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

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.

Figure 1

Schematic design of the trial including the treatment period (Part A) and the follow‐up period (Part B)

Figure 2

Structural formula of [¹⁴C]pimasertib. The asterisk indicates the position of the [¹⁴C]atom

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 t_max of the oral 60 mg pimasertib dose on Day 1. The error bars represent the standard deviation for n = 6 patients

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