title: Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients.
abstract: This trial (NCT: 01713036) investigated the absolute bioavailability, mass balance and metabolite profile of pimasertib in a new design combining these investigations in a single group of patients.
  
  
  
  Six male patients with pathologically confirmed, locally advanced or metastatic solid tumours were enrolled. Exclusion criteria included Eastern Cooperative Oncology Group performance status >1. In Part A of the trial, patients received a 60 mg oral dose of unlabelled pimasertib followed by an intravenous (i.v.) tracer dose of [14C]pimasertib 2 μg (equalling 9 kBq) as a bolus injection, one hour after the oral dose, on Day 1. On Day 8, all patients received 60 mg pimasertib capsules spiked with 2.6 MBq of [14C]pimasertib. Patients received 60 mg oral unlabelled pimasertib twice daily from Day 3 to Day 21 of Part A and in subsequent 21-day cycles in Part B.
  
  
  
  Following i.v. administration, [14C]pimasertib exhibited a geometric mean total body clearance of 45.7 l h-1(geometric coefficient of variation [geometric CV]: 47.2%) and a volume of distribution of 229 l (geometric CV: 42.0%). Absolute bioavailability was 73%. The majority of the oral [14C] dose (85.1%) was recovered in excreta. Total radioactivity was mainly excreted into urine (52.8%) and faeces (30.7%) with 78.9% of the [14C] dose recovered as metabolites. Two major circulating metabolites were identified in plasma: a carboxylic acid (M445) and a phosphoethanolamine conjugate (M554). The safety profile was in line with the published pimasertib trials.
  
  
  
  Pimasertib showed a favourable pharmacokinetic profile with high absolute bioavailability and a unique metabolic pathway (conjugation with phosphoethanolamine).
authors.affiliation: Merck KGaA, Clinical Pharmacology, 64293, Darmstadt, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: von Richter
authors.affiliation: Merck KGaA, Early Clinical Oncology, 64293, Darmstadt, Germany.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Massimini
authors.affiliation: Merck KGaA, DMPK, 85567, Grafing, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Scheible
authors.affiliation: PRA International, EDS Patient Pharmacology, 1076, Budapest, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Udvaros
authors.affiliation: Merck KGaA, Clinical Pharmacology, 64293, Darmstadt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Johne
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D001682:Biological Availability; D002250:Carbon Radioisotopes; D004983:Ethanolamines / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000652:urine
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D004983:Ethanolamines; C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D009536:Niacinamide; C005448:phosphorylethanolamine; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: 14C; absolute bioavailability; elimination route; mass balance; pimasertib