Application of a Novel ‘Make and Test in Parallel’ Strategy to Investigate the Effect of Formulation on the Pharmacokinetics of GDC-0810 in Healthy Subjects

Abstract

PurposeGDC-0810, administered orally, was used in Phase I and II clinical studies to treat estrogen receptor positive breast cancers. It contains N-methyl-D-glucamine (NMG) salt of GDC-0810 with 10% sodium lauryl sulfate (SLS) as a surfactant and 15% sodium bicarbonate (NaHCO3) as an alkalizing agent to aid dissolution. To improve the processability of the formulation and reduce potential mucosal irritation in future Phase III clinical studies, the salt form and the amount of excipient required further optimization. To achieve this, we employed a novel “Make and Test in Parallel” strategy that facilitated selecting formulation in a rapid timeframe.MethodsRapidFACT®, a streamlined, data-driven drug product optimization platform was used to bridge Phase I/II and Phase III formulations of GDC-0810. Five prototype formulations, varying in either the form of active pharmaceutical ingredient and/or the levels of the excipients SLS and NaHCO3 were assessed. Uniquely, the specific compositions of formulations manufactured and dosed were selected in real-time from emerging clinical data.ResultsThe study successfully identified a Phase III formulation with a reduced SLS content, which when administered following a low-fat meal, gave comparable pharmacokinetic exposure to the Phase I/II formulation administered under the same conditions.ConclusionsOur novel ‘Make and Test in Parallel’ approach enabled optimization of GDC-0810 formulation in a time- and cost-efficient fashion.

GDC-0810 Pharmacokinetics and Transporter-Mediated Drug Interaction Evaluation with an Endogenous Biomarker in the First-in-Human, Dose Escalation Study

“…Thus, new ER-targeting therapies are needed to delay disease progression and achieve optimal disease control for ER1 BC patients. GDC-0810 (Cheeti et al, 2018) was a new molecular entity (NME) developed to be an orally bioavailable, selective ER degrader that antagonizes estrogen-mediated ER signaling (Lai et al, 2015;Cheeti et al, 2018). In the first-in-human (FIH) phase 1a study, GDC-0810 was assessed in patients with ER1, human epidermal growth factor receptor 2-negative (HER2-) BC.…”

Immunotherapy and drug sensitivity predictive roles of a novel prognostic model in hepatocellular carcinoma

“…Brilanestrant, an orally bioavailable selective estrogen receptor degrader, has strong anti-tumor activity in human breast cancer both in vitro and in vivo 53,54 . Moreover, it has been evaluated in Phase II clinical studies in breast cancer 55 . However, rare studies reveal its anti-tumor www.nature.com/scientificreports/ activity in liver cancer.…”