Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2016 Dec;82(6):1498-1508.
doi: 10.1111/bcp.13078. Epub 2016 Sep 19.

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

Oliver von Richter  1 , Giorgio Massimini  2 , Holger Scheible  3 , Istvan Udvaros  4 , Andreas Johne  1
Affiliations
Clinical Trial

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

Oliver von Richter et al. Br J Clin Pharmacol. 2016 Dec.

Abstract

Aim: 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.

Methods: 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 [14 C]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 [14 C]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.

Results: Following i.v. administration, [14 C]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 [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.

Conclusion: Pimasertib showed a favourable pharmacokinetic profile with high absolute bioavailability and a unique metabolic pathway (conjugation with phosphoethanolamine).

Trial registration: ClinicalTrials.gov NCT01713036.

Keywords: 14C; absolute bioavailability; elimination route; mass balance; pimasertib.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Schematic design of the trial including the treatment period (Part A) and the follow‐up period (Part B)
Figure 2
Figure 2
Structural formula of [14C]pimasertib. The asterisk indicates the position of the [14C]atom
Figure 3
Figure 3
Dose normalized (60 mg) linear and semi‐log (insert) mean plasma concentration time profiles of pimasertib (filled dots) following oral administration of pimasertib and of [14C]pimasertib (open triangles) following i.v. administration of a 2 μg tracer dose of [14C]pimasertib during tmax of the oral 60 mg pimasertib dose on Day 1. The error bars represent the standard deviation for n = 6 patients
Figure 4
Figure 4
(A) Linear and semi‐log (insert) mean plasma concentration time profiles of pimasertib (filled dots) following oral administration of 60 mg pimasertib on Day 1 (concentrations provided in ng ml−1) and of 2.6 mBq [14C]pimasertib (open triangles) following oral administration of 2.6 mBq [14C]pimasertib on Day 8 (concentrations provided as ng eq ml−1). The error bars represent the standard deviation for n = 6 patients. (B) Cumulative recovery of total [14C]radioactivity following oral administration of 2.6 mBq [14C]pimasertib on Day 8 expressed as a percentage of the administered [14C]dose in excreta (urine + faeces, filled black dots), urine (open squares), and faeces (open diamonds). The error bars represent the standard deviation for n = 6 patients
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SP, et al. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res 2016; 44: D1054–D1068. - PMC - PubMed
    1. Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, et al. The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 2015; 172: 6024–6109. - PMC - PubMed
    1. Kim K, Kong S‐Y, Fulciniti M, Li X, Song W, Nahar S, et al. Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti‐myeloma activity in vitro and in vivo . Br J Haematol 2010; 149: 537–549. - PMC - PubMed
    1. World Intellectual Property Organization . WO2006045514. 3‐arylamino pyridine derivatives. 2006. Available at https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006045514&red... (last accessed 12 August 2015).
    1. World Intellectual Property Organization . WO2013178320. Solid state forms of n‐((s)‐2,3‐dihydroxy‐propyl)‐3‐(2‐fluoro‐4‐iodo‐phenylamino)‐isonicotinamide. 2013. Available at https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013178320&red... (last accessed 12 August 2015).

Publication types

MeSH terms

Associated data