title: Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors.
abstract: Trametinib (Mekinist®) is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) approved in the United States as a single agent and in combination with dabrafenib (Tafinlar®) for treatment of patients with unresectable or metastatic melanoma with a positive BRAF V600E/V600K mutation for which a pediatric oral solution formulation is being developed. This open-label, two-period, two-treatment, randomized, crossover study assessed the relative bioavailability of the trametinib pediatric oral solution compared to the tablet formulation after a single-dose administration to adult patients with solid tumors. Primary pharmacokinetic endpoints derived from standard non-compartmental methods were AUC0-inf , AUC0-t , and Cmax . As expected, Cmax was higher and Tmax earlier for the pediatric oral solution compared to the tablet formulation. Administration of the trametinib pediatric oral solution resulted in a 12%, 10%, 18%, and 71% higher AUC0-inf , AUC0-last , AUC0-24 , and Cmax , respectively, as compared to the tablet formulation. Safety results were aligned with the known safety profile of trametinib. No serious or non-serious adverse events resulted in study drug withdrawal. Palatability of the pediatric oral solution was evaluated and found to be acceptable to most adult patients, but may differ in the pediatric population.
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Allred
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: YanYan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Pinnacle Oncology Hematology, Scottsdale, AZ, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Bendell
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Orford
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004339:Drug Compounding; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D017060:Patient Satisfaction; D019999:Pharmaceutical Solutions; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets; D013649:Taste; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D019999:Pharmaceutical Solutions; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013607:Tablets; C560077:trametinib; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: MEK inhibitor; bioavailability; pediatric solution; pharmacokinetics; trametinib