Mirdametinib

Mirdametinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, mirdametinib inhibited kinase activity of MEK1 and MEK2 and downstream phosphorylation of ERK.

In a mouse model of NF1, oral dosing of mirdametinib inhibited ERK phosphorylation and reduced neurofibroma tumor volume and proliferation.

Mirdametinib exposure-response relationships and the time course of pharmacodynamic response are not fully characterized.

Cardiac electrophysiology

At approximately six times the steady-state exposure associated with the recommended dose of 2 mg/m², clinically significant QTc interval prolongation was not observed.

Mirdametinib pharmacokinetic parameters are summarized in the following table.

Pharmacokinetic parameters and characteristics of mirdametinib:

Abbreviations: AUC: area under the plasma concentration-time curve; AUC_inf: AUC from dosing extrapolated to infinity; CI: confidence interval; CES: carboxyl esterase enzyme; C_max: maximum plasma concentration; CV: coefficient of variation; GMR: geometric least squares mean ratio; UGT: uridine diphosphate (UDP)-glycosyltransferase

Specific populations

Effects of age, sex, and race

No clinically significant differences in mirdametinib pharmacokinetics were observed based on age (2 to 86 years), sex, and race (11% African American or Black, 12% Asian, 72% White).

The effects of moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease (ESRD) on mirdametinib pharmacokinetics are unknown.

Drug interaction studies

No clinical DDI studies have been conducted. The effect of concomitant strong CYP3A4 inducers (that also co-induce UGTs, P-gp, and CES enzymes) on mirdametinib PK is currently unknown.

In vitro studies

CYP enzymes: Mirdametinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Mirdametinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4.

Transporter systems: Mirdametinib does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters.

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

Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day (approximately 15 times the human exposure at the clinical dose of 2 mg/m² twice daily based on AUC).

Mirdametinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats.

In a dedicated fertility study, male rats were treated with mirdametinib for 28 days before mating with untreated females to Gestational Day 1. Female rats were treated with mirdametinib for 14 days before mating with untreated males to Gestational Day 7. No effects on mating performance or fertility in males or females were observed at doses up to 1 mg/kg/day (approximately 2 times the human clinical dose of 2 mg/m² twice daily based on BSA). In a 3-month repeat-dose toxicology study in rats, mirdametinib caused decreased ovarian organ weight and increased follicular cysts associated with decreases in the number of corpora lutea at doses ≥0.3 mg/kg/day (approximately 2 times the human exposure at the clinical dose of 2 mg/m² twice daily based on AUC). Findings in male rats included hypoplasia of the spermatogenic epithelium in the testis, decreased content in the epididymis, and inflammation of the prostate at 1 mg/kg (approximately 8-times the human exposure at the clinical dose of 2 mg/m² based on AUC). The reversibility of effects on ovary and male reproductive organs was not assessed.