Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients

Abstract

Keywords14 C, absolute bioavailability, elimination route, mass balance, pimasertib AIMThis 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. METHODSSix 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.) RESULTS Following i.v. administration, [14 C]pimasertib exhibited a geometric mean total body clearance of 45.7 l h À1 (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 [ 14 C] 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 [ 14 C] 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. CONCLUSIONPimasertib showed a favourable pharmacokinetic profile with high absolute bioavailability and a unique metabolic pathway (conjugation with phosphoethanolamine). British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pimasertib is a new selective, oral inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1/2).• Comprehensive information about the pharmacokinetics, including absolute bioavailability, metabolism and elimination routes, of cancer drugs is often incomplete. WHAT THIS STUDY ADDS• Description of a trial design combining investigation of absolute bioavailability and mass balance/metabolite identification in a single group of six male cancer patients.• Identification of a new metabolic pathway for drugs, i.e. conjugation with phosphoethanolamine.• Information about key pharmacokinetic parameters and the drug disposition of pimasertib in cancer patients. Tables of Links

Metabolism of the MEK1/2 Inhibitor Pimasertib Involves a Novel Conjugation with Phosphoethanolamine in Patients with Solid Tumors

“…elimination pathways and metabolites of drugs in vivo, are basic trials to characterize the pharmacokinetics (PK) of drugs and, therefore, are also recommended by such guidelines as the US Food and Drug Administration Guidance for Industry, Safety Testing of Drug Metabolites (Center for Drug Evaluation and Research, 2008), the International Conference on Harmonisation (ICH), Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (International Conference on Harmonisation, 2009), and the European Medicines Agency's Guideline on the Investigation of Drug Interactions (European Medicines Agency, 2012). Final mass balance and total radioactivity data as well as early clinical findings have been reported previously from the human mass balance phase I study (NCT 01713036) that investigated the metabolic profile, mass balance, and oral bioavailability of pimasertib in patients with locally advanced or metastatic solid tumors (von Richter et al, 2016). In the current report, we describe in more detail the biotransformation of pimasertib following a single oral dose in the phase I study, and identify the metabolic profile of pimasertib in patients with advanced cancers.…”

“…An open-label, single-center trial conducted in six male patients [age 18-65 years; Eastern Cooperative Oncology Group (ECOG) performance status #1] with locally advanced or metastatic solid tumors [defined by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1] was performed. Full details of the patients, study design, dosing, and execution of the clinical part of this phase I study have previously been reported (von Richter et al, 2016). This report provides details of the identification of [ 14 C]-pimasertib metabolites in biologic samples taken from these patients.…”

“…All pharmacokinetic (PK) analyses, including the areas under the curves for total radioactivity, pimasertib, and metabolite (AUC TR , AUC test , and AUC metabolite ) have been described previously (von Richter et al, 2016). In the current study, the percentage of metabolite in plasma was calculated from: (metabolite peak/total peak area) Â 100.…”

Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers

“…The use of a tracer IV dose reduces formulation work and, in line with ICH M3(R2) [31], may also not require generation of additional preclinical IV data to cover administration in humans. To optimize the approach, both investigations can even be performed in the same group of participants [32]. However, this approach was not applied in this study, due to practical considerations related to uncertainties regarding the duration of the excreta collection periods in part A of the study, which turned out to be shorter than initially expected.…”

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

“…This compound stabilizes p53 and activates its pathway, resulting in the interruption of the cell proliferation, cell cycle arrest and apoptosis, and is currently in phase I clinical trials for cancer treatment [122][123][124][125]. Another clinical trial was initiated with cancer patients involving safety and efficacy of MI-77301 [126] and Pimasertib (AS-703026), which is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2 [127].…”