Population pharmacokinetics and pharmacodynamics of GSK525762 in patients with solid tumors
Anu Shilpa Krishnatry (1), Sara Harward (2), Thierry Horner (3), Arindam Dhar (3), Christine L. Hann (4), Peter O. Dwyer (5), Geoffrey I. Shapiro (6), Sarina A. Piha-Paul (7) and Geraldine M. Ferron-Brady (1)
(1) Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (2) Infectious Diseases Therapy Area Unit, GlaxoSmithKline, Research Triangle Park, North Carolina (3) Oncology, GlaxoSmithKline, Collegeville, Pennsylvania (4) John Hopkins University School of Medicine, MD, USA (5) Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA, USA (6) Dana Farber Cancer Institute, Boston, MA, USA (7) University of Texas MD Anderson Cancer Center, TX, USA
Objectives: To develop a population PK/PD model describing the PK and platelet time profile following oral dosing of a potent pan-BET inhibitor, GSK525762, in patients with solid tumors, including NUT midline carcinoma (NMC) and to use the model to predict platelet changes for other conditions.
Methods: PK and platelet data from oncology patients (N=86) receiving daily administration of GSK525762 at doses of 2 to 100 mg from a first time in patient study were included in the analysis. The data also included PK from 10 subjects who participated in a single dose cross over pilot bioavailability study followed by repeated administration. Plasma concentrations were fitted to a PK model using non-linear mixed-effects modelling implemented in NONMEM V7.2 [1]. Different models to describe the autoinduction of clearance (CL) were tested. Patient demographics, hepatic/renal function labs and cancer related covariates were tested on the PK parameters. Platelet data was modeled using a semi-mechanistic PKPD model [2].
Results: A two compartment model with first-order absorption (ka) with lag; between-subject variability on CL, central (Vc) and peripheral (Vp) volume of distribution, and Ka; inter-occasion variability on Ka and CL and proportional residual error model adequately described GSK525762 pharmacokinetics. The autoinduction effect on CL was described by an empirical model including induced / pre-induced CL, induction lag time and turnover rate of the induced enzyme (Kout) [3]. A more mechanistic enzyme model was not supported by the data. The PK parameters were Ka= 3.0 h-1, lag= 0.15 h, Vc= 61.3 L, CL = 12.9 L/h, Vp = 19.0 L , Kout= 0.125 day-1 and Q= 1.51 L/h. Body weight was the only covariate identified and impacted Vc. GSK525762 effect on the platelet was best described with an Emax model and covariates could not be identified.
Conclusion: The PK and PD model adequately described the time-course of concentration and platelet count, including following dose adjustment, and was used to simulate alternate or reduced dosing schedules. GSK funded study.
References: [1] Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Maryland, USA. [2] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO (2002) Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20:4713–4721. [3] Pharmacokinetics, 2nd Ed. Gibaldi M and Perrier D. Marcel Dekker, New York, 1982.