Selumetinib Pharmacokinetics
1. Absorption
Mean absolute bioavailability in adults: 62%.
Median time to peak concentration at steady state in pediatric patients: 1-1.5 hours.
Food effect: Population pharmacokinetic analysis in children and adolescents with NF1 and inoperable plexiform neurofibromas, adult cancer patients, and healthy adults indicated that low-fat or high-fat meals have no clinically relevant effect on selumetinib exposure.
2. Distribution
It is unknown whether selumetinib distributes into human milk.
Plasma protein binding: approximately 98.4% (96% bound to albumin,<35% bound="" to="" alpha-1-acid="" glycoprotein="">
3. Elimination
Metabolism: Primarily metabolized by CYP3A4, with minor contributions from CYP2C19, 1A2, 2C9, 2E1, and 3A5. Glucuronidation via UGT1A1 and UGT1A3. Metabolism to the active metabolite N-desmethyl selumetinib is mediated by CYP2C19 and CYP1A2, with contributions from CYP2C9 and CYP2A6. N-desmethyl selumetinib is metabolized via the same pathways as selumetinib.
Elimination routes: urine 33% (<1% as="" unchanged="" drug="">
Half-life: mean elimination half-life in pediatric patients is approximately 6.2 hours.
4. Pharmacokinetics in Special Populations
Mild hepatic impairment (Child-Pugh A): total and unbound systemic exposures of selumetinib decreased by 14% and 31%, respectively.
Moderate hepatic impairment (Child-Pugh B): total and unbound systemic exposures increased by 59% and 41%, respectively.
Severe hepatic impairment (Child-Pugh C): total and unbound systemic exposures increased by 57% and 3.2-fold, respectively.
Compared with individuals with normal renal function (Clcr ≥90 mL/min), systemic exposure in patients with end-stage renal disease (Clcr<15 ml="">
Race (White, Asian, Black) has no clinically significant effect on the pharmacokinetics of selumetinib or N‑desmethyl selumetinib.
Selumetinib Storage
Oral capsules: Store at 20–25°C (excursions permitted between 15–30ºC). Keep in the original bottle, keep the bottle tightly closed, and protect from moisture.
Selumetinib Mechanism of Action
Inhibitor of mitogen-activated extracellular signal-regulated kinases MEK1 and MEK2.
In genetically engineered mouse models of NF1‑related neurofibromas that mimic human NF1 genotype and phenotype, oral administration of selumetinib inhibits ERK phosphorylation and reduces the number, volume, and proliferation of neurofibromas.
