Abstract 1289: Population pharmacokinetics (PK) of the MEK inhibitor GSK1120212 from the first-time-in-human study in patients with solid tumors or lymphoma
Authors: Donna S. Cox, Duane A. Boyle, Daniele Ouellet, Jeffrey R. Infante, Leslie A. Fecher, Michael J. Fossler
Journal: Cancer Research (2011)

Abstract Background: GSK1120212 is a reversible, highly selective allosteric inhibitor of MEK1/MEK2. MEK111054, a first-time-in human study (FTIH) is an open-label, multiple-dose, dose escalation trial designed to investigate the safety, PK and pharmacodynamics (PD) of GSK1120212 in patients with solid tumors or lymphoma. A population PK model of GSK1120212 was developed and validated from the dose-escalation part of the FTIH trial. Materials and Methods: GSK1120212 single (0.125-10 mg) and repeat (0.125-4 mg) dose plasma concentrations were obtained from MEK111054 that utilized both continuous and loading dose regimens with daily administration of GSK1120212. Plasma GSK1120212 concentrations were determined using a validated analytical method based on liquid-liquid extraction, followed by HPLC-MS/MS analysis. Population PK analysis was performed on 1373 plasma samples from 55 patients ranging in ages from 35 to 77 years. Population PK analysis was performed using a nonlinear mixed effects modeling method (NONMEM, v. 7.1.0). Concentrations were transformed into the log domain and the residual variability was described by an additive error model. The influence of covariates such as gender, age, weight and BMI on PK parameter estimates was assessed. The final model was validated using a visual predictive check (VPC) of the simulated (n=1000) and observed data. Results: Plasma concentration-time data for GSK1120212 were best described by a two-compartment model with first-order absorption and elimination. The final model also incorporated two sequential absorption rates (KA1 and KA2) with a change point (MTIME) estimated at 0.41 hours post-dose. Final model population mean (%CV) parameter estimates for clearance (CL/F), volume of the central compartment (V2/F), volume of the peripheral compartment (V3/F), and intercompartmental clearance (Q/F) were 6.76 L/hr (7%), 125 L (18%), 746 L (11%), and 114 L, respectively. Interindividual variability ranged from 43 to 88%, interoccassion variability ranged from 8-74%, and the residual variability was 13 ng/mL. Covariates did not influence the pharmacokinetics of GSK1120212. VPC supported the validity of the model and was a good predictor of observed single and repeat dose data in the current study. Conclusion: The population PK model of GSK1120212 in patients with solid tumors or lymphoma provided a description of PK and an understanding of its variability which aided dose selection decisions. Once daily dosing without a loading dose was selected for future studies in order to maintain concentrations above the preclinical antiproliferation IC90. The established population PK model will aid in the development of future population PK/PD assessments with both tumor response and adverse event data. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1289. doi:10.1158/1538-7445.AM2011-1289