconazole, a potent CYP450 2C19 and moderate CYP450 3A4 inhibitor, selumetinib Cmax and AUC increased by 26% and 53%, respectively.
Concomitant use of erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase selumetinib Cmax and AUC by 23% and 41%, respectively.
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 selumetinib may increase the risk and
ADJUST DOSING INTERVAL: Food may decrease the rate and extent of the oral absorption of selumetinib.
When a single 75 mg dose of selumetinib (1.5 times the approved maximum recommended dose) was administered with a high-fat meal (1000 calories; 50% fat) in healthy adults, mean Cmax and AUC of selumetinib decreased by 50% and 16%, respectively, and time to reach peak concentration (Tmax) was delayed by approximately 1.5 hours compared to administration in the fasted state.
When a single 50 mg dose of selumetinib was administered with a low-fat meal (400 calories; 25% fat) in healthy adults, selumetinib Cmax and AUC decreased by 60% and 38%, respectively, and Tmax was delayed by approximately 0.9 hours.
MANAGEMENT: Koselugo should be administered on an empty stomach at least 1 hour before or 2 hours after a meal.
Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with selumetinib.
Koselugo Drug Interaction
Major: diltiazemModerate: suvorexantUnknown: interferon gamma-1b, brentuximab, tadalafil, doxorubicin, everolimus, leflunomide, indacaterol, deutetrabenazine, moxifloxacin, sulfamethoxazole / trimethoprim, amisulpride, probenecid, bictegravir / emtricitabine / tenofovir alafenamide, bosutinib, sodium phenylbutyrate, buspirone, alteplase, aztreonam
Koselugo Disease Interaction
Volume of Distribution
The mean apparent volume of distribution of selumetinib at steady state in pediatric patients ranged from 78 L to 171 L.
A study in healthy adult males found a mean apparent volume of distribution of 146 L.
Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found that the apparent volume of distribution values at steady-state ranged from 73.2 - 148.1 L.
Elimination Route
Based on several studies investigating selumetinib at various doses in both pediatric and adult populations, the Tmax generally ranges between 1- 1.5 hours. In healthy adults, the mean absolute oral bioavailability was reported to be 62%. Koselugo should be administered on an empty stomach since food significantly decreases serum concentrations of the drug.
Half Life
Koselugo is characterized by a short half-life. The elimination half-life associated with a dose of 25 mg/m2
In a study observing the pharmacokinetic effects of various selumetinib regimens in select Japanese patients, the half-life ranged from 9.2- 10.6 hours.
In other studies where selumetinib 75 mg is administered twice daily, the half-life is reported to be approximately 13 hours.
Clearance
The clearance of selumetinib in pediatric patients is 8.8 L/hr. A study in healthy adult males found a clearance value of 15.7 L/hr. Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found clearance values that ranged from 9.2 - 15.9 L/hr.
Elimination Route
Approximately 59% of selumetinib is eliminated in the feces, while 33% is eliminated in the urine.
Innovators Monograph
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