Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors

Abstract

SummaryBackground: Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple dose pharmacokinetics of entrectinib in patients and two studies in healthy volunteers investigating the absorption/distribution/metabolism/excretion (ADME) of entrectinib, its relative bioavailability, and effect of food on pharmacokinetics. Methods: The patient study is open-label with dose-escalation and expansion phases. Volunteers received entrectinib (100–400 mg/m2, and 600–800 mg) once daily with food in continuous 28-day cycles. In the ADME study, volunteers received a single oral dose of [14C]entrectinib 600 mg. In the third study, volunteers received single doses of entrectinib 600 mg as the research and marketed formulations in the fasted state (Part 1), and the marketed formulation in the fed and fasted states (Part 2). Entrectinib and its major active metabolite M5 were assessed in all studies. Results: Entrectinib was absorbed in a dose-dependent manner with maximum concentrations at ~4 h postdose and an elimination half-life of ~20 h. Entrectinib was cleared mainly through metabolism and both entrectinib and metabolites were eliminated mainly in feces (minimal renal excretion). At steady-state, the M5-to-entrectinib AUC ratio was 0.5 (with 600 mg entrectinib research formulation in patients). The research and marketed formulations were bioequivalent and food had no relevant effect on pharmacokinetics. Conclusions: Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food.

EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model

“…( B ) Graphs depicting cell viability of OV-054 DSRCT (blue) and the two Ewing sarcoma models (gray), upon a 5-day incubation with different drug concentrations (µM). Known plasma concentrations are shown with the vertical dashed line [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC

“…The pharmacokinetics of entrectinib in adult patients with solid tumours, like those of its major active metabolite, M5, are linear [20,33] and not dose-or time-dependent [20]. Peak plasma concentrations of entrectinib and M5 were seen ≈ 4-6 h following single and multiple doses of oral entrectinib in the fed state; steady-state concentrations of entrectinib and M5 were reached within 2 weeks [34]. The estimated steady-state accumulation ratios for entrectinib and M5 were 1.89 and 2.01, respectively [20,33].…”

“…Entrectinib is metabolized primarily by cytochrome P450 (CYP) 3A4 (≈ 76%) to M5; it is also conjugated by uridine 5′-diphospho-glucuronosyltransferase 1A4 to its N-glucuronide conjugate (M-11) [20]. Entrectinib is predominantly eliminated through hepatic metabolism; renal clearance has a minor role [83% of a radiolabelled oral dose was excreted in faeces (36% as unchanged entrectinib; 22% as M5); 3% was excreted in urine] [20,34]. The estimated apparent clearances of entrectinib and M5 are 19.6 and 52.4 L/h, respectively; the estimated elimination half-lives are 20 and 40 h, respectively [20].…”

In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK)

“…Other, more minor pathways of metabolism included direct glucuronidation (M11) as well as N-oxidation and benzyl hydroxylation by CYP enzymes. Together these additional routes accounted for < 25% metabolism in vitro and none of the products were major circulating metabolites except M11 [7]. As M11 is a glucuronide conjugate which is not expected to show pharmacological activity, further in vivo examination Table 4 Summary of midazolam and 1'-hydroxymidazolam plasma pharmacokinetic parameters with and without coadministration of single and multiple dose entrectinib (600 mg/day) following a single 7.5 mg midazolam dose AUC inf area under the plasma concentration-time curve extrapolated to infinity, C max maximum plasma concentration, ND not done, t 1/2 terminal elimination half-life, T max time of maximum plasma concentration a Unadjusted geometric means (geometric coefficients of variation) for all except T max which is median (minimum, maximum) b Maximum value was due to one outlying subject Unadjusted' refers to raw data, and 'adjusted' refers to data that have been subjected to statistical analysis.…”

“…In a mass balance study, entrectinib has been shown to be mainly eliminated through hepatic clearance, with negligible renal clearance (< 1% of the dose is excreted unchanged in urine) [ 7 ]. There are two major circulating metabolites of entrectinib in humans, M5 and M11, contributing 12% and 19%, respectively, of total circulating radioactivity.…”