Chemical formula: C₁₇H₁₁F₆N₇O Molecular mass: 443.313 g/mol PubChem compound: 71481097
Selinexor is a reversible covalent selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1). XPO1 is the major mediator of the nuclear export of many cargo proteins including tumour suppressor proteins (TSPs), growth regulators and mRNAs of growth promoting (oncogenic) proteins. XPO1 inhibition by selinexor leads to marked accumulation of TSPs in the nucleus, cell cycle arrest, reductions in several oncoproteins such as c-Myc and cyclin D1, and apoptosis of cancer cells. The combination of selinexor and dexamethasone and/or bortezomib demonstrated synergistic cytotoxic effects in multiple myeloma in vitro and increased anti‐tumour activity in murine xenograft multiple myeloma models in vivo, including those resistant to proteasome inhibitors.
The effect of multiple doses of selinexor up to 175 mg twice weekly on the QTc interval was evaluated in patients with heavily pre-treated haematologic malignancies. Selinexor had no large effect (i.e. no greater than 20 ms) on QTc interval at the therapeutic dose level.
Following oral administration of selinexor peak plasma concentration, Cmax is reached within 4 hours. Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not have a clinically significant effect on the pharmacokinetics of selinexor.
Selinexor is 95.0% bound to human plasma proteins. In a population pharmacokinetic (PK) analysis, the apparent volume of distribution (Vd/F) of selinexor was 133 L in cancer patients.
Selinexor is metabolised by CYP3A4, multiple UDP-glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs).
Following a single dose of 80 mg selinexor the mean half-life (t1/2) is 6 to 8 hours. In a population PK analysis, the apparent total clearance (CL/F) of selinexor was 18.6 L/h in cancer patients.
Age (18 to 94 years of age), sex, or race had no clinically significant effect on the pharmacokinetics of selinexor.
In the population PK dataset, age and race were not identified as a significant covariate, gender was identified as a significant covariate.
The degree of renal impairment was determined by creatinine clearance as estimated by the Cockcroft- Gault equation. Results from population PK analyses of patients with normal (n=283, CLcr: ≥90 mL/min), mild (n=309, CLcr: 60 to 89 mL/min), moderate (n=185, CLcr: 30 to 59 mL/min) or severe (n=13, CLcr: 15 to 29 mL/min) renal dysfunction indicated that creatinine clearance had no impact on the PK of selinexor. Therefore, mild, moderate, or severe renal impairment is not expected to alter selinexor PK, and no adjustments in the dose of selinexor are required in patients with renal dysfunction.
Population PK analysis indicated that mild hepatic impairment (bilirubin >1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN, n=119) had no clinically significant effect on the PK of selinexor. In a clinical study using NCI-ODWG criteria to classify the degree of hepatic impairment, no clinically relevant change in selinexor pharmacokinetics was seen in patients with moderate hepatic impairment (TB >1.5 to 3 x ULN and any AST, n=7).
In patients with severe hepatic impairment (TB >3 x ULN and any AST, n=6) up to a 32% higher dose normalized exposure was seen in comparison to patients with normal hepatic function. Hepatic impairment did not result in any clinically relevant changes in plasma protein binding of selinexor.
Findings in the repeat dose 13-week rat study were decrements in body weight gain and food consumption, and haematopoietic/lymphoid hypoplasia, and male/female reproductive organ effects. In the 13-week monkey study, the treatment-related effects observed included body weight loss, gastrointestinal effects, and lymphoid/haematologic depletion. Gastrointestinal toxicities, including anorexia, decrements in body weight gain and reduced food consumption were noted to be CNS-mediated. No safety margin for these toxicities could be established.
Selinexor was not mutagenic in a bacterial reverse mutation assay. Selinexor was not clastogenic in either the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.
Carcinogenicity studies have not been conducted with selinexor.
Fertility studies in animals have not been conducted with selinexor. In repeat-dose oral toxicity studies, selinexor was administered for up to 13 weeks in rats and monkeys. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed in rats, decreased ovarian follicles were also observed in rats, and single cell necrosis of testes was observed in monkeys. These findings were observed at systemic exposures approximately 0.11, 0.28, and 0.53 times, respectively, the exposure (AUClast) in humans at the recommended human dose of 80 mg. Developmental effects were seen with daily exposure in pregnant rats at systemic exposures below the exposure (AUClast) in humans at the recommended human dose of 80 mg.
A guinea pig sensitisation assay showed that selinexor at 25% induced a mild Grade II dermal contact hypersensitivity response at 24 and 48 hours.
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