III-068 Yuan Pétermann

Population pharmacokinetic model of encorafenib and binimetinb in real life settings

Yuan J. Pétermann1* – Abbas Khani1,2* – Alicja Puszkiel3,4 – Benoit Blanchet3,5 – Chantal Csajka1,6,7 - Monia Guidi1,7,8

1 Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland 2 Neurotechnology Group, Institute of Neuroinformatics, ETH Zurich, Zurich, Switzerland 3 Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, Paris, France. 4 UMR-S1144, INSERM, Faculty of Pharmacy, Université Paris Cité 5 UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, University Paris, PRES Sorbonne Paris Cité, Paris, France. 6 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland 7 Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva & Lausanne, Switzerland 8 Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

Objectives: The RAS/RAF/MEK/ERK signaling pathway plays a pivotal role in the pathogenesis of numerous cancers, leading to the development of drugs targeting this pathway and the need to determine therapeutic targets. Binimetinib and encorafenib are MEK and BRAF inhibitors, respectively, that gained Food and Drug Administration (FDA) approval in 2018 for the treatment BRAFV600E or BRAFV600K mutated metastatic or unresectable melanoma (1). Despite their recent approval, limited information exists regarding their pharmacokinetic profile in the target population, which might differ from clinical trial settings with more restrictive inclusion criteria (2). In this study, an exploratory population pharmacokinetic (popPK) analysis was performed on plasma concentrations of encorafenib and binimetinib to characterize their pharmacokinetics and variability in real life conditions and to identify potential covariates susceptible to alter their pharmacokinetics (TKI). In completion to future pharmacokinetic-pharmacodynamic (PK/PD) characterization, these analyses will help assessing the relevance of those drugs for therapeutic drug monitoring based on real-world data with potential clinical implications therein, as 

Methods: 

Patients receiving encorafenib and binimetinib and undergoing routine therapeutic drug monitoring at Cochin Hospital (Paris, France) were enrolled in this analysis. A classical stepwise analysis comparing various compartmental models with linear absorption and elimination was conducted independently for the two drugs in NONMEM (version 7.5.1). An inter-individual variability on pharmacokinetic parameters was tested sequentially assuming a log-normal distribution. The lack of plasma samples in the absorption phase of encorafenib prevented the estimation of the absorption constant rate (ka), which was fixed to 2.15 h-1 so to obtain a time to peak concentration (Tmax) of 2h as reported in (4). Error models were tested to capture the residual unexplained variability (RUV).

Biological plausible covariates, including hepatic function as classified by the National Cancer Institute Organ Dysfunction Working Group (5), sex, body weight, body mass index, fat-free mass, and age[GM1] , were evaluated for their potential impact on encorafenib and binimetinib pharmacokinetics.

Results: 

The popPK analyses were performed on a total of 154 binimetinib and 175 encorafenib plasma concentrations sampled from 26 and 27 patients, respectively. Median (range) administered dose was 45 (30 – 45) mg given twice daily for binimetinib, and 450 (300 – 450) mg once daily for encorafenib.

The pharmacokinetics of binimetinib was best described by a one-compartment model with linear absorption and elimination. The base model estimated a ka of 1.61 h-1, a clearance (CL) of 23.4 L/h, and a volume of distribution of the central compartment (V) of 127 L, similar to the FDA monography (1,4),. Inter-individual variability (CV %) was observed on both the volume of distribution (60%) and the clearance (34%). A proportional error model of 43% was chosen for RUV.

The same structural model best described encorafenib pharmacokinetics, including an interindividual variability on the bioavailability (F) fixed to 1, most probably related to a potential food effect on F[AP1] . Base model parameter estimates were a CL of 27 L/h and a V of 112 L, similar to the FDA monography (1,4), with a 30% interindividual variability in bioavailability on F. An important RUV, described by a proportional (CV% 50.2%) and additional (10.7 ng/mL) error model, best described encorafenib[AP2] [PY3]  data.

None of the tested covariates demonstrated a significant improvement in the binimetinib and encorafenib data description.

Conclusions: 

While PK parameters were found to be similar to those reported in the literature, this exploratory study, conducted on a small set of patients with sparse sampling, revealed substantial inter- and intra-individual differences in the pharmacokinetics of both binimetinib and encorafenib. These findings underscores the necessity for further investigations to understand their potential suitability as candidates for therapeutic drug monitoring.

References:

  1. Shirley M. Encorafenib and Binimetinib: First Global Approvals. Drugs [Internet]. 2018 Aug;78(12):1277–84. Available from: http://dx.doi.org/10.1007/s40265-018-0963-x
  2. Liu R, Rizzo S, Whipple S, Pal N, Pineda AL, Lu M, et al. Evaluating eligibility criteria of oncology trials using real-world data and AI. Nature [Internet]. 2021 Apr;592(7855):629–33. Available from: http://dx.doi.org/10.1038/s41586-021-03430-5
  3. van der Kleij MBA, Guchelaar NAD, Mathijssen RHJ, Versluis J, Huitema ADR, Koolen SLW, et al. Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology. Clin Pharmacokinet [Internet]. 2023 Oct;62(10):1333–64. Available from: http://dx.doi.org/10.1007/s40262-023-01293-9
  4. Center for Drug Evaluation, Research. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Internet]. U.S. Food and Drug Administration. FDA; 2018 [cited 2024 Mar 4]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-and-binimetinib-combination-unresectable-or-metastatic-melanoma-braf
  5. Elmeliegy M, Yang DZ, Salama E, Parivar K, Wang DD. Discordance Between Child-Pugh and National Cancer Institute Classifications for Hepatic Dysfunction: Implications on Dosing Recommendations for Oncology Compounds. J Clin Pharmacol [Internet]. 2021 Jan;61(1):105–15. Available from: http://dx.doi.org/10.1002/jcph.1702
  6. Zhang Y, Vagiannis D, Budagaga Y, Sabet Z, Hanke I, Rozkoš T, et al. Encorafenib Acts as a Dual-Activity Chemosensitizer through Its Inhibitory Effect on ABCC1 Transporter In Vitro and Ex Vivo. Pharmaceutics [Internet]. 2022 Nov 24;14(12). Available from: http://dx.doi.org/10.3390/pharmaceutics14122595

Reference: PAGE 32 (2024) Abstr 11018 [www.page-meeting.org/?abstract=11018]

Poster: Drug/Disease Modelling - Oncology