Rubin Lubomirov, Carlos Fernández-Teruel, Ignacio González GarcÃa, Salvador Fudio
PharmaMar S.A., Colmenar Viejo (Madrid), Spain
Objectives: To develop a population pharmacokinetic-based targeted exome sequencing (PopPK-TES) strategy aiming to assess the impact of genetic variants on pharmacokinetics of lurbinectedin in patients with advanced cancer.
Methods: Lurbinectedin, a new RNA polymerase II inhibitor, is currently being tested in a Phase III study in patients with small cell lung cancer (SCLC), and Phase I/II studies of other solid tumors. The plasma concentrations of lurbinectedin from advanced cancer patients participating in 12 phase I and II clinical trials were pooled and fitted to a population pharmacokinetic (PopPK) model using non-liner mixed-effects modelling implemented in NONMEM v7.3 [1]. On the basis of PopPK analysis, restricted to the subset of patients who gave written informed consent for genetic testing, lurbinectedin interpatient variability on clearance (etaCL) was used as a phenotype, considering that this parameter would best reflect the remaining unexplained variance in lurbinectedin elimination that could be accounted for by genetic variations. Histogram plots and the “probit” distribution of etaCL values were used to identify the subpopulations of low and high CL outliers (i.e. patients with high and low lurbinectedin plasma exposure, respectively) as cases and controls, respectively. The germinal DNA (gDNA) was extracted from peripheral blood mononuclear cells. Targeted exome sequencing of 42 genes involved in lurbinectedin metabolism and transport was performed in an Ion PGM™ System for Next-Generation Sequencing (NGS) using an Ion 318™ chip v2 for every ten samples. The analysis of the identified variants in PGM v5.0.2 was done with Ion Reporter v5.2 software and Annotate Variants Single v5.2 workflow, specific for GRCh38_human_5.0. The associations in the case and control population were assessed by comparing allelic frequencies between cases and controls using PLINK 2.0 [2].
Results: A three-compartment mammillary model with linear distribution and elimination from central compartment was suitable to describe the time course of plasma concentrations of lurbinectedin after i.v. administration to advanced cancer patients. The model estimated a volume of distribution at steady state of 434 L that caused the distribution to deep tissues and a low central volume of 16.7 L while CL was 11.1 L/h. The model detected several covariates that affected CL: serum albumin, serum alpha1-acid-glycoprotein (AAG), body surface area (BSA), the presence of strong or moderate CYP3A4 inhibitors, and cardiac function measured by left-ventricular ejection fraction (LVEF). Histogram plots and the “probit” distribution of etaCL values of the subset of 180 patients signed written informed consent for genetic testing, allow the identification of subpopulations of low (n=10) and high (n=10) CL outliers. gDNA of these 20 patients was used to perform NGS of promoters (including 1 Kbs up-stream), all exons and 3’-UTR of 42 genes. The detected genetic variants were analyzed comparing their allelic frequencies between cases and controls. Genetic variants located in relevant genes were identified.
Conclusions: The applied PopPK-TES approach may allow discover genetic variants associated with the variability in pharmacokinetics of lurbinectedin in patients with advanced cancer. These results need further confirmation in an independent population of advanced cancer patients treated with lurbinectedin.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2017. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M A, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81:559–575.
Reference: PAGE 27 (2018) Abstr 8489 [www.page-meeting.org/?abstract=8489]
Poster: Drug/Disease Modelling - Oncology