KOSELUGO Capsule Ref.[10403] Active ingredients: Selumetinib

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized.

Cardiac Electrophysiology

At a dose 1.5 times the maximum recommended dose, KOSELUGO does not prolong the QT/QTc interval to any clinically relevant extent.

At the recommended dosage of 25 mg/m² twice daily in pediatric patients (2 to ≤18 years old), the mean maximum plasma concentration (C_max) (coefficient of variation [CV%]) following the first dose and at steady state was 731 (62%) ng/mL and 798 (52%) ng/mL, respectively. The mean area under the plasma drug concentration curve (AUC_0-12h) following the first dose was 2009 (35%) ng•h/mL and the AUC_0-6h at steady state was 1958 (41%) ng•h/mL. Selumetinib AUC and C_max increases proportionally over a dose range from 20 mg/m² to 30 mg/m² (0.8 to 1.2 times the recommended dose). The accumulation was 1.1-fold following administration of KOSELUGO 25 mg/m² twice daily.

Absorption

The mean absolute oral bioavailability of selumetinib was 62% in healthy adults. The median time to peak plasma concentrations (T_max) at steady-state in pediatric patients was 1 to 1.5 hours.

Effect of Food

Mean C_max and AUC of selumetinib decreased by 50% and 16%, respectively, following a high-fat meal (1000 calories, 50% fat) in healthy adults administered a single-dose of 75 mg (1.5 times the approved maximum recommended dosage). T_max was delayed by approximately 1.5 hours following a high-fat meal.

Selumetinib C_max and AUC decreased by 60% and 38%, respectively, following a low-fat meal (400 calories, 25% fat) in healthy adults administered a single-dose of 50 mg. T_max was delayed by approximately 0.9 hours following a low-fat meal.

Distribution

The mean apparent volume of distribution at steady state (V_ss) of selumetinib across a dose range of 20 mg/m² to 30 mg/m² (0.8 to 1.2 times the recommended dosage) ranged from 78 L to 171 L in pediatric patients.

The plasma protein binding was 98.4% in humans in vitro. Selumetinib binds to serum albumin (96%) and α-1 acid glycoprotein (<35%).

Elimination

In pediatric patients, selumetinib had an apparent oral clearance (CL/F) of 8.8 L/hr and a mean elimination half-life of approximately 6.2 hours following a dose of 25 mg/m².

Metabolism

Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. It is estimated that 56% of the observed intrinsic clearance of selumetinib could be attributed to CYP metabolism and about 29% attributed to direct glucuronidation by UGT enzymes in vitro. The active metabolite, N-desmethyl selumetinib, is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and metabolized through the same routes as selumetinib.

N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma, but is approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.

Excretion

After a single oral dose of radiolabeled selumetinib 75 mg (1.5 times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (<1% as parent).

Specific Populations

Racial or Ethnic Groups

No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on race (White, Asian, Black).

Patients with Renal Impairment

Following administration of a single dose of 50 mg, selumetinib exposures were similar in subjects with end stage renal disease (CLcr <15 mL/min) who required dialysis compared to subjects with normal renal function (CLcr ≥90 mL/min).

Patients with Hepatic Impairment

Following administration of a single-dose of selumetinib, dose normalized total AUC_0-INF decreased by 14% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 59% in subjects with moderate hepatic impairment (Child-Pugh B) and by 57% in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function. Selumetinib unbound AUC_0-INF decreased by 31% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 41% in subjects with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Strong or Moderate CYP3A4 Inhibitors: Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased selumetinib AUC by 49% and C_max by 19%. Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 41% and C_max by 23%.

Effect of Fluconazole: Concomitant use of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor) increased selumetinib AUC by 53% and C_max by 26%.

Effect of Strong or Moderate CYP3A4 Inducers: Concomitant use of rifampicin (strong CYP3A4 inducer) decreased selumetinib AUC by 51% and C_max by 26%. Concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by 38% and C_max by 22%.

In Vitro Studies

CYP Enzymes: Selumetinib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1. Selumetinib does not induce CYP3A4, CYP1A2, or CYP2B6.

Transporter Systems: Selumetinib does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters.

Selumetinib is a substrate of BCRP and P-gp transporters.

Carcinogenicity

Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice at exposures 24 times (males) and 36 times (females) and in 2-year carcinogenicity study in rats at exposures 20 times (male) and 15 times the human exposure (AUC) at the clinical dose of 25 mg/m².

Mutagenicity

Selumetinib was not mutagenic or clastogenic in vitro. Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses >160 mg/kg (~38 times the human C_max at the clinical dose of 25 mg/m²).

Impairment of Fertility

In a 6-month mouse study, selumetinib did not affect male mating performance at any dose up to 20 mg/kg twice daily (approximately 33 times the human exposure based on AUC at the clinical dose of 25 mg/m² twice daily). In female mice exposed to selumetinib at 12.5 mg/kg twice daily, mating performance and fertility were not affected. The NOAEL for both maternal toxicity and effects on reproductive performance was 2.5 mg/kg twice daily (approximately 5 times the human exposure based on AUC at the clinical dose of 25 mg/m² twice daily).

In a 26-week repeat-dose toxicology study, selumetinib at a dose of 20 mg/kg (approximately 33 times the human exposure based on AUC at the clinical dose of 25 mg/m² twice daily) led to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.

14.1 Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)

The efficacy of KOSELUGO was evaluated in SPRINT Phase II Stratum 1, an open-label, multicenter, single arm trial (NCT01362803). Eligible patients were required to have NF1 with inoperable PN, defined as a PN that could not be completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients were also required to have significant morbidity related to the target PN. Morbidities that were present in ≥20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Patients received KOSELUGO 25 mg/m² orally twice daily until disease progression or unacceptable toxicity.

The major efficacy outcome measure was overall response rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥20% reduction in PN volume confirmed at a subsequent tumor assessment within 3-6 months). The target PN, defined as the PN that caused relevant clinical symptoms or complications (PN-related morbidities), was evaluated for response rate using centrally read volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Tumor response was evaluated at baseline and while on treatment after every 4 cycles for 2 years, and then every 6 cycles. An additional efficacy outcome measure was duration of response (DoR).

A total of 50 pediatric patients received KOSELUGO. The median age was 10.2 years (range 3.5 to 17.4 years); 60% were male; and 84% were White, 8% were Black and 2% were Asian.

Efficacy results are provided in Table 8. The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years).

Table 8. Efficacy Results from SPRINT Phase II Stratum 1:

CI – confidence interval, DoR – duration of response.
^* The ORR assessment was conducted by a single National Cancer Institute reviewer who was a SPRINT investigator and who evaluated all PN imaging from patients enrolled at all trial sites.
^† Responses required confirmation at least 3 months after the criteria for first response were met.
^‡ Complete response: disappearance of the target lesion; Partial response: decrease in target PN volume by ≥20% compared to baseline

An independent centralized review of tumor response per REiNS criteria resulted in an ORR of 44% (95% CI: 30, 59).